literature review on immunization

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• Published: 22 August 2022

A systematic literature review to clarify the concept of vaccine hesitancy

• Daphne Bussink-Voorend   ORCID: orcid.org/0000-0002-9873-1404 1 ,
• Jeannine L. A. Hautvast 1 ,
• Lisa Vandeberg   ORCID: orcid.org/0000-0002-7229-2378 2 ,
• Olga Visser 1 &
• Marlies E. J. L. Hulscher   ORCID: orcid.org/0000-0002-2160-4810 3  

Nature Human Behaviour volume  6 ,  pages 1634–1648 ( 2022 ) Cite this article

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• Human behaviour
• Infectious diseases
• Preventive medicine

Vaccine hesitancy (VH) is considered a top-10 global health threat. The concept of VH has been described and applied inconsistently. This systematic review aims to clarify VH by analysing how it is operationalized. We searched PubMed, Embase and PsycINFO databases on 14 January 2022. We selected 422 studies containing operationalizations of VH for inclusion. One limitation is that studies of lower quality were not excluded. Our qualitative analysis reveals that VH is conceptualized as involving (1) cognitions or affect, (2) behaviour and (3) decision making. A wide variety of methods have been used to measure VH. Our findings indicate the varied and confusing use of the term VH, leading to an impracticable concept. We propose that VH should be defined as a state of indecisiveness regarding a vaccination decision.

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In 2019, vaccine hesitancy (VH) was named by the World Health Organization (WHO) as one of the top-10 threats to global health, following a five-fold global increase in measles, a disease that can be prevented by vaccination 1 , 2 . The largest increase was reported in the WHO regions covering Europe and the Americas 2 . The impact of these measles outbreaks is substantial, with rises in morbidity, mortality and costs 3 , 4 , 5 . The increasing incidence of measles and other vaccine-preventable diseases has been attributed to a failure to reach adequate immunization coverage rates 2 , 6 . In the European region, VH has been identified as the main barrier to vaccination coverage 7 , 8 . This is in contrast to other regions, such as sub-Saharan Africa, where immunization coverage rates are challenged by a combination of barriers, including access and availability 9 .

In the past decade, VH has become a key topic of research in various fields, following rises in vaccine-preventable diseases, the introduction of new vaccines, the spread of misinformation and lagging vaccination coverage 10 . Moreover, the COVID-19 pandemic has drawn further attention to the role of VH in limiting the uptake of vaccines and failure to achieve collective immunity 11 , 12 , 13 . This has led to the proliferation of scientific literature on VH in the public health, biomedical and social science research fields 10 .

In 2012, the WHO established a strategic advisory group of experts (SAGE) working group with the mandate of defining VH and suggesting how to monitor and address it. The working group proposed a broad definition, describing a VH continuum from acceptance to refusal of vaccines or as a delay in acceptance or refusal despite the availability of the vaccines. The working group described VH as “A complex behavioural phenomenon specific to vaccines, context, time, and place and influenced by factors of complacency, convenience, and confidence” 14 . This broad definition emphasizes variability by describing that VH may vary between types of vaccines and different contexts, may change over time or between different geographical locations and is influenced by various determinants.

The concept of VH has been described and applied in various ways. When definitions are broad and lack clarity, this can lead to the emergence of different concepts with overlapping domains, with various concepts being used interchangeably by some and recognized as distinct entities by others 15 . Additionally, lack of conceptual clarity can lead to inadequate operationalization and cause confusion among researchers 15 . This is problematic because when studies use similar terminology with a different meaning, their results are incomparable across subgroups, locations or contexts. A clear conceptualization is needed to develop meaningful measures allowing comparison of results 16 .

A lack of conceptual clarity is observed in the literature on VH, where VH is variously conceptualized as a psychological state and as different types of vaccination behaviour 17 , 18 . In addition, the terms ‘vaccine confidence’, ‘low uptake’ and ‘low intention to vaccinate’ are often equated with VH 19 , 20 . Confusion among researchers is then illustrated by inconsistencies in the applied definitions 21 , 22 . It has even been argued that VH is a catch-all category, aggregating many different concepts rather than being one measurable construct; and this is impeding progress in the research field 23 .

A good concept definition consists of characteristics, attributes or features that are unique to that concept and distinguish it from other closely related concepts 15 . Given the importance of VH for predicting and influencing individual vaccination decisions, it is important to explore the uses of VH and propose an optimal operationalization, distinguishing VH from other closely related concepts. Such clarification could enable a universally adopted definition and aid further research in this area.

The purpose of this systematic review was to provide an overview of how VH is operationalized in the literature in terms of conceptualizations, subpopulations and measurements. Following an assessment of the various conceptualizations, we differentiated the common themes, related concepts, research fields and vaccine types. The scope and structure of this systematic review is visualized in Fig. 1 . On the basis of an interpretation of these findings, we suggest a way forward by proposing a renewed definition for VH.

Aiming to give an overview of VH, we recognize three types of operationalizations: conceptualizations (blue), identification of subpopulations (orange) and measurements (green). Conceptualizations of VH are analysed at three levels: (1) common themes, (2) closely related concepts and (3) potential variation in conceptualization between research field and vaccine type. Each type of operationalization and its levels are discussed in separate sections.

Study selection and characteristics

The search strategy yielded 7,427 publications. After screening the titles and abstracts, 919 publications were selected for full-text screening. A total of 420 publications met the inclusion criteria. Seven additional studies were found through citation searching, two of which met the inclusion criteria, adding up to a total of 422 studies. Some studies met the criteria of more than one category, with 36 studies categorized under VH conceptualizations, 63 under VH subpopulations and 373 under VH measurements. The search process is summarized in the PRISMA flow chart (Fig. 2 ) 24 . The characteristics of included studies are described in more detail in Supplementary Table 1 .

Visualization of the process involving identification of records from databases, screening of records, assessing reports for eligibility, inclusion of eligible studies and exclusion of non-eligible reports with reasons for exclusion. The number of records or reports in each step of the process is shown in brackets.

The included studies cover a wide geographical distribution. The limited majority (54%) originated in high-income countries (HIC), mainly the United States, Canada, Italy, Australia and France. A smaller group (43%) originated in low- and middle-income countries (LMICs), primarily China, India and Turkey. The remaining studies (3%) originated in a combination of HIC and LMICs. The majority (60%) were published in 2021 and 2022.

The included studies approach VH in relation to various vaccine types: 51% pertaining to COVID-19, 29% to childhood, 4% to human papillomavirus, 4% to influenza and 2% to miscellaneous vaccines. Additionally, 11% of the studies concern vaccines in general. Various research fields are represented, including public health (43%), biomedical science (30%), paediatrics (15%) and social sciences (12%). Mixed methods appraisal tool (MMAT) scores were calculated for 88% of the included studies, while the others could not be assessed due to their study types. The majority (68%) scored 3 or higher, indicating that 60% of the quality criteria were met.

Vaccine hesitancy conceptualization

From the 36 studies on VH conceptualization, we extracted and analysed 304 excerpts. Supplementary Table 2 shows the extracted text excerpts for each study. Our thematic analysis revealed that 93 excerpts describe an overall characterization of VH. The majority of these (69%) describe the nature of VH as heterogenous 14 , 21 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , complex 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 29 , 33 , 35 , 38 , 39 , 40 , 41 , 42 , 43 or varied, depending on the type of vaccine and the context 14 , 18 , 20 , 21 , 23 , 27 , 28 , 30 , 33 , 35 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 .

VH is conceptualized in 208 excerpts. The thematic analysis revealed three predominant conceptualizations in 165 (79%) excerpts: cognitions or affect, behaviour and decision making. These three conceptualizations overlap in the majority of the studies and excerpts. Illustrative excerpts of each conceptualization are presented in Table 1 . The remaining 45 (22%) excerpts represent a fragmented group of conceptualizations, without emerging themes.

Vaccine hesitancy conceptualized as cognitions or affect

From all 36 studies 14 , 17 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 98 excerpts were extracted as conceptualizing VH in terms of cognitions or affect, including questioning, emotions or beliefs regarding vaccination. For this conceptualization, we rank-ordered the most frequently used descriptions of VH, including having or expressing concerns 21 , 25 , 26 , 27 , 29 , 30 , 34 , 35 , 36 , 40 , 42 , 43 , 46 , 51 , 53 , doubts 21 , 28 , 29 , 36 , 43 or questions 21 , 26 , 47 and being reluctant 23 , 27 , 29 , 32 , 36 , 38 , 45 , 49 , 53 , 54 or unsure 14 , 21 , 27 , 29 , 34 . Many authors describe VH as pertaining to beliefs 34 , 49 , attitudes 21 , 26 , 37 , 43 , 51 or both 23 , 29 , 30 , 55 . Furthermore, vaccine-hesitant individuals are described as ambivalent to vaccination or perceiving ambiguity in vaccine-related risks 21 , 36 , 50 , 53 .

Vaccine hesitancy conceptualized as behaviour

From 35 studies 14 , 17 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 94 excerpts were extracted as conceptualizing VH as a behaviour. The majority of the excerpts describe VH in terms of various behaviours 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 27 , 29 , 31 , 32 , 34 , 35 , 37 , 38 , 39 , 40 , 41 , 44 , 45 , 51 , as illustrated by the following example: “VH refers to a ‘delay’ in acceptance or ‘refusal’ of vaccines” 14 . Other excerpts describe VH as a range or continuum between the extreme ends of accepting all vaccines and refusing all vaccines 21 , 22 , 27 , 28 , 29 , 30 , 31 , 33 , 36 , 38 , 43 . In a minority of the excerpts, VH is described as a specific type of vaccination behaviour, including vaccinating as recommended (despite reluctance, concerns or feeling unsure) 26 , 46 , 47 , 49 , refusing vaccines 28 or delaying vaccines and choosing an alternative schedule 50 . Some studies explicitly state that VH should not be described as a vaccination behaviour 17 , 18 , 36 , 40 . Within articles, there were inconsistencies in the behavioural descriptions of VH 18 , 22 , 26 , 27 , 28 , 29 , 31 , 38 , 41 .

Vaccine hesitancy conceptualized as decision making

From 19 studies 18 , 21 , 23 , 26 , 27 , 30 , 31 , 32 , 36 , 37 , 38 , 40 , 42 , 44 , 45 , 50 , 52 , 53 , 30 excerpts were extracted as conceptualizing VH in terms of vaccine decision-making. Some authors adopt the term VH when describing individuals who are undecided, indecisive or under consideration, and not yet having made a final vaccine decision 21 , 23 , 26 , 31 , 32 , 45 , 50 . Vaccine-hesitant individuals are described as being in various states of indecision 23 , 31 , 32 , 37 or as seeking more information to make ‘the right decision’ about vaccination 21 , 53 . Moreover, some authors describe VH as an approach to 38 or a transient stage in the process of vaccine decision-making itself 21 , 23 , 37 .

Vaccine hesitancy and related concepts

VH is often described in relation to other concepts. We extracted 142 excerpts from 31 studies describing closely related concepts 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 27 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 53 . The three most common concepts are confidence or trust, complacency and convenience. Together, these are referred to as ‘the 3 Cs’ 14 and described in 69 of 142 (49%) excerpts. Most often, the 3 Cs are described as having a causal relationship with VH and as representing determinants 14 , 18 , 20 , 29 , 33 , 35 , 38 , 41 , 48 , 56 .

From 25 studies, 46 excerpts were extracted as describing confidence 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 27 , 29 , 30 , 33 , 34 , 35 , 36 , 38 , 39 , 41 , 42 , 43 , 44 , 46 , 47 , 48 , 52 . ‘Confidence’ is defined as the trust that people have in the immunizations, the healthcare system itself, and the process leading to decisions on licensing or recommended schedules 14 , 27 , 35 . Few studies describe the (lack of) trust or confidence as a component of VH 23 , 34 , 52 .

From 22 studies 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 29 , 30 , 33 , 35 , 38 , 39 , 40 , 41 , 43 , 44 , 47 , 48 , 50 , 52 , 41 excerpts were extracted on the theme of complacency. ‘Complacency’ is the individual evaluation of the risks and benefits of vaccines and of the need to vaccinate 14 , 18 , 20 , 35 . The concept of complacency in relation to VH is described as the tendency to perceive the risks of vaccination as unknown or disproportionally high and the risks of the vaccine-preventable disease as low 44 , 50 . Vaccine-hesitant individuals are more committed to assessing vaccine risks and seeking ways to minimize them 23 , 40 , 47 , 50 .

From 15 studies 14 , 18 , 20 , 21 , 22 , 25 , 29 , 33 , 35 , 38 , 39 , 41 , 42 , 43 , 48 , 27 excerpts were extracted as describing the theme of convenience. ‘Convenience’ concerns not only physical availability and geographical accessibility of vaccines, but also the user-friendliness of and ability to understand immunization services 14 , 18 , 35 , 42 . In our analysis, we found that many authors refer to convenience by describing VH as the delaying or refusal of vaccines ‘despite availability’ 14 , 18 , 21 , 22 , 23 , 25 , 26 , 29 , 33 , 35 , 38 , 39 , 41 . This description acknowledges that availability of vaccines is related to vaccine uptake, while VH itself is not influenced by availability issues. However, one study adopts inconvenience and difficulty to access vaccines as dimensions of VH 42 .

Variations between research fields and vaccine types

We identified the respective research field and vaccine type of each study in the qualitative analysis to explore related differences in descriptions of VH. We identified 19 public health studies 18 , 21 , 23 , 25 , 26 , 27 , 28 , 29 , 32 , 33 , 36 , 37 , 38 , 41 , 45 , 47 , 50 , 51 , 53 , 6 paediatric studies 14 , 31 , 34 , 35 , 39 , 48 , 8 social science studies 17 , 20 , 22 , 42 , 44 , 46 , 49 , 52 and 3 biomedical studies 30 , 40 , 43 . The primary difference observed was that conceptualizations of VH in terms of decision making emerged predominantly in the public health 18 , 21 , 23 , 32 , 38 , 50 , 54 and social science fields 42 , 44 , 52 . In studies conceptualizing VH in terms of cognitions or affect, the terms ‘beliefs’ and ‘concerns’ were used in all research fields, while ‘reluctance’, ‘doubts’ and ‘questions’ were used almost exclusively in the public health field. The conceptualization of VH as a behaviour occurred in all research fields.

VH was discussed in relation to vaccination in general 14 , 17 , 18 , 22 , 23 , 27 , 28 , 29 , 32 , 33 , 35 , 36 , 38 , 41 , 42 , 43 , 46 , 48 , 49 or specifically with regard to childhood vaccines 21 , 25 , 26 , 30 , 31 , 34 , 37 , 39 , 40 , 47 , 50 , 51 , 53 , in 19 and 13 of the studies, respectively. The remaining 4 studies discussed VH in relation to COVID-19 44 , 45 , 52 and influenza 20 . Our analysis compared the studies on general vaccination and childhood vaccines but found no major differences in their respective conceptualizations.

Vaccine hesitancy subpopulations

Of the 422 included studies, 63 identified various VH subpopulations. We extracted text excerpts describing the classifications of these subpopulations and the authors’ rationales for the distinctions. The analysis identified themes aligned with the three VH conceptualization categories. Fourteen studies grouped VH subpopulations on the basis of criteria from the conceptualization as cognitions or affect 21 , 23 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 and 3 studies grouped VH on the basis of the conceptualization of decision making 69 , 70 , 71 . VH subpopulations grouped solely on the basis of criteria from the behaviour conceptualization were not found. However, 19 studies grouped hesitant individuals on the basis of criteria from the conceptualizations of both cognitions or affect, and behaviour 26 , 47 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 . The remaining 27 studies did not identify subpopulations in terms of the three conceptualizations. Twelve studies identified subpopulations on the basis of degree of VH 51 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 . Although degree of VH does not directly contribute to understanding of the VH concept, the instruments used to quantify it and determine cut-off values for the subpopulations contain valuable information about the operationalizations. These instruments are discussed in the following section. In addition, a group of 10 studies distinguished a VH subpopulation by asking about willingness to be vaccinated but used different criteria to do so 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 . This method was mainly found in studies on COVID-19 vaccination, published in 2021. This demonstrates the emergence of a conceptual VH category that was not identified from the conceptual studies. The final 5 studies grouped subpopulations according to miscellaneous criteria 45 , 49 , 110 , 111 , 112 . An overview is provided Supplementary Table 3 .

Measurements of vaccine hesitancy

Of the 422 studies included, 373 report a measurement of VH in individuals. An overview is provided in Supplementary Table 4 , grouping the studies according to the instruments used. The most common, albeit highly heterogenous, method used in 210 (56%) studies is a brief VH assessment comprising 1–3 questions 64 , 65 , 66 , 68 , 71 , 74 , 75 , 84 , 85 , 88 , 90 , 96 , 97 , 98 , 100 , 102 , 103 , 105 , 106 , 107 , 108 , 109 , 111 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 . The questions, as well as the criteria or cut-off points used to define hesitancy, vary widely between the studies. The majority of questions used in this method cover operationalizations of VH that did not emerge from our conceptual analysis, including intention and willingness. A group of 124 studies assess VH by asking about vaccination intention. For example, one measurement asks “What would you do if a COVID-19 vaccine were available?”. Respondents answering either “I would eventually get a vaccine, but wait a while first”, “I would not get a vaccine” or “I’m not sure” are all classified as hesitant 169 . A group of 35 studies assess VH by asking about willingness, exemplified by the question: “Are you willing to receive the COVID-19 vaccination?”. Respondents answering “yes, but I choose to delay timing of injection” are considered hesitant 100 . Furthermore, 23 studies assess VH by an explicit verbatim assessment of experienced hesitancy levels. This is exemplified by the question: “Overall, how hesitant about childhood vaccines would you consider yourself to be?”. Respondents answering “not too hesitant”, “not sure”, “somewhat hesitant” or “very hesitant” are considered hesitant 136 . Finally, a minority of 14 studies assess VH with questions covering conceptualizations that did emerge from our conceptual analysis; for example, by asking about previous vaccination behaviour: “Have you ever hesitated, delayed, or refused getting a vaccination for your child or yourself due to reasons other than allergies and sickness?”. Respondents answering “yes” to this question are considered hesitant 122 . The remaining 14 studies use miscellaneous questions to assess VH. Notably, the intention and willingness measures to assess VH are found mainly in studies published in 2021 on COVID-19 vaccination, while the other methods have been used throughout the covered period and in the context of different vaccines.

The second most common method, applied by 132 (35%) studies, is the use of a validated instrument. The most common instrument, used in 70 studies, is the parent attitudes about childhood vaccines (PACV) survey, introduced by Opel et al. 34 . The PACV consists of 15 questions about immunization behaviour, beliefs about vaccine safety and efficacy, attitudes toward vaccine mandates and exemptions, and trust 299 , thereby operationalizing VH as both cognitions or affect, and behaviour. Trust (or confidence) is also included in this instrument. In our conceptual analysis, confidence emerged as a distinct concept, albeit closely related to VH. Clear cut-off points for hesitancy were formulated and applied in the vast majority of the studies using this instrument (shown in Supplementary Table 4 ). The PACV is variously used in its original form 34 , 91 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , or in adapted 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 , 353 , 354 , 355 or shorter versions 51 , 62 , 89 , 93 , 95 , 356 , 357 , 358 , 359 , 360 , 361 .

Other studies use a variety of validated and broadly used instruments. The SAGE instrument is applied in 13 of the studies 41 , 362 , 363 , 364 , 365 , 366 , 367 , 368 , 369 , 370 , 371 , 372 , 373 , with questions reflecting the different conceptualizations (cognitions or affect, behaviour and decision making) and related concepts including convenience, complacency and confidence 41 . The vaccine hesitancy scale (VHS), used in 39 studies 83 , 99 , 374 , 375 , 376 , 377 , 378 , 379 , 380 , 381 , 382 , 383 , 384 , 385 , 386 , 387 , 388 , 389 , 390 , 391 , 392 , 393 , 394 , 395 , 396 , 397 , 398 , 399 , 400 , 401 , 402 , 403 , 404 , 405 , 406 , 407 , 408 , 409 , 410 , was derived from a subscale of the SAGE instrument, narrowed to conceptualize VH as cognitions or affect and include the related concept of confidence 69 . The studies using the SAGE instrument and VHS use varying outcomes or cut-off values (or no outcomes or cut-off values at all) to define hesitancy (shown in Supplementary Table 4 ). The Oxford COVID-19 vaccine hesitancy scale was recently designed exclusively for the assessment of VH for COVID-19 vaccination and subsequently applied in 5 studies 44 , 411 , 412 , 413 , 414 . Other instruments described in the context of VH but intended to assess other concepts include the 5C scale 22 of psychological antecedents of vaccine behaviour, the vaccine acceptance scale (which covers the domains cognitions and affects, confidence and legitimacy of government vaccine mandates 46 ) and the multidimensional vaccine hesitancy scale covering perceptions regarding vaccines in general 42 . Instruments assessing confidence have also been applied to assess hesitancy 415 .

The remaining 31 (8%) studies use a variety of unique, self-developed methods to measure hesitancy. These are classified as ‘miscellaneous’ 25 , 50 , 52 , 69 , 73 , 92 , 94 , 416 , 417 , 418 , 419 , 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 , 428 , 429 , 430 , 431 , 432 , 433 , 434 , 435 , 436 , 437 , 438 , 439 . Examples include measurement of VH based on vaccination rates from medical records 418 and statistical procedures used to group participants according to their patterned responses to a questionnaire 92 , 439 .

Our systematic review reveals that VH is conceptualized in the literature as involving cognitions or affect, behaviour and decision making, representing three distinct but interacting entities. Closely related concepts include confidence or trust, perceptions of the need to vaccinate and of risk (complacency), and convenience. VH subpopulations are grouped according to a variety of criteria, with the majority originating in the three identified conceptualizations. Studies measuring VH have used a wide variety of instruments. The most commonly applied instruments include a brief assessment comprising 1–3 variable questions and the PACV for childhood vaccines. The instruments operationalize hesitancy using one or more of the three identified conceptualizations, but also introduce novel conceptualizations including intention and willingness. When synergizing the findings on different VH operationalizations, we found psychological and behavioural operationalizations, with the psychological operationalizations being cognitions or affect, and decision making.

Our findings illustrate the challenge of operationalizing VH, with studies adopting different conceptualizations, subpopulations and measurements. Dubé et al. acknowledged this challenge of operationalizing the VH concept due to its heterogeneity and the diversity in attitudes and behaviours 29 . Furthermore, our findings align with a recent study demonstrating the many interpretations of VH used across Europe 440 . These inconsistencies in terminology are even evidenced in the Merriam-Webster dictionary, where ‘hesitancy’ is defined as a quality or state of being that involves indecision or reluctance 441 , aligning with VH conceptualized as decision making and cognitions or affect, while ‘vaccine hesitancy’ is defined as the reluctance or refusal to vaccinate 442 , thereby also including a conceptualization of behaviour.

In the introduction, we describe interchangeable use of various terms with VH 19 , 20 . In our review, we also found numerous examples, including ‘confidence’ 443 , ‘low intention’ 444 and ‘unwillingness’ 270 . We identify these concepts as related but not synonymous to VH. For instance, some authors note that confidence or trust are used interchangeably in relation to VH 19 , 22 , suggesting equivalent meanings. Others describe an inverse relationship, meaning that lower levels of confidence are associated with higher levels of VH 19 , 33 , 54 , 56 , 445 . In line with this, VH is described as originating from a lack of confidence 446 and as a possible indicator of declining confidence 56 .

Additionally, in our analysis of subgroups and measurements, we found that VH is frequently operationalized in terms of willingness and intention, which we did not find in our conceptual analysis of VH. Willingness and intention to vaccinate, similar to the ‘vaccine confidence’ concept, are inversely related concepts that are unequivocally linked to VH but are and should not be treated as synonymous. Using these terms interchangeably is not only inappropriate but also contributes to confusion and unclarity of the VH concept. This clarity is needed because unclear concepts give rise to differences in our understanding of its determinants, correlates and consequences, hindering efforts to study and address VH 15 , 23 , 440 . Furthermore, at an operational level, there may be a mismatch between a concept and its measures 15 . This is demonstrated in our review by the highly variable methods we found to measure VH, leading to incomparable results. Particularly during 2021, there has been a plethora of studies reporting VH measurements that, due to divergent definitions and methods, have been of questionable value. As a way forward, we base our reasoning for a renewed definition of VH on the three main identified conceptual categories—behaviour, cognitions or affect, and decision making—as these have proven most promising by their repeated representation in conceptual, subgroup and measurement studies

We argue that conceptualizing VH as vaccination behaviour is untenable, as mere behaviour is insufficiently discriminating between hesitant and non-hesitant individuals. For instance, people may accept vaccines with or without hesitation or reject vaccines with or without hesitation. As concepts are ideally defined by a unique set of features that distinguishes them from other closely related concepts 15 , vaccination behaviour alone is not sufficient to define VH. Furthermore, vaccination behaviour is generally used as the indicator of (non-)acceptance of vaccination. Thus, to use this also to define another concept would create confusion. Authors have commented on the blurred distinction between VH and refusal of vaccines 25 , 39 and criticized behavioural operationalization for its failure to capture VH 17 , 18 , 23 , 25 , 40 . Although we agree that certain types of vaccination behaviour may be manifestations of VH, we argue that including behaviour in the definition and operationalization of VH is neither necessary nor sufficient.

Our analysis shows that VH is furthermore defined by two closely linked conceptualizations that we identify as psychological—cognitions or affect, and decision making. Larson et al. exemplify this stance, arguing that VH is by nature a state of indecision and reluctance 32 . We propose to reject types of vaccination behaviour as a viable conceptualization of VH; this logically results in the proposition that VH should be considered a psychological construct. This is in line with authors who have argued that VH is a psychological state rather than a behaviour 18 , 22 , 26 , 32 , 40 , inspiring our current investigation of what exactly this vaccine-hesitant state entails. In the conceptualization cognitions or affect, VH is mainly described as ‘doubts’, ‘concerns’ and ‘reluctance’ regarding vaccination. Following our analysis, we interpreted these descriptions as different ways of how VH may be affected, experienced or expressed at an individual level, representing a layer surrounding the central element of VH. We therefore interpret cognitions and affect to go hand-in-hand, but not to be at the core of hesitancy. Moreover, we conclude that cognitions or affect are insufficiently distinctive to define VH.

This interpretation does not mean that the identified cognitions or affect are irrelevant to VH. On the contrary, they may prove crucial in shaping VH. However, to arrive at a clear definition of VH, cognitions and affects should be treated as clearly defined entities as well. Only by unravelling and distinguishing them can the exact nature of their relationship with VH be clarified in further research.

In the conceptualization decision making, VH was described as being ‘undecided’, ‘indecisive’, ‘in consideration’ or ‘not yet making a vaccine decision’. All these descriptions include an element of indecision, and this provides a unique and distinctive feature for VH. Additionally, we found that this conceptualization is predominantly discussed in studies in the public health field. This is rather logical, as one would expect this field of research to take a more pragmatic approach, examining the presence of VH at a stage where people have been offered a vaccine or to anticipate public sentiments around willingness to accept a vaccine when it is offered. This probably triggers a decision-making process where VH can emerge and manifest. On the basis of these findings, we argue that VH is a psychological state of being undecided, indecisive or not yet making a decision regarding vaccination.

The study selection was conducted independently by different members of our research team. However, one possible limitation is that we did not attempt to exclude studies of lower quality, as we wanted to maintain a robust selection of studies to enable a broad overview of the relevant literature. Our MMAT assessment, however, indicates that the majority of the studies are of medium quality. A second limitation is that a considerable number of the included conceptual studies (17 of the 36) 14 , 18 , 20 , 21 , 22 , 23 , 25 , 26 , 29 , 35 , 38 , 39 , 40 , 41 , 42 , 43 , 44 quoted the VH definition introduced by the SAGE working group, which may have led to an amplification of the SAGE definition. This may indicate that this definition is well recognized, but potentially overshadows less recognized conceptual definitions of VH. We chose to include all quoted definitions and found that many studies used more than one. We did not look further into conflicting definitions within the articles, but doing so could yield interesting insights.

In conclusion, we propose a definition of VH as a psychological state of indecisiveness that people may experience when making a decision regarding vaccination. We acknowledge that experiencing concerns, doubts or reluctance regarding vaccination may play a vital role in shaping VH. However, we argue that these factors have the highest potential to advance scientific knowledge when treated as relevant constructs integral to shaping VH, rather than treating them as synonymous to VH. Operationalizing VH by measuring or distinguishing subpopulations should ideally be directed at this state of indecision. To avoid confusion, it is important to separate VH from vaccination behaviour, which is already a well-defined concept. This proposal of a renewed definition of a concept that has been used for a decade could be perceived as ‘putting old wine in new bottles’. However, we feel that due to the large amount of highly varied literature, and given the importance of VH research in predicting, explaining and influencing immunization behaviour, it is necessary to take a snapshot of the status quo. The conclusion of this review is that VH is, for now, an impracticable concept, due to the confusing use of multiple, varied operationalizations. To aid further research, the VH concept must be clearly conceptualized and adapted from its broad and inclusive form to a pragmatic and refined alternative. Working on such an alternative, the field should first reach consensus on the definition and then measure VH accordingly. This approach allows for a much-needed comparison between studies to improve our understanding of VH determinants, correlates and consequences on an individual and societal level. Our way forward is to simplify and clarify the operationalization of VH by returning to its root core of indecisiveness.

This systematic review was registered on 11 November 2020 in the PROSPERO database (CRD42020211046). The record and study protocol are available at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=211046 .

Relevant publications were searched using the PubMed, Embase and PsycINFO databases to ensure coverage of all relevant research areas in the medical, public health and social science fields. The CINAHL database was also considered, but a pilot search revealed that its unique contributions were limited.

An experienced research librarian used the following keywords to develop a search strategy (Supplementary Methods ): ‘vaccination’, ‘immunization’, ‘vaccination refusal’, ‘vaccination avoidance’, ‘vaccination hesitation’, ‘vaccine hesitancy’, ‘vaccine uptake’, ‘vaccination behaviour’, ‘vaccination attitude’, ‘vaccine confidence’, ‘vaccine acceptance’ and ‘vaccine barriers’. The limitations included a publication date of between 2010 and the date of the search (14 January 2022). Conference abstracts were excluded from the search of the Embase database.

Eligibility criteria

The included studies were all published in peer-reviewed journals and written in English. All study types were eligible, except editorials and commentaries, as we sought to include original studies. Studies on animal vaccines were excluded.

The purpose of this review was to clarify the VH concept by analysing how it is operationalized. We recognized operationalizations at two main levels: conceptual and empirical. This resulted in three main groups: (1) studies describing or defining the VH concept and studies applying the concept by (2) identifying VH subpopulations and (3) measuring VH in individuals. This approach allowed comparison between conceptual and empirical operationalizations of VH.

Study selection

In the first selection round, two members of the research team used RAYYAN software to independently assess the titles and abstracts. Studies were selected when the title or abstract contained the term ‘vaccine hesitancy’. Studies were also selected if the title or abstract indicated that the full text contained further information on VH conceptualization, subpopulations or measurements. Papers without an abstract were selected for full-text screening. After double-screening, the results were de-blinded to allow the researchers to discuss their conflicting judgements until consensus was reached.

In the second selection round, the full texts were screened. The first 30% of studies were double-screened to establish a uniform method. Studies were screened on whether they met the criteria for one or more of the three categories (conceptualization, subpopulations and measurements). The category of ‘conceptualization’ included studies that describe, discuss or explore the VH concept or propose a novel VH measurement instrument. Studies falling into only the second category (subpopulations) were excluded if they merely distinguished between hesitant and non-hesitant groups, since a dichotomous grouping does not contribute to understanding of VH. The references from the included full-text articles were screened to find additional studies matching the selection criteria.

We deviated posthoc from our preregistered study protocol by adjusting the study selection criteria as follows. Initially, we also included studies containing the term ‘vaccine confidence’ (that is, with no mention or operationalization of vaccine hesitancy) as indicated in our study protocol. During the process, we realized that this deviated from our primary aim to clarify the VH concept by differentiating its related concepts. Therefore, we adapted the protocol and excluded 16 studies that were exclusively on vaccine confidence from our analysis

Data collection

The study characteristics were extracted from each of the full-text articles. Data were extracted by one researcher and verified by a second member of the research team. The variables included the first author, year of publication, research field of the first author, type of study, type of participants, number of participants, type of vaccination and country in which the study was conducted (with corresponding economic status) 447 . For the studies that do not include data collection, the country of origin was determined using the affiliation of the first author.

From the studies on VH conceptualization, text excerpts that define or describe VH or describe the relationship of VH to other concepts were extracted. These excerpts were further analysed in the qualitative analysis. From studies that describe different VH subpopulations, information about the categorization of these various subgroups was extracted, including the rationale for the distinguished subpopulations. From studies that describe VH measurements, the instrument(s) and criteria used to define VH were extracted.

Synthesis of results

The text excerpts extracted from the studies conceptualizing VH were thematically coded using ATLAS.ti software. Three research team members developed a coding book of themes and subthemes after independent coding of 30% of the studies. Thereafter, one researcher continued the coding process for the remaining studies. Any emerging new codes were discussed with the other research team members. The results were analysed qualitatively, and the predominant themes were identified by the three team members. When possible, results were grouped by research field and vaccine type to allow for comparison.

The data extracted from the studies describing VH subpopulations were summarized in a table and grouped according to the common themes identified. The data extracted from the studies describing a VH measurement were summarized in a table and grouped according to the instrument or method used. Where multiple measurement instruments are used in one study, the tool used to determine hesitancy was selected as the main instrument.

Quality assessment

The quality of each study was assessed using the MMAT 448 . This tool contains appraisal guidelines for different study types, covering the majority of the included studies. An overall score was calculated (1–5) on the basis of additional communication about the MMAT 2018 version, with higher scores indicating higher quality levels 449 . The first 20% of studies were assessed independently by two members of the research team to ensure consistency. Thereafter, one member of the research team continued the assessment.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Data availability

All data generated or analysed during this study are included in this article and its Supplementary Information . This systematic review is registered in PROSPERO (CRD42020211046).

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J.L.A.H. and M.E.J.L.H. received funding from The Netherlands Organisation for Health Research and Development (ZonMw project number 839190002). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank J. van Haren for her valuable contribution in sorting and organizing the data of this systematic review.

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Overview of vaccine hesitancy subpopulations.

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• Published: 28 July 2021

Factors influencing childhood immunisation uptake in Africa: a systematic review

• Abubakar Nasiru Galadima 1 ,
• Nor Afiah Mohd Zulkefli 1 ,
• Salmiah Md Said 1 &
• Norliza Ahmad 1  

BMC Public Health volume  21 , Article number:  1475 ( 2021 ) Cite this article

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Vaccine preventable diseases are still the most common cause of childhood mortality, with an estimated 3 million deaths every year, mainly in Africa and Asia. An estimate of 29% deaths among children aged 1–59 months were due to vaccine preventable diseases. Despite the benefits of childhood immunisation, routine vaccination coverage for all recommended Expanded Programme on Immunization vaccines has remained poor in some African countries, such as Nigeria (31%), Ethiopia (43%), Uganda (55%) and Ghana (57%). The aim of this study is to collate evidence on the factors that influence childhood immunisation uptake in Africa, as well as to provide evidence for future researchers in developing, implementing and evaluating intervention among African populations which will improve childhood immunisation uptake.

We conducted a systematic review of articles on the factors influencing under-five childhood immunisation uptake in Africa. This was achieved by using various keywords and searching multiple databases (Medline, PubMed, CINAHL and Psychology & Behavioral Sciences Collection) dating back from inception to 2020.

Out of 18,708 recorded citations retrieved, 10,396 titles were filtered and 324 titles remained. These 324 abstracts were screened leading to 51 included studies. Statistically significant factors found to influence childhood immunisation uptake were classified into modifiable and non-modifiable factors and were further categorised into different groups based on relevance. The modifiable factors include obstetric factors, maternal knowledge, maternal attitude, self-efficacy and maternal outcome expectation, whereas non-modifiable factors were sociodemographic factors of parent and child, logistic and administration factors.

Different factors were found to influence under-five childhood immunisation uptake among parents in Africa. Immunisation health education intervention among pregnant women, focusing on the significant findings from this systematic review, would hopefully improve childhood immunisation uptake in African countries with poor coverage rates.

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Vaccine Preventable Diseases (VPDs) are still the most common cause of childhood mortality with an estimated 3 million deaths every year, mainly in Africa and Asia [ 1 ]. A study conducted by the World Health Organization (WHO) and United Nations International Children’s Emergency Fund (UNICEF) in 2014, reported that an estimate of 29% deaths among children aged 1–59 months were due to vaccine preventable diseases [ 2 ]. In 2014, there were 24.1 million reported cases of pertussis, with the African region accounting for the highest proportion of 7.8 million (33%) cases [ 3 ].

Immunisation is considered to be one of the most successful and cost-effective public health sustainable interventions for human beings against diseases that affect our health [ 4 ]. Routine immunisation plays a key role to significantly reduce child mortality due to vaccine preventable diseases. WHO revealed that immunisation has been estimated to prevent 3 million deaths globally every year [ 5 ]. Between the years 2000 and 2016, a decrease of 84% in the measles mortality rate was recorded worldwide due to measles vaccination [ 6 ]. Likewise, a reduction in pertussis mortality was also recorded globally from 390,000 deaths in 1999 among children younger than 5 years of age to 160,700 deaths in 2014 as a result of vaccine effectiveness against pertussis [ 6 , 7 ].

According to the Expanded Programme on Immunization (EPI), every child in Africa must receive one dose of Bacillus Calmette Guerin (BCG), Oral Polio Vaccine (OPV0) and Hepatitis B Vaccine (HBV1) at birth, Penta1 & OPV1 at 6 weeks of age, Penta2 & OPV2 at 10 weeks of age, Penta3 & OPV3 at 14 weeks of age and measles and yellow fever at 9 months of age. Despite the benefits of childhood immunisation, routine vaccination coverage for all recommended EPI vaccines has remained poor in some African countries such as Nigeria (31%; 2018), Ethiopia (43%; 2019), Uganda (55%; 2016) and Ghana (57%; 2014). The coverage is higher in some of the African countries, such as in Tanzania in the year 2016 and Kenya in 2014 (75 and 78%, respectively) [ 8 , 9 , 10 , 11 , 12 , 13 ]. Diphtheria Pertussis and Tetanus (DPT3) coverage is also low in African countries such as Nigeria (50%) [ 8 ]. However, these coverages are still below the targets endorsed by WHO in the 2012 Global Vaccine Action Plan, which aimed to ensure delivery of universal access to immunisation with associated targets reaching 90% of the national vaccination coverage and at least 80% vaccination coverage in every district [ 14 ].

Previous observational studies conducted among African countries and other parts of the world highlighted various factors that influenced childhood immunisation uptake. These factors are socio-demographic factors including maternal age, maternal educational status, paternal educational status, mother’s marital status, maternal occupation, family income, wealth index and ethnicity [ 15 , 16 , 17 , 18 ] and obstetric factors including antenatal care follow-up, postnatal care follow-up, preceding birth interval and place of delivery [ 18 , 19 , 20 , 21 ]. Despite the poor childhood immunisation uptake in African countries, no current systematic review has been conducted that focuses on describing, in detail, the factors influencing childhood immunisation uptake in Africa. Therefore, the aim of this study is to collate evidence on the factors that influence childhood immunisation uptake in Africa as well as to provide evidence for future researchers in developing, implementing and evaluating intervention among African populations, which will improve childhood immunisation uptake. This study will assist in developing health promotional programs and policies on childhood immunisation in Africa.

This systematic review was conducted and reported in accordance with published Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [ 22 ].

Electronic database search

We designed and implemented a comprehensive systematic literature search with the assistance of an experienced librarian using a well-developed strategy. The following databases were searched on the same date, from date of inception to 26th of October 2020: Medline, PubMed, CINAHL and Psychology & Behavioral Science Collection. The search strategy comprised a combination of medical subheading (MeSH) terms and keywords: childhood immunization uptake, factors, influencing or affecting, child or newborn or infant or baby, immunisation or vaccines or vaccination or pentavalent vaccine or Penta vaccine or Bacillus Calmette Guerin vaccine or BCG or Diphtheria Tetanus and Pertussis or DTP or Oral Polio vaccine or OPV or Measles vaccine or Yellow fever vaccine or Pneumococcal Conjugate vaccine or PCV or Hepatitis B vaccine or Hep B vaccine, uptake or adherence or compliance or coverage (Supplemental file 1 ).

The search strategy was developed in Medline and adapted for the other databases in order to account for differences in indexing. We restricted it to humans in the search process. Reference lists of included studies were also searched.

We included any observational (cross-sectional, case-control and cohort), mixed method study (convergent, exploratory and explanatory type) and qualitative study design (phenomenological study and case study) conducted in Africa published in the English language with findings relating to childhood immunisation uptake. The participants of these studies were caregivers with children under 5 years of age. The included studies also reported data on association between possible predictors and childhood immunisation or provided details of any non-compliance (vaccine refusal). We also included peer-reviewed full text publications reporting an association between at least one individual factor and uptake of childhood immunisation. Moreover, no restrictions were imposed on the year of publication.

We excluded articles without any description of study design, intervention studies (randomised controlled trial and quasi experimental design), review articles or systematic reviews and studies which made no mention of any of the Expanded Programme on Immunization target vaccines according to the National Program on Immunization (Table  1 ).

Description of study outcomes

Parental socio-demographic factors: maternal age, maternal education, paternal education, income, place of residence, maternal occupation and religion; child socio-demographic factors: child age and gender; religion and cultural beliefs; obstetric history: place of delivery, antenatal care follow-up and postnatal care follow-up; health care system: distance to hospital and availability of vaccine; knowledge; outcome expectation and self-efficacy (Table  2 ).

Selection of studies

All searched articles were evaluated for eligibility in order to be included in the review. The main researcher first removed all duplicates and screened the titles using Microsoft Excel. Abstract screening was then conducted independently by two reviewers. The full text of any article considered potentially relevant was also retrieved independently by the two reviewers. Consensus was reached by discussion or involvement of a third reviewer when there were differences of opinion.

Data extraction

A data extraction form was designed and piloted for this review. The form was used to extract the following data: study characteristics such as authors’ name and year of publication, study location, method, study design, sample size, results and factors. Data was extracted independently by the two reviewers to ensure accuracy. Any difference of opinion was resolved by discussion or involvement of a third reviewer.

Categorisation of factors associated with immunisation coverage

The qualitative synthesis of the factors influencing childhood immunisation uptake among parents of children under-five years of age are categorised into two groups, namely modifiable and non-modifiable factors. Modifiable factors are considered to be factors that are intrinsic to mothers/caregivers (can be changed through health education intervention targeting mothers/caregivers) while non-modifiable factors are considered to be factors that are extrinsic to mothers/caregivers (cannot be changed through health education intervention targeting mothers/caregivers). This classification would enable researchers to plan an appropriate health education intervention, with the use of appropriate health behavioural theory.

Assessment of methodological quality

ANG and NZ assessed the methodological quality for each of the included studies using the criteria outlined in the Joanna Briggs Institute (JBI) for both quantitative and qualitative studies [ 30 ], which includes 8 items for cross-sectional study design and 10 items for both case-control and qualitative study designs respectively . Any disagreement was resolved by discussion. In this review, we grouped articles into three categories: high, moderate and low quality for their methodological qualities using the JBI critical appraisal tools; studies scoring >  70% were considered as high quality, 60–69% were moderate quality and < 60% were low quality. This review may be prone to publication bias as grey literature/unpublished literature and studies that are not published in the English language were not considered.

Data synthesis

No meta-analysis was conducted, however, the results obtained from the systematic review were synthesised and placed in a logic framework. The various results obtained from the systematic review were shown in the logic framework and discussed in a narrative synthesis manner. The descriptive information and data for each of the included studies were captured using a table formulated by the researchers. These included study author, year and location; method; study design; sample size; results and factors. ANG synthesis ed the data and created a table with input from both NZ and SS. ANG and NZ reported factors under two different categories namely: modifiable and non-modifiable factors.

In this review, a wide range of AOR and 95% confidence intervals (upper limit and lower limit) from different studies were reported and confidence interval that does not include 1 and p -value less than 0.05 with AOR greater than 1 are considered as statistically significant.

Of 18,708 recorded citations retrieved, 8279 duplicates and 33 articles published in languages other than the English language were removed. After screening 10,396 titles, 324 records remained and their abstracts were screened. Seventy-nine records remained after abstracts were screened and their full texts were assessed for eligibility. We excluded 44 studies in total, of which 16 studies were not conducted in Africa, 12 studies did not make mention of the EPI vaccine, 9 were review studies and 7 were intervention studies. In total, 51 studies were included, of which 35 were from the main database search, 8 from forward citation tracking and 8 from reference tracking. All the included studies looked into factors influencing childhood immunisation uptake in one of the African countries (Fig.  1 ). Table  3 contained a summary of the factors that influence under-five childhood immunisation uptake among mothers/caregivers. The studies used different study designs to investigate the factors that influence under-five childhood immunisation uptake among parents.

PRISMA flow diagram for the identification, screening, eligibility, and inclusion of studies

The majority of our epidemiological studies achieved at least 70% scores which is considered high [ 16 , 18 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 43 , 44 , 45 , 48 , 50 , 51 , 52 , 55 , 57 , 58 , 59 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ] and the overall risk of bias was moderate in 10 studies (Table 3 ) [ 15 , 19 , 39 , 46 , 47 , 49 , 53 , 54 , 56 , 60 ]. Out of the 10 studies, 6 had a moderate risk of bias in the confounding domain and 4 had a moderate risk of bias in the outcome assessment domain. However, none of the included epidemiological studies demonstrated either a serious or low risk of bias < 60%.

Study locations

The studies were conducted in various countries within Africa, namely Angola, Cameroon, Congo and Mozambique with one study each [ 25 , 32 , 33 , 44 ]. Burkina Faso, Gambia, Ghana and Tanzania contributed two studies each [ 24 , 28 , 31 , 39 , 40 , 41 , 53 , 55 ]. Kenya and Uganda contributed three studies each [ 19 , 26 , 42 , 43 , 54 , 63 ] and Ethiopia had 14 studies [ 16 , 20 , 23 , 29 , 34 , 35 , 36 , 37 , 38 , 59 , 65 , 66 , 67 , 69 ]. Most of the studies were conducted in Nigeria with a total number of 19 studies [ 15 , 18 , 27 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 56 , 57 , 58 , 60 , 61 , 62 , 64 , 68 ]. The majority of the study respondents were parents of children who were within the childhood immunisation schedule range. The studies focused on factors that influence or determine childhood immunisation uptake. The majority of these studies were carried out mainly in West Africa (Nigeria) due to poor childhood immunisation uptake in the nation. This demonstrated that most of the researches were still attempting to determine the main factors that play a role in influencing childhood immunisation uptake, which would enable researchers to address the issues for the development of future health education intervention programs.

Study type and respondents

The majority of the studies were a cross-sectional study design with a total number of 42 studies, 3 qualitative study design [ 38 , 50 , 64 ], 4 mixed method [ 23 , 37 , 41 , 68 ] and 2 case-control [ 34 , 59 ]. The number of study respondents varied across the studies with 14 being the smallest and 7815 the largest (Table 3 ).

Factors associated with immunisation coverage

Modifiable factors.

The factors that are considered modifiable in this review are obstetric factors, maternal knowledge, maternal outcome expectation, maternal attitude, maternal self-efficacy and environmental factors. These factors were found to statistically influence childhood immunisation uptake in Africa and reported a wide range of AOR and 95% confidence intervals (upper limit and lower limit) from different studies.

In respect to obstetric factors, place of delivery was evident in five studies which are all statistically significant with AOR  2.11–3.13 and 95% confidence intervals (CI): 1.09, 7.13) [ 26 , 44 , 63 , 65 , 67 ] and three studies also reported postnatal care follow-up with AOR 1.8–5.8; 95% CI: 1.21, 3.16 [ 20 , 59 , 63 ]. Six studies revealed antenatal care follow-up with AOR  2.4–3.7; 95% CI: 1.1, 10.0 [ 16 , 19 , 65 , 66 , 67 , 69 ], likewise maternal tetanus toxoid was reported in two studies with AOR  2.43–3.2; 95% CI: 1.10, 10.00 [ 27 , 36 ].

Many studies reported factors relating to maternal knowledge, for example, knowledge on child immunisation (AOR = 3.3; 95% CI: 1.87, 7.43) [ 34 , 67 ], knowledge on preventive objective of immunisation ( p  < 0.05) [ 31 ], lack of knowledge on vaccines which accounted for 50% reason for non-compliance [ 57 ], knowledge on child vaccination schedule, which was reported in three studies with AOR  2.9–4.3; 95% CI: 1.42, 8.0 [ 26 , 35 , 59 ]. Likewise, awareness on immunisation and immunisation programs were also revealed in three studies with AOR  = 1.9–2.8; 95% CI: 1.44, 2.49 [ 20 , 25 , 37 ]. Two studies reported the impact of knowledge of VPDs (AOR  = 2.5; 95% CI: 1.5, 4.2) [ 16 , 61 ]. For maternal attitude and self-efficacy, three studies reported availability of child immunisation records with AOR  = 2.38–7.7; 95% CI: 1.43, 10. 06) [ 20 , 31 , 47 ]. Likewise, four studies documented fear of vaccine side effects (AOR  = 1.92; 95% CI: 1.01, 3.70) [ 23 , 57 , 60 , 62 ], negative beliefs towards childhood immunisation uptake [ 46 ], good perception of immunisation (AOR  = 2.60; 95% CI: 1.50, 4.51) [ 49 ] and confidence towards vaccine safety ( p  < 0.05) [ 46 ].

With regards to maternal outcome expectation, three studies reported knowledge on benefit of childhood immunisation uptake (AOR  = 5.51; 95% CI: 1.52, 19.94) [ 23 , 35 , 54 ] and one study documented severity of VPDs ( p  = 0.045) [ 45 ]. With regards to environmental factors, two studies reported religious belief (OR  = 1.65: 95% CI: 1.15, 2.36) [ 44 , 64 ]. Likewise, two studies also attributed cultural belief [ 56 , 60 ].

Non-modifiable factors

In this review, parental socio-demographic factors (maternal age, maternal education, paternal education, maternal marital status, area of residence, wealth index, number of siblings, religion, ethnicity and family income), child socio-demographic factors (gender, age) and environmental factors (distance to health facility, mode of transportation, accessibility of vaccination site, satisfaction with vaccine services, quality of vaccine provider clients relationship and availability of vaccine) are considered as non-modifiable factors. These factors were found to statistically influence childhood immunisation uptake in Africa and reported a wide range of AOR and 95% confidence intervals (upper limit and lower limit) from different studies.

In respect to parental socio-demographic factors, three studies reported maternal age with AOR  = 1.08–9.54; 95% CI: 1.08, 18.09; p  < 0.05 [ 23 , 36 , 38 ], nine studies reported maternal educational status which were all statistically significant with AOR  = 3.55–7.50; 95% CI: 1.02, 10.60 [ 15 , 18 , 26 , 55 , 65 , 66 , 67 , 69 ], three studies reported paternal education (AOR  = 3.1; 95% CI: 1.3, 7.4) [ 16 , 48 , 59 ], three studies reported maternal occupation and mothers’ marital status respectively (AOR  = 1.62–3.01; 95% CI: 1.0, 5.8) [ 16 , 24 , 58 , 65 ]. Another two studies reported area of residence (AOR  = 2.70; 95% CI: 1.52, 4.81) [ 18 , 26 ], wealth index was documented in three studies (AOR  = 1.4–2.38; 95% CI: 1.06, 3.73) [ 20 , 65 , 69 ], three studies reported family income (AOR  = 3.2; 95% CI: 1.4, 7.4) [ 16 , 31 , 59 ], one study reported number of siblings (APR  = 1.42; 95% CI: 1.05, 1.71) [ 25 ], two studies reported religion ( p  < 0.05) [ 19 , 44 ], three studies documented nomadic lifestyle (OR  = 11.06; 95% CI: 4.29, 28.54) [ 26 , 43 , 68 ] and ethnicity was also reported in two studies (AOR  = 2.47; 95% CI: 1.28, 4.76) [ 26 , 51 ]. Regarding child socio-demographic factors, child age was reported in two studies ( p  < 0.05) [ 25 , 56 ] whilst one study reported gender (OR  = 2.98; 95% CI: 1.21, 7.35) [ 46 ]. In relation to environmental factors, distance to health facility was attributed in four studies which were all statistically significant with AOR  = 2.11–3.10; 95% CI: 1.46, 6.30 [ 16 , 26 , 44 , 67 ], one study reported mode of transportation (AOR  = 1.54; 95% CI: 1.20, 1.97) [ 40 ], accessibility of vaccination site was also documented in one study (AOR  = 4.54; 95% CI: 2.34, 8.77) [ 29 ], four studies reported satisfaction with vaccine services (AOR  = 2.63; 95% CI: 1.1, 6.3) [ 28 , 56 , 60 , 64 ], quality of vaccine provider clients relationship was recorded in one study (AOR  = 1.86; 95% CI: 1.03, 3.50) [ 28 ] and vaccine availability in three studies [ 56 , 60 , 68 ].

The main reason for conducting this systematic review was to identify the factors that influence under-five childhood immunisation uptake among parents. In this review, many factors have been found to influence childhood immunisation uptake and are categorised and reviewed below.

Parental socio-demographic factors

Maternal age was revealed to be a factor influencing childhood immunisation uptake in a case-control study conducted in Ethiopia that involved 548 children aged between 12 to 23 months, in which mothers over 19 years of age were approximately 10 times more likely to have their children fully immunised compared to mothers under 19 years of age [ 23 ]. This may be due to knowledge gained over time on the importance of immunisation by mothers over 19 years of age, combined with the negative impact on children due to lack of immunisation. This finding is supported by two studies conducted in Ethiopia [ 36 , 37 ].

In this review, maternal education was the most common reported parental socio-demographic factor found to influence childhood immunisation. Mothers with at least a primary or secondary school education were found to be approximately eight times more likely to have their children fully immunised compared to mothers with no formal education [ 56 ]. This is more likely due to the fact that as the educational status of mothers improves, the seeking behaviour of children may perhaps increase, which in turn have positive impacts towards childhood immunisation uptake [ 56 ]. Furthermore, this could also be a result of changes that accompany maternal education, such as changes in attitudes, traditions and beliefs, increased autonomy and control over household resources which enhance healthcare seeking [ 26 ]. Similar findings have been reported in many studies [ 15 , 18 , 26 , 55 , 65 , 66 , 67 , 69 ].

From a cross-sectional study conducted in the Sinana District of Ethiopia, consisting of 591 children aged 12–23 months, paternal education was also found to be statistically associated with the child immunisation status. Children with fathers who had a secondary or higher educational level, were three times more likely to be fully vaccinated compared with children whose fathers had no formal education [ 16 , 48 , 59 ]. As the educational status of fathers improves, the seeking behaviour of children may perhaps increase, which in turn may have positive impacts towards childhood immunisation uptake [ 48 ].

Results from a cross-sectional study conducted in the Sinana District of Ethiopia, consisting of 591 children aged 12–23 months, has found maternal occupation to be statistically associated with child immunisation uptake. The proportion of children who were not fully vaccinated was found to be higher among mothers who were housewives [ 16 ]. Mothers whose occupation was in the farming sector, were less likely to be totally dependent on their spouses in terms of financial support and were found to be almost twice as likely to complete the immunisation of their children, compared with mothers who were housewives. A likely reason for this would be that mothers would not be reliant on their spouses to provide transport fees in order to take their children to be immunised. They most probably have been exposed to information on the benefit of childhood immunisation uptake through access to media [ 16 ]. This finding is supported by another cross-sectional study conducted in Ethiopia [ 65 ].

The marital status of a mother was also reported to have an influence towards childhood immunisation. In a descriptive cross-sectional study conducted in Ghana involving 280 mothers, it was found that divorced mothers were 3 times less likely to complete immunisation schedules of their children compared to mothers who were married [ 24 ]. In a cross-sectional study conducted in Nigeria involving 232 mothers (children aged 12–23 months), married women were observed to have a significantly adequate knowledge of immunisation which may increase the likelihood of achieving a higher rate of immunised children compared with their counterparts who were either single/divorced/widowed or separated [ 58 ]. The marital status of a mother may enhance her knowledge in the sense that those that are married may have more access to education compared to single mothers who may have other responsibilities and would instead tend to put their education aside in order to meet the needs of their children [ 24 ]. The supportive role of their partners may also enhance her knowledge if both partners jointly try to find ways to better the health status of their offspring [ 58 ].

A cross-sectional study from this review that was conducted in Kenya, which consisted of 298 mothers with children aged 12–23 months, demonstrated that area of residence statistically influenced childhood immunisation uptake. Children who lived in urban areas were 12 times more like to be vaccinated compared to children living in rural communities [ 26 ]. In Nigeria, results obtained using NDHS data involving 5754 children aged between 12 and 23 months, also revealed a statistical association between area of residence and child immunisation status. Children residing in urban areas were more likely to be vaccinated compared to children living in rural communities. This may probably be attributed to the fact that parents living in urban areas were more likely to be educated which may increase their knowledge towards the benefit of childhood immunisation uptake compared to parents living in rural areas [ 18 ].

Three different cross-sectional studies conducted in Ethiopia among children aged 12–23 months found wealth index to be a factor influencing childhood immunisation uptake. Children born to mothers from a rich index group were found to be twice as likely to be fully vaccinated compared with children from mothers from a poor wealth index group [ 20 , 65 , 69 ]. Rich parents may have more access to media and probably have more exposure to information on the benefit of childhood immunisation uptake.

Family income was found to be another factor influencing childhood immunisation uptake in a cross-sectional study conducted in Burkina Faso consisting of 591 children aged between 12 and 23 months. The study found that if the income of a family is greater than 1000 ETB or 52 USD, it increases the tendency of having children fully vaccinated in that family by approximately three times when compared to a poor family with a lesser income [ 16 ]. The family with a higher income may have easier access to Immunisation Centres due to accessible effective transportation options and would have less financial challenges when compared with families with a lower income. This finding was also supported by two cross-sectional study designs [ 31 , 59 ].

The number of siblings was also found to be a factor affecting childhood immunisation uptake in a cross-sectional study conducted in Angola involving 1209 children under 5 years of age. A family comprising 2 to 3 siblings were more likely to vaccinate their children compared with a family with less than 2 siblings [ 25 ]. This may be due to experience gained over time on the importance of immunisation as well as the medical complications that have occurred in children due to lack of immunisation.

Religion has been revealed by studies to be a factor influencing childhood immunisation uptake. From a cross-sectional study conducted in Uganda using Uganda Demographic Health Survey data, childhood immunisation uptake was affected by religious affiliations. Children from Muslim families had a lesser chance of been fully vaccinated compared with children from Catholic families [ 19 ]. Likewise, in Mozambique parents with no religious affiliation were found to be twice as likely not to complete their childhood immunisation uptake [ 44 ]. This could be due to the circulation of false information obtained via religious networks. This false information may be linked to negative beliefs of vaccines, for example, the belief that vaccines are composed of anti-fertility drugs [ 70 ].

Nomadic lifestyle was found to be associated with child immunisation uptake in Kenya. Children born to a family who practice a nomadic lifestyle, were found to be 11 times more likely not to be fully vaccinated compared with children born to a family that do not practice a nomadic lifestyle [ 26 , 43 , 68 ]. The family who practices a nomadic lifestyle may constantly change their location, switching from one place to another where immunisation services may not be readily accessible [ 26 ].

Ethnicity was found to be a factor affecting childhood immunisation uptake in Nigeria in which children belonging to the Igbo ethnic group were about three times more likely to be fully vaccinated compared to children belonging to an ethnic group such as Hausa, Yoruba and others [ 51 , 56 ]. These disparities could be attributed to the factors prevalent at community level, for example, in the Hausa community there is low level of education, high poverty, poor utilisation of antenatal care and home delivery and all these factors are associated with poor immunisation uptake. It could also be due to a misconception regarding the safety of vaccines and fear of vaccine side effects [ 51 ]. These findings are consistent with the findings from a systematic review conducted to determine the significant factors of adherence among parents or caregivers of under-five childhood immunisation schedules, even though the review did not specifically focus on Africa [ 71 ].

Child socio-demographic factors

Child gender was found to be associated with child immunisation uptake in Ibadan, Nigeria where a male child is about three times more likely to be immunised compared with a female child [ 46 ]. This may be attributed to the beliefs of parents that immunisation will have negative impacts on their daughters when they reach child bearing age.

A contradictory finding was revealed with regards to influence of child age on immunisation uptake. In Nigeria, higher immunisation uptake was observed in children above 1 year of age (84.4%) compared with children below 1 year (63.6%) and this could be due to the fact that some mothers delay child immunisation until their children reach a certain age, due to negative beliefs that their children are too young to be immunised [ 56 ]. In Angola, higher immunisation uptake was seen in children who were 1 year of age or less compared with children that were above 1 year of age. This could be attributed to the lectures received by mothers towards benefits of timely childhood immunisation uptake during their antenatal and postnatal care. It is likely that the content of health education delivered to the mothers has changed with more emphasis placed on the benefit of childhood immunisation uptake [ 25 ].

Obstetric factors

Antenatal care follow-up (ANC) was found to be a factor influencing childhood immunisation uptake in a cross-sectional study conducted in Ethiopia that involved 591 children aged between 12 and 23 months. The study showed mothers who frequently attend ANC during their pregnancy were about four times more likely to have their children fully vaccinated compared with mothers who did not attend ANC regularly [ 16 ]. This finding is supported by the findings of a study conducted in Uganda and four more studies from Ethiopia [ 19 , 65 , 66 , 67 , 69 ]. Mothers who frequented health facilities during pregnancy may have received counselling on childhood immunisation where the importance of timely childhood immunisation uptake may be prioritised regularly [ 16 ].

The postnatal check-up was also found to be an influencing factor towards childhood uptake where children who received a check-up within 2 months after birth were twice more likely to be fully vaccinated compared to those who did not receive a check-up after delivery [ 20 , 59 , 63 ]. This can be attributed to educational sessions that mothers were exposed to during postnatal visits where the importance of timely immunisation of the baby may be emphasised [ 20 ].

The maternal tetanus toxoid (MTT) vaccine was also noted to be a factor influencing childhood immunisation uptake. Mothers who received at least one dose of the MTT vaccine were three times more likely to have their children fully immunised compared with mothers who did not receive any dose of the MTT vaccine [ 27 , 36 ]. This could be attributed to the knowledge that mothers may have obtained regarding the benefit of childhood immunisation uptake during the MTT vaccination in their health centre [ 27 ].

Children who were delivered in hospitals were more likely to have a complete vaccination status compared with children delivered at home [ 26 , 44 , 63 ]. Mothers who had hospital deliveries may receive advice after delivery where the importance of timely immunisation of the baby may be emphasised and therefore, they are more likely to receive their vaccines [ 44 ].

Maternal knowledge

Having a good maternal knowledge on child immunisation was revealed to be a predictor for childhood immunisation uptake in a case-control study conducted in Northern Ethiopia. Children of mothers with a good knowledge on childhood immunisation were found to be three times more likely to be completely immunised compared with children whose mothers had a poor knowledge on childhood immunisation [ 34 ]. This finding is consistent with the previous systematic review conducted in Sub-Saharan Africa [ 72 ].

In Burkina Faso, mothers with a knowledge on preventive objectives of immunisation were more likely to have their children immunised compared with mothers with limited knowledge [ 31 ]. In a household-level cluster survey consisting of 7815 children conducted in Nigeria that involved 40 polio high-risk districts of Nigeria, lack of maternal knowledge regarding vaccines was found to be the main reason contributing to poor childhood immunisation uptake which accounted for 50% of reasons for non-vaccination [ 57 ].

Maternal knowledge on vaccines and VPDs were also shown to influence childhood immunisation uptake in Southeast Ethiopia, where children whose mothers had a good knowledge on vaccines and VPDs were found to be three times more likely to be fully vaccinated compared with children of mothers who had a poor knowledge of vaccines and VPDs [ 16 ]. A similar finding was also found in Nigeria [ 61 ]. Maternal knowledge on child vaccine schedules was revealed to statistically influence child immunisation uptake where mothers who had knowledge on schedules of vaccines were found to be four times more likely to fully immunise their children compared with mothers who had no knowledge of vaccine schedules [ 26 , 35 , 59 ]. Mothers with knowledge of immunisation schedules may know the exact time for each childhood immunisation uptake and they might also know the benefit of timely immunisation uptake for their children. Parents who were aware of immunisation and immunisation programs were three times more likely to have their children immunised compared with their counterparts [ 20 , 25 , 37 ]. Childhood immunisation uptake can be negatively affected by the level of knowledge of mothers. The more knowledge they acquire, the higher the tendency of increasing their confidence towards childhood immunisation uptake.

Maternal attitude and self-efficacy

Studies have shown that mothers who have their child immunisation records were more likely to have their children fully immunised compared with mothers without child immunisation records [ 20 , 31 , 47 ]. In Nigeria, the poor attitude of mothers accounted for 16% of the reasons for poor childhood immunisation uptake [ 57 ]. Among 248 defaulting mothers in Ibadan, Nigeria, more than half of this group reported that the reason for defaulting was that they considered childhood immunisation to be a waste of time [ 46 ]. The children whose mothers had a positive perception towards vaccine side effects, were twice more likely to be fully immunised compared with children whose mothers had a negative perception towards vaccine side effects [ 23 ]. Many studies also reported fear of vaccine side effects influenced immunisation uptake [ 57 , 60 , 62 ]. Mothers who lacked confidence in vaccine safety, were less likely to have their children immunised [ 46 ]. Mothers with a good perception on immunisation were three times more likely to have their children fully immunised compared with mothers with a poor perception on immunisation [ 49 ]. The attitudes of mothers towards childhood immunisation uptake is influenced by their perception. This in turn can decrease their confidence regarding childhood immunisation uptake.

Maternal outcome expectations

Mothers who knew the benefits of childhood immunisation were six times more likely to have their children fully immunised compared with their counterparts [ 23 , 35 ]. Having an expectation towards the protection that follows childhood immunisation significantly influences childhood immunisation [ 54 ]. Furthermore, knowing the seriousness of VPDs was also found to be a predictor for non-compliance [ 45 ]. The more knowledge mothers acquired with regards to the benefit of child immunisation and consequences of not immunising a child, the higher the tendency of increasing their practice confidence towards childhood immunisation uptake. This finding is consistent with the findings from a systematic review previously conducted that aimed to identify factors associated with immunisation coverage in poor urban areas and slums [ 73 ].

Environmental factors

Environmental factors are classified as social factors and health care systems or logistic factors. Religious belief was revealed to be one of the social factors influencing childhood immunisation uptake in Mozambique. Mothers who considered immunisation as unacceptable in their religion were less likely to have their children fully immunised compared with mothers who did not consider immunisation as unacceptable in their religion [ 44 ]. Lack of adequate involvement by religious and traditional leaders in immunisation activities was found to be a reason for immunisation failure in Borno State, Nigeria [ 64 ].

In Nigeria, cultural beliefs against immunisation are found to be destructive towards childhood immunisation uptake [ 56 , 60 ]. This could probably be due to the circulation of false information via the use of either family or religious networks towards vaccines. For example, beliefs that vaccines were composed of anti-fertility drugs and therefore could destroy the eggs of females and cause damage to the reproductive system [ 70 ]. Traditional and religious leaders are highly respected and are generally regarded and accepted as the custodians of traditions entrusted to them to provide traditional guidance to their respective communities. Therefore, their involvement in immunisation activities will help increase immunisation acceptance and uptake since the community trust their views on various matters [ 64 ].

In Kenya, distance to health facilities was found to affect childhood immunisation uptake among 298 respondents. Children belonging to mothers or caregivers who travelled a short distance to the health facility for immunisation were 18 times more likely to be fully vaccinated compared with children whose mothers or caregivers travelled further to a health facility for their children’s immunisations [ 26 ]. This was supported by three studies conducted in Mozambique and Ethiopia [ 16 , 44 , 67 ]. These findings were in line with the previous systematic review conducted in Sub-Saharan Africa [ 72 ]. The mode of transportation for immunisation was also found to be an influencing factor where mothers who make use of public transport were twice more likely to have their children fully immunised compared to mothers who walked [ 40 ].

Accessibility of vaccination sites was found to be a predictor for childhood immunisation uptake in Southern Ethiopia. Mothers who considered immunisation sites to be accessible were 5 times more likely to have their children fully immunised compared to mothers who did not consider it accessible [ 29 ].

Satisfaction with vaccine services was also found to influence childhood immunisation uptake in Tanzania among 380 mothers of children aged 12–23 months. Mothers who are satisfied with vaccine services were about three times more likely to have their children vaccinated compared with mothers who were unsatisfied with vaccine services [ 28 , 56 , 60 , 64 ]. The way vaccine providers behave could either enhance or discourage mothers from taking their children for vaccinations [ 28 ].

The quality of the vaccine provider and client relationship was also found to be a predictor for childhood immunisation uptake in Tanzania among 380 participants. Mothers who had a positive perception towards quality of vaccine provider and client relationship were twice more likely to have their children fully immunised compared to mothers who had a negative perception towards quality of vaccine provider and client relationship [ 28 ]. This could probably be due to the way vaccine providers behave which may either enhance or discourage mothers from taking their children for vaccinations [ 28 ].

In Nigeria, the unavailability of vaccines when required was also found to be another reason for defaulting on childhood immunisation uptake [ 56 , 60 , 68 ]. Mothers may have spent a considerable amount of money in order to access health care on several occasions. However, the service was not always available which resulted in them becoming discouraged and they failed to complete the immunisation uptake of their children [ 56 ].

The findings of the study will benefit policy makers in making decisions and formulating appropriate guidelines and policies with regards to childhood immunisation uptake in Africa. These findings can also enable other researchers to plan an appropriate health education intervention encompassing an appropriate health behavioural theory to address the factors affecting childhood immunisation uptake among African countries. The strengthening of childhood immunisation policies, strategies and further research examining the causal relationship on childhood immunisation in Africa are required.

Social cognitive theory (SCT) is one of the health theories commonly used in health education interventions [ 74 , 75 ] which describes human behaviour through the influence of personal and environmental factors [ 76 ]. The theory accounts for human behaviour, cognition and environment and is the only health theory that takes into account reciprocal interaction, unlike other theories such as Information-Motivation-Behavioural Skills model [ 74 , 77 ]. In this systematic review, there are many factors that has been found to influence childhood immunisation uptake in Africa such as personal factors (parental sociodemographic factors, obstetric factors, knowledge gaps, negative attitudes, outcome expectation and lack of self-efficacy) and environmental factors (social factors and healthcare system) [ 16 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 70 ]. Therefore, using this theory may enable researchers to address both the personal and environmental factors influencing childhood immunisation uptake.

The majority of our included studies achieved at least high scores [ 16 , 18 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 43 , 44 , 45 , 48 , 50 , 51 , 52 , 55 , 57 , 58 , 59 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ] and the overall risk of bias was moderate in ten studies [ 15 , 19 , 39 , 46 , 47 , 49 , 53 , 54 , 56 , 60 ]. Moreover, none of the included studies revealed either a serious or low risk of bias.

Our study has acknowledged some limitations. This review may be prone to publication bias as grey literature/unpublished literature and studies that are not published in the English language were not considered. Conducting a quantitative meta-analysis in this systematic review may be very important for analysing quantitative trends. The majority of the literature cited in this review is observational in nature and therefore, this study is lacking evidence for causation. Furthermore, many studies relied on survey data which may increase the risk of nonresponse bias or selection bias.

In conclusion, various factors influencing childhood immunisation uptake in Africa were identified from this systematic review. The factors were categorised into two main groups, modifiable and non-modifiable factors which were later divided further. The modifiable factors (obstetric history, maternal knowledge, maternal attitude and self-efficacy and maternal outcome expectation) were revealed as having a direct relationship with the childhood immunisation uptake. Many factors and results attained from this review could enable the researchers to further understand and develop necessary intervention in order to address the issue of the factors influencing childhood immunisation uptake. Finally, we recommend an immunisation health education intervention among pregnant women focusing on the significant findings from this systematic review which may hopefully improve childhood immunisation uptake among countries with poor coverage in Africa.

Availability of data and materials

All data generated during this study are included in this article.

Abbreviations

Adjusted Odd Ratio

Confidence Interval

Adjusted Prevalence Rate

Ethiopia Demographic Health Surveillance

Nigeria Demographic Health Surveillance

Farafenni Health and Demographic Surveillance

Nairobi Urban Health and Demographic Surveillance System

Tanzania Health and Demographic Surveillance System

Nouna Health and Demographic Surveillance System

Uganda Demographic Health Surveillance System

Tetanus Toxoid

Antenatal Care

Postnatal Care

Vaccine Preventable Diseases

Expanded Program on Immunization

National Program on Immunization

Routine Immunization

Health Extension Workers

Oral Polio Vaccine

Expanded Programme on Immunization

Adjusted Prevalence Ratio

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The authors gratefully acknowledge electronic database searches done using Sultan Abdul Samad Library, Universiti Putra Malaysia.

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ANG conceived the study with NZ, and SS advised on the methods. ANG undertook the searches and titles for screening. ANG, NZ and SS agreed final inclusions and undertook data extraction. ANG, NZ, SS and NA contributed to write-up and editing of the final paper. All authors have read and approved the final version of this manuscript.

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Database search terms used; Fig. 1: PRISMA flow diagram for the identification, screening, eligibility, and inclusion of studies; Table 1: Eligibility criteria table; Table 2: Operational definition; Table 3: Summary of systematic review factors influencing childhood immunisation uptake.

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Galadima, A.N., Zulkefli, N.A.M., Said, S.M. et al. Factors influencing childhood immunisation uptake in Africa: a systematic review. BMC Public Health 21 , 1475 (2021). https://doi.org/10.1186/s12889-021-11466-5

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To introduce vaccine safety and efficacy, the two main public concerns for vaccine use. This is a review of the literature including but not limited to scientific publications and government documents that are related to vaccine safety and efficacy. The publication dates range from 1984 to 2020. Vaccine safety and efficacy are the two main concerns of vaccine use. The Food and Drug Administration (FDA) has a rigid policy for vaccine licensure and strict surveillance after vaccine deployment to ensure the safety of the vaccine. Vaccine efficacy is a critical criterion of the vaccine pre-licensure clinical trials and post-licensure surveillance. Double-blind, randomized, and clinical controlled studies and case-controlled studies are the two main methods to evaluate the vaccine efficacy. In this study, knowledge of vaccine safety and efficacy from numerous studies and researches are combined to provide an overall view and facilitate the understanding of vaccines. Vaccine administration is essentially a parental or personal decision. It is important to inform the public about the importance and benefits of vaccinations. As the number of vaccines increases, there is a need for a universal framework for vaccine assessment to facilitate international communications and encourage interdisciplinary studies. Vaccine inventions for contagious diseases like COVID-19 are urgent.

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Too little but not too late: Results of a literature review to improve routine immunization programs in developing countries

• Tove K Ryman 1 ,
• Vance Dietz 1 &
• K Lisa Cairns 1  

BMC Health Services Research volume  8 , Article number:  134 ( 2008 ) Cite this article

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Globally, immunization services have been the center of renewed interest with increased funding to improve services, acceleration of the introduction of new vaccines, and the development of a health systems approach to improve vaccine delivery. Much of the credit for the increased attention is due to the work of the GAVI Alliance and to new funding streams. If routine immunization programs are to take full advantage of the newly available resources, managers need to understand the range of proven strategies and approaches to deliver vaccines to reduce the incidence of diseases. In this paper, we present strategies that may be used at the sub-national level to improve routine immunization programs.

We conducted a systematic review of studies and projects reported in the published and gray literature. Each paper that met our inclusion criteria was rated based on methodological rigor and data were systematically abstracted. Routine-immunization – specific papers with a methodological rigor rating of greater than 60% and with conclusive results were reported.

Greater than 11,000 papers were identified, of which 60 met our inclusion criteria and 25 papers were reported. Papers were grouped into four strategy approaches: bringing immunizations closer to communities (n = 11), using information dissemination to increase demand for vaccination (n = 3), changing practices in fixed sites (n = 4), and using innovative management practices (n = 7).

Immunization programs are at a historical crossroads in terms of developing new funding streams, introducing new vaccines, and responding to the global interest in the health systems approach to improving immunization delivery. However, to complement this, actual service delivery needs to be strengthened and program managers must be aware of proven strategies. Much was learned from the 25 papers, such as the use of non-health workers to provide numerous services at the community level. However it was startling to see how few papers were identified and in particular how few were of strong scientific quality. Further well-designed and well-conducted scientific research is warranted. Proposed areas of additional research include integration of additional services with immunization delivery, collaboration of immunization programs with new partners, best approaches to new vaccine introduction, and how to improve service delivery.

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Immunizations are a cornerstone of public health: the World Health Organization (WHO) estimates, that in 2006, immunizations saved two to three million lives [ 1 ]. Nonetheless, in that same year 1.4 million children are estimated to have died from vaccine preventable diseases (measles, Haemophilus influenzae type B [Hib], pertussis, tetanus, yellow fever, and poliomyelitis), a reflection of the incomplete coverage with existing vaccines that persists in many parts of the world [ 1 ]. In 2006, of the 157 WHO member states defined as "developing", only 42 (27%) had three doses of diptheria-pertussis-tetanus (DPT) coverage greater than 80% in all districts [ 2 ]. At the same time, new opportunities exist to strengthen immunization coverage in developing countries, such as increased funding through platforms such as the Global Immunization Vision and Strategy (GIVS), as well as novel ideas for integration with other health services. These recent developments have encouraged a macro-analytic approach to ensure that systems function so that children receive needed vaccines. While these new approaches are welcomed, at the micro level, immunization service delivery in health facilities needs to be strengthened.

Immunization programs need continued support with proven strategies and fresh approaches to reduce the incidence of diseases that may be prevented through the use of traditional vaccines, and to permit the effective introduction of new vaccines. There are 23 new or improved vaccines for children and adolescents in development [ 3 ]. Integrating these vaccines into routine programs will substantially increase the needed expenditure on routine immunizations. To fully take advantage of these new vaccines it is essential to identify and utilize proven strategies for improving routine immunization programs at the service delivery level. Despite the attention that global immunization has attracted in recent years in terms of the introduction of new vaccines and the strengthening of health systems, there is a clear need to ensure that program managers are aware of what strategies at the health facility level will be needed to strengthen programs. To help identify these strategies a review of gray literature and a systematic review of published literature were conducted. In this paper, we present the strategies that may be used at the community or facility level that have been shown to strengthen routine immunization programs. This review builds on two similar reviews of immunization service strategies in developing countries which were published between 2004 and 2005, one of published literature and the other of gray literature [ 4 , 5 ]. Although similar to this review, additional papers not identified by the previous reviews have been included as our approach was broader and included all papers reporting on a strategy used to strengthen routine services. For the other reviews, the existence of primary data evaluating the effectiveness or cost-effectiveness of the strategy to improve coverage was required. With this review, primary data on effectiveness of the strategy was not required for inclusion, as we wanted to identify all possible strategies since effectiveness is not always generalizable.

Although routine immunization programs and mass campaigns are complementary strategies used to increase immunization coverage, this review focused on routine immunization programs. This information will be of interest to immunization managers at national and sub-national levels, as well as those interested in increasing population coverage with other recommended health interventions.

Literature Search

We searched on-line library journal databases using 42 terms (Table 1 ) for papers published in English, French, or Spanish from 1975 through 2004, in total 11,235 papers were identified. We also searched the gray literature by requesting information from 35 websites including WHO regional databases, dissertation, theses and gray literature database websites and contacting 31 experts in the field of which 20 replied and 11 provided references. In total, close to 11,500 papers were identified, the vast majority of which were not routine immunization specific. Based on a review of titles, abstracts and executive summaries, 264 papers were collected. These papers were reviewed by one person and narrowed down to those that presented a study or project conducted to improve routine immunization programs among humans in a low- or middle-income country. Papers assessing immunization campaigns were excluded. Only 60 papers (50 published and 10 unpublished) met these criteria; these papers were then systematically reviewed.

Review Methods

The 60 papers identified through our literature search were first classified into one of three methodological groups: observational studies, studies with evaluation before and after the intervention, and studies with comparison groups. Next, each paper was rated based on a standardized assessment unique to each methodology and data were systematically abstracted. This rating was based on whether elements considered critical to the scientific quality of the study and to the reader's ability to understand adequately the intervention and its impact were present. No effort was made to validate the methods reported, for example that the sample size was correct, rather instead to confirm that the data necessary to verify methods were presented in the paper and that the methods seemed appropriate. The elements assessed included information about and appropriateness of the target population, the use of randomization in the study if appropriate, the presence of clearly defined study questions and outcomes, the identification of possible confounders, the quality of data analysis, evidence of sufficient time to evaluate the intervention, and a discussion of study limitations and how study results compared to published literature (Table 2 ). The rating ascribed to each paper that described studies with before-and-after interventions or with comparison groups represented a consensus between two reviewers while observational studies were rated by a single reviewer. The same rating was applied to all paper types, however only one reviewer was used for observational studies as many of the criteria we used in the assessment were not applicable for observational studies (e.g. methods for obtaining controls, sample size calculations, accounting for confounders, etc). Papers with a score of more than 60% (number of assessment elements reported in the paper over total elements assessed) were reported and papers with a score below this cut-off were excluded due to difficulty in interpreting the results that they presented. Furthermore papers were excluded that were found to present inconclusive results or focused on strategies to improve the overall health systems as opposed to a particular routine immunization strategy.

Only 25 papers met our criteria for inclusion in this review (Table 3 ). All of the gray literature papers were excluded; most of these papers lacked detailed information or methodology details and so received too low a score to be included. The remaining papers were grouped by the general approach used to improve immunization programs (Figure 1 ). There were numerous groupings which could have been used to organize the findings, and some papers inevitably overlap. Ultimately, we chose categories that we felt would be most beneficial and the most "user-friendly" for national and sub-national program managers to identify strategies. The four groups were: bringing immunizations closer to communities (n = 11), using information dissemination to increase demand for vaccinations (n = 3), changing practices in fixed sites (n = 4), and using innovative management practices (n = 7). In the selected papers, the most consistently reported outcome indicator was the percentage change in fully vaccinated children (FVC), although some papers used other outcomes such as percentage change in vaccination coverage for specific antigens, dropout from routine immunizations as measured by coverage for an early vaccine when compared to that of a later vaccine, or timeliness of vaccination for a specified antigen.

Review Methods . see attached file 1.

Bringing immunizations closer to the community

The studies included in this category used non-health workers to encourage people to seek immunization services, or increased access to immunization services by bringing services to communities, and additionally in some cases by increasing demand through educating communities.

Many of these papers documented how the involvement of community members can improve immunization utilization. For example, strengthening demand for immunization services was part of the Integrated Child Development Services Program in India which began in 1975. In this program one village woman for every 1000 population was selected to provide health information to village residents, maintain lists of women and children who needed immunizations, motivate families to bring children for immunizations, assist with immunizations, and follow-up on immunization side effects, as well as to provide other community services. After more than five years of implementation, the proportion of vaccinated children was higher in the intervention group than in the control group for every antigen, ranging from a 35% difference for DPT3 vaccine to a 43% difference for Bacille Calmette-Guerin (BCG) [ 6 ].

In Bangladesh and South Africa, tools were developed to assist community workers in tracking their home visits. An observational study in Bangladesh evaluated using semi-literate and illiterate local women in an urban setting to track defaulters using a color-coded tracking system, to refer them to services and accompany mothers to immunization clinics. During the 13-month intervention (1987–1988), 87% percent of children referred by these volunteers completed the recommended immunization series and 96% of women that were referred received tetanus vaccine [ 7 ]. A similar program in South Africa evaluated giving record cards to Village Health Workers (VHWs) to record home visits over a one-year period (1988) in an intervention district. VHWs used the cards to identify children to visit, document visit frequency, and track health interventions including immunizations. Sixty-seven percent of children born during the program had completed their third dose of Oral Polio Vaccine (OPV) by eight months of age compared with 50% in the cohort of children (13 to 24 months) born before the program was implemented. However, coverage with measles vaccine by 10 months of age among children aged 13 to 24 months was higher compared to children exposed to the program [ 8 ].

In two papers the use of home visits for education and/or service delivery was evaluated. In Ghana, non-health workers conducted door-to-door visits and referred all children less than five years of age to routine immunization clinics. In addition, a health worker conducted home visits for children who failed to finish their immunization series. Over a six-month period (7/1991–2/1992), the percentage of FVC increased from 60% to 85% in the intervention group, whereas in the control group coverage increased from 61% to 67% [ 9 ]. In Mexico, trained community members were used to conduct home visits during which immunization education was provided along with needed vaccines. This intervention increased the percentage of FVC less than one year of age from 21% to 77% in five months (1994), compared with the control group where coverage increased only from 30% to 35% [ 10 ].

Other successful strategies focused on increasing access to immunization services. In Kenya, school buildings were utilized as immunization centers, with an educational component provided by schoolchildren who circulated immunization information within their communities. Furthermore, mobile teams were used to increase access. Coverage outcomes varied according to population density. In high population density areas the percentage of FVC increased from 54% to 82% and in low density areas it increased from 25% to 57% over an unspecified period. Coverage at follow-up in comparison high density areas was 69% compared to the 82% and in low population density areas 27% compared to the 57% [ 11 ]. In a district of Papua New Guinea, health post staff were trained in administering immunizations to permit vaccines to be given closer to rural communities. In this study, conducted between 1983 and 1987, measles coverage increased from 4% to 75% in the intervention district, compared with the control district where coverage increased from 5% to 58% [ 12 ]. In Nigeria, access to immunization services was improved by increasing the number of locations offering immunizations and adding mobile clinics in the evenings. The area in which this intervention was conducted saw an increase in FVC from 5% to 43% over a two-year period (1984–1986) [ 13 ].

Conflict areas are generally difficult to reach because of security concerns. Three papers evaluated strategies that provided immunizations in conflict areas of Mozambique. Strategies involved using bush planes to gain access to people, providing incentives to attract people to immunization sites, going house-to-house to motivate parents to bring their children for immunization, and working with communities to coordinate provision of services [ 14 – 16 ].

Using information dissemination to increase demand for vaccination

Information can be provided through numerous channels to either increase awareness of the benefits of immunization or to promote participation. These strategies increase demand for vaccination without changing the service delivery. Mass communication campaigns have the potential to reach large numbers of people, if access to the type of media selected is good. In the Philippines, a mass media campaign focusing on measles vaccination delivered through routine services was evaluated. An increase in the percentage of FVC from 54% in 1989 to 65% in 1990 was reported; this increase was attributed to the impact of the media campaign [ 17 ]. In Bangladesh, an increase in immunization coverage was linked to the use of inter-personal communication among mothers participating in a non-government organization (NGO) credit program that encouraged child immunization without providing additional immunization services. Increased coverage of several antigens was reported among the children of women who participated in the NGO program relative to the children of women who did not participate in the NGO program. For example, in 1995, measles coverage was 68% among children of participants compared with 59% in children of non-participants [ 18 ]. In the West Bank providing information at the local level through training community members regarding immunizations and providing resource rooms with information on immunization did not increase vaccine coverage, however the timeliness of immunizations, defined as children receiving vaccines at the appropriate age, improved (1985–1996) [ 19 ].

Changing practices in fixed sites

Improved quality of health facility practices can increase coverage through reducing dropout (children that start the vaccination series, but did not complete the series) and missed opportunities (children that were available for vaccination, but that were not vaccinated). In Ethiopia, the use of reminder stickers for parents resulted in decreasing dropout between DPT1 and DPT2 to seven percent in the intervention district compared with 13% in the comparison district during 1992 [ 20 ]. A study conducted in Sudan compared two methods to reduce missed opportunities for vaccination: moving the immunization location close to the consultation room in the health facility to provide immediate immunizations to children who had recently been seen in consultation, and having the physician write a prescription for immunizations during curative visits. Each method resulted in an increase of 32% more children being vaccinated during the intervention week than during the week prior to the intervention [ 21 ]. An urban Nigerian health center increased coverage of children fully vaccinated by one year of age by 18% in 1982 through reducing wait times by creating a quick immunization line [ 22 ]. In a Mexican children's hospital the missed opportunities for immunization were reduced by immunizing all hospitalized children who were not up-to-date with their vaccines. This led to the number of childhood immunizations delivered monthly increasing from 150 to 600 in 1991 [ 23 ].

Using innovative management practices

Reviewed papers addressed two management issues: who should manage immunization systems and how systems might be improved to provide the highest quality services. In Cambodia, increased coverage and improved equity were achieved by contracting immunization services to NGOs in selected districts (1997–2000). Although these districts had higher immunization coverage and improved equity compared to immunization programs run by the Ministry of Health, the annual per capita cost of contracting out services was almost twice that of providing services through the Ministry of Health [ 24 ].

Coverage can also be increased through better use of data and community information. In Bolivia, high-risk populations in selected communities were visited biannually from 1992 to 1994 and members of these populations assisted in identifying their priority health problems. Among these targeted populations, 78% percent of children aged 12 to 23 months were fully vaccinated in established programs compared with only eight percent in comparable populations in control communities [ 25 ]. Similarly, in Papua New Guinea health staff met to determine how best to improve services. They redefined health facility catchment areas and built a reporting system to collect accurate and meaningful data. These interventions were associated with an increased coverage of DPT2 from 64% in 1980 to 89% in 1984 [ 26 ].

Other management methods have been used to improve service quality. In Indonesia, experienced nurses in well-performing health centers peer-trained nurses in poorly-performing health centers (1993–1994). This intervention was low-cost and was associated with increases in coverage for all antigens, such as an increase of 25 percentage points in measles coverage in health centers participating in this program as compared to health centers that did not participate [ 27 ]. In Madagascar, in 2000, the use of auto-disable syringes was found to improve the availability of immunizations. Health workers were more willing to vaccinate on non-immunization days since the additional work of syringe and needle sterilization was not required. Missed opportunities for vaccination were thus reduced and coverage was increased. Use of auto-disable syringes also improved injection safety [ 28 ]. In Nicaragua, food incentives were introduced (1985) to create demand for immunization services. Mobile outreach without food incentives had 63% attendance but when food incentives were added, attendance increased to 102%. The coverage >100% was described as most likely occurring because of census errors, as mechanisms were put in place to reduce the opportunity for ineligible children to receive the food incentives. A static clinic achieved 94% attendance with food incentives [ 29 , 30 ].

A striking finding from this literature review was the paucity of well-conducted studies examining ways in which routine immunization programs in developing countries may be improved through interventions at the community or facility level. Despite an exhaustive literature search through which we identified greater than 11,000 papers, only 25 were ultimately eligible for inclusion in this review, of which only four projects were conducted in the last ten years. Furthermore, many of these 25 papers were of only moderate scientific quality. This may be in part because scientific research was not the primary purpose of the activity that many of the papers reported. Nonetheless, this situation is surprising in light of the fact that the Expanded Program on Immunization (EPI) has existed for more than a quarter of a century, and the importance and cost-effectiveness of achieving high population coverage with vaccines has been repeatedly recognized [ 31 ].

Although every paper included in this review aimed to show an improvement in immunization coverage, a wide range of indicators were used to measure success. A meta-analysis could not be conducted due to the variety of indicators reported. Some strategies were implemented in areas where baseline coverage was relatively high, thus limiting the potential increase in coverage. Other strategies were evaluated in places with low baseline coverage, and thus had the potential to result in large coverage increases. For these reasons, it is difficult to determine which strategies were most successful. Furthermore, some strategies may be more successful in certain social or health care settings than others. It is challenging to determine the generalizability of the findings, as less than half of the papers included a complete discussion of findings including topics such as comparison of findings from other similar studies.

The 25 papers identified reveal how community and facility-based strategies to strengthen routine immunization programs may result not only in increased vaccination coverage, but in other benefits. For example, projects designed to increase coverage were associated with improved timeliness of vaccination, improved knowledge regarding vaccines, improved quality, and increased equity.

Evidence from the papers suggests non-health workers can provide numerous services including education, mobilization, and tracking of target populations. Often these non-health workers are very successful because of their community knowledge, the respect they are given by the community, and the fact that they have access to community members who may not be reached by mass media such as radio or television. Community members can be used to promote specific antigens based on their expertise; for example, Traditional Birth Attendants (TBAs) may be best at increasing coverage of vaccines delivered early in life (i.e., BCG, DPT1). Home visits by non-health – worker volunteers can be very successful at motivating parents to utilize immunization services. During house visits, these volunteers can identify families not utilizing services; these families can then be followed-up by health workers.

In general, the sustainability of interventions as perceived by papers' authors was not addressed in the papers reviewed, and few programs were evaluated for enough time to determine sustainability. Given the number of interventions relying on volunteers, sustainability is of particular concern. Researchers should evaluate the residual impact of the intervention, to better understand the sustainability of the project. For example evaluating if the program resulted in change in infrastructure or practices that would continue to improve immunization coverage after the project was over. In this paper, no data have been presented on the cost-effectiveness of the various interventions discussed. These data have not been included since the two other reviews, previously mentioned [ 4 , 5 ], have reviewed and published the cost-effectiveness, as well as effectiveness, of various immunization service strategies.

Our literature review had a number of limitations. Although we attempted to conduct a thorough search for papers, those not readily available through databases, or on the web may have been missed. Furthermore the literature-gathering process was conducted through the use of a computer from an office; a more complete review may have been achieved through visiting locations to access literature in person [ 5 ]. The methods used to assess the quality of papers and thus determine their eligibility for inclusion in this review may have been biased toward published papers as many gray literature papers did not discuss the study methodology used in enough detail to allow it to be assessed. As such, no gray literature papers were included in this review. Furthermore, the majority of papers, published and unpublished, reported positive results, thus excluding opportunities to learn from unsuccessful interventions.

Additional Research

Although a wide range community and facility-based strategies to strengthen immunization programs were covered in the papers reviewed, there remain many areas for further research. Some of the topics we felt were lacking from the papers reviewed may not be specific to immunization and as such were not identified through our search strategy. For example, we found few studies related to health facility management, facility staffing, or community financing of health facilities. However, it seems likely that such studies exist. Topic areas which we identified as important and were likely not missed due to our search strategy were highlighted as needing further research (Table 4 ). Attention to these areas will be important as immunization services are integrated with other health interventions and new vaccines are introduced. Studies should strive to use rigorous scientific methods, for example by calculating minimum sample sizes based on clearly articulated assumptions, assessing confounders, using control areas when appropriate, using randomization to select intervention areas, and using statistical tests as indicated in data analysis. Furthermore, the results of these studies should be widely disseminated. In addition to peer-reviewed publication, studies can be disseminated through Interagency Coordinating Committees, newsletters, WHO regional bulletins, and press releases.

This paper summarizes the literature in terms of what is reported to have been successful in improving routine immunization programs through community and facility-based interventions over the past thirty years. Information obtained from well conducted scientific studies will be crucial to assist program managers to implement strategies to achieve high coverage. These activities coupled with the attention being given to the health systems approached advocated by the GAVI Alliance and other donors will be crucial to ensure that all levels of the immunization system function effectively. The potential health improvements from vaccines will continue to increase as new vaccines become available and as the price of these vaccines becomes more affordable. Nonetheless, as the true impact of vaccination depends heavily on the ability of immunization programs to reach every targeted individual without clear local delivery strategies countries will not be in a position to take full advantage of the potential for reduction of disease. Data from these papers confirms the need for well managed immunization programs providing high quality accessible services in conjunction with community demand. These key elements are also the basis of the WHO Reaching Every District (RED) strategy [ 32 ], a broad, all-encompassing approach covering five areas of immunization programs. Findings from this paper also indicate that all elements of an immunization program need to be addressed. For example, easily-accessed, high-quality services will not be utilized if community demand is lacking. With this in mind, it is critical to build upon lessons from the past and to continue to conduct research on how high vaccination coverage can be achieved in every community.

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The authors are grateful to Karen Wilkins, Elizabeth Luman, Steve Hadler, Philip Brachman, and Aaron Wallace.

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TKR: Made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. Has also been involved in drafting the manuscript, revised it critically for important intellectual content and given final approval for the version to be published. VD: Made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. Has also been involved in drafting the manuscript, revised it critically for important intellectual content and given final approval for the version to be published. KLC: Has been involved in drafting the manuscript, revised it critically for important intellectual content and given final approval for the version to be published.

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Ryman, T.K., Dietz, V. & Cairns, K.L. Too little but not too late: Results of a literature review to improve routine immunization programs in developing countries. BMC Health Serv Res 8 , 134 (2008). https://doi.org/10.1186/1472-6963-8-134

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COVID-19 Vaccination and the Rate of Immune and Autoimmune Adverse Events Following Immunization: Insights From a Narrative Literature Review

Naim mahroum.

1 International School of Medicine, Istanbul Medipol University, Istanbul, Turkey

2 Zabludowicz Center for autoimmune diseases, Sheba Medical Center, Ramat-Gan, Israel

3 St. George School of Medicine, University of London, London, United Kingdom

Aviran Ohayon

Ravend seida, abdulkarim alwani, mahmoud alrais, magdi zoubi, nicola luigi bragazzi.

4 Laboratory for Industrial and Applied Mathematics (LIAM), Department of Mathematics and Statistics, York University, Toronto, ON, Canada

Despite their proven efficacy and huge contribution to the health of humankind, vaccines continue to be a source of concern for some individuals around the world. Vaccinations against COVID-19 increased the number of distressed people and intensified their distrust, particularly as the pandemic was still emerging and the populations were encouraged to be vaccinated under various slogans like “back to normal life” and “stop coronavirus”, goals which are still to be achieved. As fear of vaccination-related adverse events following immunization (AEFIs) is the main reason for vaccine hesitancy, we reviewed immune and autoimmune AEFIs in particular, though very rare, as the most worrisome aspect of the vaccines. Among others, autoimmune AEFIs of the most commonly administered COVID-19 vaccines include neurological ones such as Guillain-Barre syndrome, transverse myelitis, and Bell’s palsy, as well as myocarditis. In addition, the newly introduced notion related to COVID-19 vaccines, “vaccine-induced immune thrombotic thrombocytopenia/vaccine-induced prothrombotic immune thrombotic thrombocytopenia” (VITT/VIPITT)”, is of importance as well. Overviewing recent medical literature while focusing on the major immune and autoimmune AEFIs, demonstrating their rate of occurrence, presenting the cases reported, and their link to the specific type of COVID-19 vaccines represented the main aim of our work. In this narrative review, we illustrate the different vaccine types in current use, their associated immune and autoimmune AEFIs, with a focus on the 3 main COVID-19 vaccines (BNT162b2, mRNA-1273, and ChAdOx1). While the rate of AEFIs is extremely low, addressing the issue in this manner, in our opinion, is the best strategy for coping with vaccine hesitancy.

Introduction

Considered one of the fastest processes of manufacturing vaccines ever, “Coronavirus Disease 2019” (COVID-19) vaccines were discovered, studied, and produced in terms of months since the declaration of COVID-19 as a pandemic by the World Health Organization (WHO) ( 1 ). While the burden of the outbreak alongside the support of the governments were the main motivations for the accelerated vaccine production, the process itself aroused concerns regarding the safety of the COVID-19 vaccines and contributed to mistrust in health authorities as well as in the vaccines themselves ( 2 , 3 ). Interestingly, distrust in COVID-19 vaccines was reported even before the vaccines were available ( 4 ). It is of great importance to mention that vaccines are highly effective in reducing the burden of infectious diseases as the history clearly shows ( 5 , 6 ), and the COVID-19 pandemic is likely to follow a similar trend after the roll-out of the COVID-19 vaccination has been fully implemented, globally. However, the fear of the lay public for adverse events following immunization (AEFIs), especially those of severe and long-term features, may constitute the main obstacle in successfully fighting against COVID-19 vaccine hesitancy ( 7 , 8 ). This is especially true for autoimmune and immune-mediated AEFIs such as idiopathic thrombocytopenia (ITP), or immune thrombocytopenia, Guillain-Barré syndrome (GBS), and transverse myelitis (TM), among others. Therefore, it is crucial to address the mounting concern by reviewing the past, present, and possible future AEFIs of vaccines in general and COVID-19 vaccines in particular, especially as millions were already vaccinated around the world, and more data has accumulated regarding the safety profile of the COVID-19 vaccines ( 9 ). Addressing AEFIs of autoimmune nature covers, to a great extent, the concerns generated by the public explicitly considering vaccine booster programs endorsed by the health authorities. The importance of facing and addressing public concerns in dealing with vaccine hesitancy cannot be overemphasized ( 10 ).

We hereby present a detailed, narrative literature review covering the various types of vaccines, their immune-mediated AEFIs, and we focus on the autoimmune AEFIs described in correlation with the main COVID-19 vaccines in use worldwide, that is to say, those most administered (approximately 95% of those delivered). The rarity of the AEFIs among vaccinated people, and the risk of severe complications that COVID-19 carries, are the key factor for fighting against vaccine hesitancy.

Types of Vaccines, Adverse Events Following Immunization, and COVID-19 Related Vaccines

Vaccines that were approved or in use against COVID-19 can be classified as follows:

Inactivated Vaccines

Inactivated or killed vaccines contain a pathogen that has been inactivated after being grown in a culture. The first utilized was the cholera vaccine introduced in 1896 ( 11 ). There are two subtypes of inactivated vaccines: the traditional whole-cell vaccine and the acellular vaccine. The latter is a more modern version and contains only 3-4 antigens rather than the hundreds of microbial antigens present in the whole-cell vaccine. This antigen reduction produces a more specific immune response, thereby reducing potential AEFIs ( 12 ), such as febrile responses ( 13 ). While traditional whole virion-inactivated influenza vaccines and whole cell pertussis vaccines commonly cause febrile responses within 24 hours of immunization, the split virion influenza vaccine and the acellular pertussis vaccine showed a decreased rate of febrile illness ( 14 , 15 ). Concerning inactivated vaccines against COVID-19, the vaccine developed by the Beijing Institute of Biological Products, known as BBIBP-CorV, and referred to as Sinopharm, is an inactivated vaccine. In a randomized, double-blind, dose-escalation, controlled phases I and II trial of the BBIBP-CorV vaccine, an acceptable safety profile and a robust humoral response to the coronavirus were reported ( 16 ). The study was conducted among 18-80 years old, healthy individuals negative for serum-specific IgM or IgG antibodies against both N and S proteins of the virus. The inactivated BBIBP-CorV vaccine was immunogenic and elicited strong humoral responses, with a 100% seroconversion rate in all groups. However, lower seroconversion rates were found in the group of individuals aged 60 and older, probably due to the atrophy/ageing of the immune system ( 17 ). The degree of local and systemic AEFIs was generally mild and occurred most after the first dose of vaccination ( 18 ).

Viral Vector-Based Vaccines

Viral vectors were first introduced in relation to gene and cancer therapy but, since then, have been adapted to vaccine development ( 19 ). The utility of vector-based vaccines is determined by the capacity of viruses to infect cells ( 20 ). High efficiency gene transduction, extremely selective gene delivery to target cells, generation of powerful immunological responses, and improved cellular immunity are the advantages of viral vector-based vaccines ( 20 ). Multiple viruses ranging from very complex large DNA viruses such as poxviruses, to simple RNA viruses such as parainfluenza virus, have been deployed as viral vectors ( 21 ). Viral vector vaccines facilitate intracellular antigen expression and trigger a highly cytotoxic T-lymphocyte response ( 22 ). A significant emphasis was made on COVID-19 vaccines based on viral vectors like the AstraZeneca, Janssen/Johnson & Johnson, and CanSino vaccines ( 19 ), which are based on adenoviruses ( 23 ). In addition to the vaccines listed above, Sputnik V, also known as Gam-COVID-Vac, is a COVID-19 adenovirus viral vector vaccine ( 24 ). Injection site pain is considered the most common local AEFI of viral vector vaccines, together with headache, fatigue, muscle pain, malaise, chills, and joint pain ( 25 ).

mRNA Vaccines

Because of their high potency, ability to evolve quickly, and potential for low-cost manufacturing and safe delivery, mRNA vaccines were found to be a promising alternative to traditional vaccine techniques. In 1990, the first effective application of in vitro transcribed (IVT) mRNA in animals was described, when reporter gene mRNAs were injected into mice and protein synthesis was detected ( 26 ). However, this finding did not lead to an increase in the mRNA vaccine investment, due to concerns regarding mRNA instability, inefficient in vivo delivery, and high innate immunogenicity. Subsequently, over the past decade, the use of mRNA vaccines has been gradually implemented due to their low potential risk of infection and insertional mutagenesis ( 27 ). Actually, the concept behind the mRNA vaccine is to deliver the mRNA of the pathogen into the human body in order to trigger an immune response and produce antibodies against the pathogen. There are two types of mRNA vaccines available for prevention of infectious diseases: self-amplifying or replicon RNA vaccines (SAM) and non-replicating mRNA vaccines. SAM vaccines have the benefit of producing their own adjuvants in the form of dsRNA structures, replication intermediates, and other motifs, which may explain their high potency. Directly injectable, non-replicating mRNA vaccines are promising vaccination products due to their convenient way of administration and low cost, especially in resource-constrained environments ( 28 ). Two of the most widely distributed COVID-19 vaccines, namely the BNT162b2 (BioNTech/Pfizer) and the mRNA-1273 (Moderna), are mRNA-based vaccines. The BNT162b2 vaccine, for instance, proved to be around 95% efficient in preventing the disease, with a relatively high safety profile ( 29 ). However, mild and short-term AEFIs were reported such as pain at the injection site, fatigue, and headache. The incidence of serious AEFIs was low.

Roll-out of COVID-19 Vaccines

As herd immunity is achieved once a large portion of the population is immune against an infectious agent preventing it from widely spreading, it is a must in overcoming the COVID-19 pandemic ( 30 ). In addition, herd immunity is also necessary to protect individuals who are unable to get vaccinated such as infants, children under the recommended age, and immunocompromised individuals ( 31 ). In turn, people become immune against a specific infection in two ways, either through acquiring the infection naturally from a pathogen, or passively by vaccination. While COVID-19 can be severe and fatal, especially in people at risk such as the elderly, those with chronic cardiovascular and respiratory disease, among others ( 32 ), vaccinations is paramount in terms of preventing disease acquisition as well as its spread. The US Food and Drug Administration (FDA) authorized the first vaccine for COVID-19 on December 11 th , 2020 ( 33 ). More specifically, the first vaccine authorized was BNT162b2 (BioNTech/Pfizer COVID-19 vaccine) under the Emergency Use Authorizations (EUA). The United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) had already authorized the use of the same vaccine, some days before, on December 2 nd , 2020 ( 34 ). Subsequently, the European Union (EU) commission authorized the vaccine on December 21 st , 2020 ( 35 ). Shortly afterward, the mRNA-1273 COVID-19 vaccine (Moderna) was authorized ( 36 ). Later on, the ChAdOx1 vaccine (AstraZeneca) was authorized as well by the UK MHRA ( 37 ). The three mentioned vaccines were the most commonly used vaccines across the globe. By the end of November, 2021, approximately 55% of the world population has received at least one dose of a COVID-19 vaccine, 7.9 billion doses have been given globally, and around 27 million new doses are administered daily ( 38 ). Asia had the most doses administered at 5.09 billion doses, followed by Europe with 942 million doses, North America with 739.54 million doses, South America with 581.31 million doses, Africa with 235.45 million doses, and finally Oceania with 49.67 million doses.

Autoimmune Adverse Events Following Immunization and Their Correlation With Vaccines in General and COVID-19 Vaccines in Particular

Autoimmune neurological adverse events following immunization, guillain-barre’ syndrome (gbs).

GBS is an autoimmune disorder characterized by an immune-mediated nerve damage generally triggered by an infectious agent leading to cross-reactive antibodies attacking axonal antigens and resulting in demyelinating polyneuropathy ( 39 ). Despite its rarity, GBS is considered as the most common cause of acute flaccid paralysis worldwide ( 40 ), with about 100,000 people developing the disorder every year ( 41 ). The disease is manifested by ascending and symmetrical flaccid paralysis leading to paresthesia, autonomic dysfunction, and respiratory muscle paralysis ( 42 ). In some instances, cranial nerve involvement is also seen, causing facial diplegia ( 43 ). The complications of GBS can be fatal, including respiratory and cardiac failure ( 44 ). The mortality rate of GBS varies widely from 1-18% ( 45 , 46 ). Numerous reports have suggested a possible relationship between GBS and vaccines. However, solid evidence was not established ( 47 , 48 ). During the COVID-19 pandemic, various reports addressed the correlation between COVID-19 and GBS; nevertheless, a concrete causal relationship is yet to be established ( 40 ).

BNT162b2 (BioNTech/Pfizer) and GBS

Several case reports were published regarding GBS following the BNT162b2 vaccine. A 82-years-old female presented two weeks following her first dose ( 49 ), and a 67-year-old male seven days after the first shot ( 50 ). In addition, a 71-year-old male with Miller-Fisher syndrome (MFS), a rare variant of GBS, presented 18 days following his first dose of BNT162b2 vaccine ( 22 ). GBS was also documented following the second dose of the vaccine. For instance, a 25-year-old female developed a clinical picture of GBS few days following her second dose of the vaccine, and a 73-year-old male twenty days following the second dose of the vaccine ( 51 ). Furthermore, Ben David and colleagues ( 52 ) conducted a retrospective cohort study aimed to assess the safety of mRNA-based COVID-19 vaccine in previously diagnosed cases of GBS between 2000-2020. Based on a database from a health organization serving more than 2.5 million members, the authors found that out of 702 members who had a diagnosis of GBS, 579 received at least one vaccine dose, and only one patient presented with a relapse of GBS several days following the second dose, which represents a minimal risk. In addition, Shasha et al. ( 53 ) investigated AEFIs profile following BNT162b2 vaccine in a sample size of over 400,000 individuals, and found that only one individual in the vaccinated group had GBS versus none in the control group. Similarly, seven cases of GBS were reported following the first dose of BNT162b2 mRNA vaccine among approximately 4 million recipients (incidence of 0.18/100,000), while no cases recorded following the second dose. The study was conducted over a period of 30 days following vaccination concluding that among recipients of the BNT162b2 mRNA vaccine, GBS may occur at the expected community-based rate ( 54 ).

mRNA-1273 (Moderna) and GBS

To the best of our knowledge, only two case reports have been published regarding GBS following Moderna, mRNA-1273 COVID-19 vaccine. Both of the cases developed after the second dose. In the first case ( 55 ), the symptoms appeared two days after vaccination presented by an axonal variant of GBS. In turn, in the second case ( 56 ), the symptoms appeared 6 weeks following the vaccination, while the electrophysiological test identified a mixed axonal and demyelinating type of GBS. Furthermore, among 16 cases of acute-onset polyradiculoneuropathy that presented within 4 weeks after first dose of SARS-CoV2 vaccines, only one person received the mRNA-1273 vaccine, whereas 14 received the ChAdOx1 vaccine ( 57 ).

ChAdOx1 (AstraZeneca) and GBS

During July 2021, the European Medicines agency (EMA) recommended that GBS should be added as a warning sign on the ChAdOx1 vaccine product information, despite being unable to decisively conclude about a causal association ( 58 ). This action was in part due to multiple reports of GBS cases occurring within a month following the first dose of the vaccine ( 59 – 67 ). The series of cases caused a major concern among leading experts. In fact, the GBS cases reported after the ChAdOx1 vaccine often presented as facial diplegia and paresthesia, a rather rare manifestation of the condition, with clinical improvement after corticosteroid and intravenous immune globulins (IVIG) therapy. The cases had no known exposure to the coronavirus and tested negative upon admission. However, as a recent study found that the COVID-19 infection was unlikely to cause GBS ( 68 ), the significance is debatable. Other baseline characteristics, such as age, gender and associated morbidity differed between cases, and scholars are therefore unable to make a clear-cut connection between them. The incidence of GBS was estimated to be approximately 0.89 to 1.89 cases per 100,000 person-years ( 69 ). A recent report issued by the UK Health Security Agency concluded that the risk of developing GBS after the first dose of ChAdOx1vaccine adds 5.6 extra cases of GBS per million doses, while having no association with respect to the second dose ( 70 ). As the condition has also been linked to the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine ( 71 ), another adenoviral vector vaccination, further investigations into the pathogenesis are required as large studies about GBS rate are lacking, and conclusions should not be drawn without further analysis.

Transverse Myelitis

TM is an immune-mediated acute or a subacute inflammatory disease of the spinal cord accompanied with motor, sensory, and autonomic symptoms ( 72 ). The clinical presentation of TM varies depending on the level of the spinal cord involved as the disease is manifested below the affected segment. Patients presenting with TM can be paraplegic, most having urinary bladder function disorders and paresthesia ( 73 ). The exact etiology of TM has not been established yet. Nevertheless, different types of vaccines were formerly linked to the appearance of TM including hepatitis B vaccine, MMRV and others ( 74 ). Most of the cases documented occurred between several days to several months from vaccination however, longer durations were also recorded.

BNT162b2 (BioNTech/Pfizer) and Transverse Myelitis

Actually, little evidence with no obvious association exists regarding the appearance of TM after the administration of BNT162b2 COVID-19 vaccine. Case reports include a 75-year-old Japanese patient who presented with TM 3 days following the first dose of the BNT162b2 vaccine ( 75 ). The authors could not elucidate a clear association between the vaccine and the clinical presentation and concluded that more epidemiological studies are needed. Furthermore, among more than 700,000 individuals who received the first dose of the BNT162b2 vaccine in Mexico, only 2 cases of TM were documented, equal to a rate of 0.28 per 100,000 cases ( 76 ).

mRNA-1273 (Moderna) and Transverse Myelitis

Concerning the mRNA-1273 COVID-19 vaccine, case reports of ADEM ( 77 ), neuromyelitis optica ( 78 ), and acute TM ( 79 ) were reported. Ismail et al. ( 80 ) reviewed central nervous system (CNS) demyelination disorders among recipients of various COVID-19 vaccinations. A total of 32 cases were registered. Among the cases, higher rates of women (68.8%) than men and a median age of 44 years were noticed. Moreover, most of the cases (71.8%) occurred following the first dose whereas more than a half of the cases had a previous history of immune-mediated diseases (53.1%). As for TM in particular, 6 cases occurred after receiving the mRNA-1273 vaccine. According to the same study, the other vaccines possibly correlating with TM were as follows: 11 cases following BNT162b2 vaccine, 8 after ChAdOx1 vaccine, 5 after Sinovac/Sinopharm vaccines, and one after each of the Sputnik and the Janssen/Johnson & Johnson vaccines.

ChAdOx1 (AstraZeneca) and Transverse Myelitis

During the phase 3 clinical trial of the ChAdOx1 vaccine, 3 participants were diagnosed with TM ( 81 ). As a result, the trial was temporarily paused enabling further investigations. Two of the cases were determined to be unrelated to the vaccine, the first one had pre-existing, undiagnosed multiple sclerosis; and the other was in fact in the control group with his symptoms appearing over 68 days post vaccination ( 82 ). As experts concluded the phenomenon was unlikely to be related to the vaccination the trial resumed however, the incidents raised global concerns regarding the safety profile of the ChAdOx1 vaccine. The longitudinally extensive TM (LETM) is a rare subtype of TM, in which the damage extends over 3 or more vertebrae ( 83 ). Reports regarding the LETM subtype started to emerge following the worldwide distribution of the COVID-19 vaccines ( 84 – 88 ). All cases occurred in patients under 60 years of age who presented with neurological symptoms starting within 3 weeks of receiving the first dose of the ChAdOx1 vaccine. As the COVID-19 infection was previously implicated in inducing acute TM ( 89 ), all reported cases tested negative on standard PCR testing. Furthermore, all cases completely recovered after treatment with either high dose corticosteroids or plasma exchange and were subsequently discharged.

Bell’s Palsy

Bell’s palsy, or facial nerve palsy, is the partial (paresis) or total (paralysis) loss of function of the facial nerve ( 90 ). The etiology of Bell’s palsy is most commonly idiopathic but may occur due to several factors such as viral infections (herpes viruses), ischemia, inflammatory and immune-mediated diseases ( 91 ). Bell’s palsy is divided into central facial palsy and peripheral facial palsy ( 92 ). Central palsy is characterized by contralateral sensory disturbances, as well as dry mouth. In turn, peripheral palsy is characterized by ipsilateral paralysis of the eyelid and forehead muscles.

In a case-control study from Switzerland which aimed to assess the correlation between the inactivated intranasal influenza vaccines and Bell’s palsy ( 93 ), a significantly increased risk of Bell’s palsy was found among vaccinated people. The risk of developing Bell’s palsy was 19 times higher than the control group. As a result, the vaccine was withdrawn from clinical use.

BNT162b2 (BioNTech/Pfizer) and Bell’s Palsy

The safety database of the BNT162b2 vaccine revealed a slight increase in the cases of Bell’s palsy in vaccinated individuals ( 94 ). There were 4 cases of Bell’s palsy in the vaccine group compared to none in the placebo group. As the rate was as expected in the general population, no causal relationship was established. Reviewing the reported safety data concluded that mRNA-based vaccines might be associated with Bell’s palsy ( 95 ). Accordingly, several case reports highlighted a similar association, including a healthy 37-year-old male who had Bell’s palsy several days following the first BNT162b2 vaccine dose ( 96 ). In addition, different population-based studies which investigated the adverse effects of the BNT162b2 vaccine reported an increase in the frequency of Bell’s palsy as well. For instance, in a nationwide study from Israel which analyzed more than 800 thousand people, the incidence of Bell’s palsy was higher in the vaccinated group compared to the control group, but without significant results ( 97 ). Similarly, Shibli and colleagues ( 98 ) researched a database of Bell’s palsy cases occurring within 21-days after the first dose and 30-days after the second dose of the vaccine in comparison to the expected cases based on a database from 2019. The authors found a slightly increased incidence of Bell’s palsy following the first dose, mainly among females aged 65 and older, with an estimated attributable risk of 4.46 per 100,000 vaccinated individuals. The study suggested an association between the vaccine and an increased risk of Bell’s palsy but with a small impact on public health. In contrast, Shasha et al. ( 53 ) reported no association between COVID-19 vaccines, including BNT162b2, and Bell’s palsy among more than 400 thousand vaccinated people compared to the control group.

mRNA-1273 (Moderna) and Bell’s Palsy

Three cases of Bell’s palsy were reported following vaccination with mRNA-1273 vaccine ( 99 – 101 ). The symptoms appeared 12 hours to 2 days after the vaccine was administered. Two cases occurred after the first dose, while one appeared following the second dose. In one patient, a prior episode of Bell’s palsy was recorded whereas the other 2 persons were healthy young people aged 35-36-year-old. Moreover, Sato et al. ( 102 ) showed that the rate of Bell’s palsy after both types of the mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) are lower or equivalent to the rate of Bell’s palsy after influenza vaccines. Additionally, a study from Singapore including 1.4 million subjects who received COVID-19 vaccination, 86.7% by BNT162b2 vaccine and 13.3% by mRNA-1273 vaccine, 11 patients were referred to hospital with Bell’s palsy and 27 patients had cranial mononeuropathy ( 103 ). According to data from the WHO pharmacovigilance database, no close association between BNT162b2 and mRNA-1273 COVID-19 vaccines and facial paralysis could be found ( 104 ).

ChAdOx1 (AstraZeneca) and Bell’s Palsy

While Bell’s palsy is a lower motor neuron disease manifesting as a unilateral facial paralysis ( 105 ), GBS may also present with facial paralysis, and most cases linked to the ChAdOx1 vaccine presented in this form ( 59 – 67 ). Therefore, it is difficult to distinguish between the two conditions. One study attempted to examine the risk of co-occurrence of Bell’s palsy and GBS following COVID-19 vaccinations and found an increased risk of co-occurrence following the ChAdOx1 vaccination ( 106 ). However, as previously mentioned, the study could not distinguish between the two conditions. Furthermore, a review of published literature failed to identify case reports of isolated Bell’s palsy linked to the ChAdOx1 vaccination. Therefore, it is impossible to draw conclusions of a possible link.

Encephalitis

Postvaccinal encephalitis was described in regard to COVID-19 vaccines. In a case series of three patients who presented with symptoms suspected of encephalitis in a range of 7-11 days of receiving the ChAdOx1 vaccine was previously documented ( 107 ). The symptoms included gait disturbance, aphasia, headaches, and seizures. As the criteria for autoimmune encephalitis was fulfilled in the three cases, treatment with systemic corticosteroids led to clinical improvement. Other causes of encephalitis including infectious agents were ruled out. All cases were mild and resolved without sequelae. Due to its rarity, the authors highlighted that the benefits of the vaccine outweigh the risks. It is noteworthy to mention hereby, that herpes simplex encephalitis was reported following ChAdOx1 vaccine ( 108 ) however, this can be regarded as an infection-related AEFI rather than autoimmune induced.

In addition, a case report of a Japanese lady admitted who developed diplopia the next day following the first dose of the BNT162b2 vaccine administration was described in the literature ( 109 ). The symptoms aggravated after the second dose of the vaccine and the patients was finally diagnosed with encephalitis based on brain MRI findings. The patient responded well and totally recovered after treatment with steroids was initiated. The authors could not prove any causal relationship in their case.

In regard to the mRNA-1273 COVID vaccine, a case report of a patient diagnosed with acute encephalitis, myoclonus and Sweet syndrome was described after receiving the first dose of the mRNA-1273 vaccine ( 110 ). The symptoms resolved following glucocorticoids treatment.

Myocarditis

Myocarditis is defined as the presence of inflammatory cellular infiltrate in the myocardium alongside tissue necrosis, which is not caused by coronary heart disease, and diagnosed by a combination of histological, immunological and immunohistochemical criteria ( 111 ). Based on etiologic factors, myocarditis can be divided into 2 subgroups: infectious, due to bacterial, viral, fungal, or parasitic infections; or non-infectious causes like autoimmunity, drugs, or vaccines ( 112 ). However, viral infections are seemingly the most common cause of myocarditis ( 113 ). Myocarditis can present with a range of symptoms from non-specific complaints such as fever and mild dyspnea, to fulminant hemodynamic imbalances and sudden death ( 114 ). In fact, myocarditis is considered as a common cause of sudden cardiac death ( 115 ). In a review article which included 1230 patients who initially had unexplained cardiomyopathy, 9% of the patients were eventually diagnosed with myocarditis ( 116 ). A link between vaccines and myocarditis was repeatedly reported in medical literature. For instance, in a review data of 35,188 individuals from the Vaccine Adverse Event Reporting System (VAERS), 8 cases of myocarditis were registered in individuals below 18 years of age, and 12 cases in elderly persons ( 117 ). However, it should be mentioned that VAERS presents some limitations, including the fact that it is a passive reporting system, and, therefore, information collected could be inaccurate, incomplete, coincidental, or unverifiable, warranting thorough epidemiological surveys to confirm such findings.

In another study designed to determine the incidence of cardiac symptoms and subclinical myocarditis/pericarditis after smallpox and trivalent influenza vaccine, out of 1081 individuals who received the smallpox vaccine, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. The study did not find any possible or probable cases of myocarditis/pericarditis following trivalent influenza vaccine however, some patients developed new cardiac symptoms like chest pain, dyspnea, and palpitations ( 118 ). One study that focused on myopericarditis following smallpox virus vaccination in the US military found that the incidence of myopericarditis was 7.5 times higher in soldiers who received the vaccine compared to the expected rate ( 119 ). Influenza vaccines as well were associated with cases of myocarditis ( 120 – 122 ). While myocarditis is well documented in regard to COVID-19 ( 123 ), the correlation with myocarditis and various types of COVID-19 vaccines is illustrated hereby.

BNT162b2 (BioNTech/Pfizer) and Myocarditis

Myocarditis was documented by several case reports in individuals after receiving the COVID-19 vaccines ( 124 – 126 ). Montgomery et al. ( 127 ) investigated the association between myocarditis and the mRNA COVID-19 vaccines in healthy military members of the US army. After approximately 2.8 million mRNA vaccine doses, 23 persons were diagnosed with myocarditis within 4 days of vaccination. Seven out of the 23 cases (30%) received the BNT162b2 vaccine and most developed the symptoms following the second dose. The study concluded that further evaluation of this rare adverse effect is warranted. Furthermore, several large-scale studies were conducted to evaluate this association in Israel. For instance, Barda and colleagues ( 128 ) evaluated 884,828 people vaccinated with BNT162b2, based on data from the largest health care organization in Israel. While the BNT162b2 vaccine was not associated with most of the side effects searched, the vaccine was strongly associated with increased risk of myocarditis. The risk was calculated as 2.7 events per 100,000 people, with highest risk among young men with a median age of 25. Another study conducted by Witberg et al. ( 129 ) searched specifically regarding the diagnosis of myocarditis among individuals in the largest health care organization in Israel that received at least one dose of the BNT162b2 vaccine. Among more than 2.5 million vaccinated members who were 16 years of age or older, the estimated incidence of myocarditis was 2.13 cases per 100,000 people. The highest incidence was documented in young male patients aged 16-29, the majority with mild to moderate disease. In addition, Mevorach and colleagues ( 130 ) followed the diagnosis of myocarditis in Israel after approximately 5.1 million people were vaccinated with two doses of the mRNA COVID-19 vaccines. A total of 283 persons developed symptoms of myocarditis, 142 (50%) occurred after the BNT162b2 vaccine, whereas 136 were eventually diagnosed with probable or definitive myocarditis. Most of the cases were mild and the highest incidence was recorded following the second dose and in young male patients aged 16-19 years. In comparison with unvaccinated people, the rate ratio 30 days after the second dose was 2.35 (95% CI, 1.10 to 5.02). The authors concluded that despite the low incidence, it increased after the BNT162b2 vaccine, all were mild in severity. Following the extension of the FDA authorization of the emergency use of the BNT162b2 vaccine to include children aged 12-16 in May 2021, Dionne et al. ( 131 ) presented a case series of 15 children with myocarditis after receiving the BNT162b2 vaccine. Similarly, myocarditis developed mainly in boys and after the second dose, all with a mild course.

mRNA-1273 (Moderna) and Myocarditis

Myocarditis is a rare post-mRNA-vaccine sequela, and was seen mostly among young, vaccinated males. Up to June 2021, around 1226 reports of myocarditis have been reported in the US after more than 296 million doses of mRNA COVID-19 vaccines administered ( 132 ). Symptoms usually began 3 days after vaccination with more than 75% of the cases happened after receiving the second dose of mRNA vaccine. The median age was 26 years of age with at least 56% of the affected people being younger than 30 years old. About 76% of the cases were found in men. Experts estimated the rate of post-vaccination myocarditis among young males aged 12-29 as 40.6 cases per million second doses of mRNA COVID-19 vaccines and 2.4 per million second doses among males aged > 30. On the other hand, a million vaccinations among young males aged 12-29 could prevent 560 hospitalizations, 138 intensive care unit (ICU) admissions, and six deaths associated with the COVID-19 infection. In turn, according to the UK MHRA, toward the end of November 2021, a total of 103 reports of myocarditis after the use of mRNA-1273 were registered. A rate of 37 suspected myocarditis cases per million doses were calculated for the mRNA-1273 COVID-19 vaccine ( 133 ). No death cases were registered. Additionally, in a study conducted by Diaz et al. ( 134 ) the mean monthly number of the cases of myocarditis during the vaccine period was found significantly higher than that before the vaccine was available (27.3 vs.16.9). The study included about 2 million subjects who received at least one dose of COVID-19 vaccine. Despite the fact that more people received the BNT162b2 vaccine than the mRNA-1273 vaccine (52.6% vs 44.4%), 55% of the cases occurred after receiving mRNA-1273 (11/20). Cases were mild, few required hospital admission, and discharged after a median of 2 days. No deaths or readmissions were reported. As mentioned earlier regarding 2.8 million doses of mRNA COVID-19 vaccines in healthy members of the US army, 23 cases of myocarditis were reported, 16 cases among persons who received the mRNA-1273 COVID-19 vaccine ( 127 ). The majority occurred after the second dose. In terms of possible pathogenetic explanation of the appearance of myocarditis, Bozkurt and colleagues ( 135 ) suggested the involvement of various mechanisms such as molecular mimicry between the viral spike protein and self-antigens. In addition, triggering of pre-existing dysregulated immune pathways in certain individuals, activation of immunologic pathways and dysregulated cytokine release, were also proposed. Regarding the higher rates of myocarditis among males, the difference in the immune response of sex hormones and underdiagnosed cases of myocarditis among women were suggested.

ChAdOx1 (AstraZeneca) and Myocarditis

While myocarditis has been extensively reported following mRNA COVID-19 vaccines, very few reports exist regarding the development of myocarditis in relation to the ChAdOx1 vaccine ( 136 ). In the latter, the patient was given a diagnosis of myopericarditis with pleuritis. The European Medicines Agency (EMA) estimated that 38 cases of myocarditis and 47 cases of pericarditis were attributed to ChAdOx1 vaccine out of 40 million vaccine doses administered in Europe until May 2021 ( 137 ). The agency ensured a monthly review of new cases but refuted the need for an accelerated investigation. In turn, the UK Health Security Agency dismissed a connection between the vaccine and reported cases, claiming that considering the extensive distribution of the ChAdOx1 vaccine in the UK, the cases are more likely attributed to the background incidence rate ( 138 ).

Vaccine-Induced Immune Thrombotic Thrombocytopenia/Vaccine-Induced Prothrombotic Immune Thrombotic Thrombocytopenia

Since the appearance of the vaccine-induced immune thrombotic thrombocytopenia (VITT)/vaccine-induced prothrombotic immune thrombotic thrombocytopenia (VIPITT) was mainly attributable to the adenoviral vector vaccines, the ChAdOx1 (AstraZeneca) and the Ad26.COV2.S (Janssen/Johnson & Johnson) vaccines, the current section starts with the AstraZeneca vaccine, then the mRNA vaccines follow.

ChAdOx1 (AstraZeneca) and VITT/VIPITT

In early 2020, as the newly authorized COVID-19 vaccinations were being distributed worldwide, cases of thrombotic events as well as thrombocytopenia following vaccination with the ChAdOx1 vaccine began to emerge ( 139 – 141 ). While the EMA and the WHO issued statements declaring the reported incidence was not enough to deduce causation and cautioning against premature pausing of vaccination programs ( 142 , 143 ), numerous European countries decided to halt the use of the vaccine pending further investigations. Subsequently, larger studies demonstrated slightly increased rates of venous thromboembolic events among the adenoviral vector vaccine recipients ( 144 , 145 ). A thorough investigation by the Pharmacovigilance Risk Assessment Committee (PRAC) introduced for the first time the notion of VITT/VIPITT ( 146 ), as a rare adverse reaction to the vaccine. VITT/VIPITT is defined as presence of venous or arterial thrombosis, thrombocytopenia, and autoantibodies (anti-PF4–polyanion or anti-PF4–heparin antibodies) within 5–30 days of vaccination with either AstraZeneca or Janssen/Johnson & Johnson COVID-19 vaccines ( 147 ). In fact, VITT/VIPITT shares many similarities with heparin-induced thrombocytopenia (HIT) as both disorders are facilitated by platelet factor 4 (PF4) autoantibodies leading to platelet activation and consumption ( 147 ). The trigger for the autoantibody formation is poorly understood, as the cases reported had no previous exposure to heparin ( 148 ), and the autoantibodies were not found to cross-react with the viral spike proteins indicating a previous infection ( 139 ). Furthermore, epidemiological data illustrated that over 85% of VITT/VIPITT cases occurred in women under 60 years of age, despite higher rates of vaccination among the elderly ( 146 ). Therefore, the findings supported the assumption that VITT/VIPITT is most likely to be an autoimmune phenomenon. While its exact pathogenesis has not been established yet, a recent study demonstrated that ChAdOx1 COVID-19 vaccine induces higher rates of inflammation and platelet activation compared to other COVID-19 vaccines ( 149 ). The VITT/VIPITT autoantibodies consequently bind to PF4 ( 150 ), a chemokine secreted from activated platelets, in a site that corresponds to the heparin-binding site. In turn, immune complexes formation induces FcγRIIA receptor mediated platelet activation leading to widespread thrombosis with secondary thrombocytopenia due to platelet consumption ( Figure 1 ) ( 148 , 150 ). As the ChAdOx1 vaccination has proven to be effective in prevention of COVID-19 infection ( 151 , 152 ), and due to the rarity of serious adverse events such as VITT/VIPITT, it is important to view this phenomenon in the proper clinical context.

The pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT). Vector-based COVID-19 vaccines, particularly ChAdOx1 COVID-19 vaccine was shown to induce platelet activation alongside platelet factor 4 (PF4) autoantibodies formation. The activated platelets secret greater amount of PF4 which binds to autoantibodies forming the PF4-IgG complex. As a result, FcγRIIA receptor mediated platelet activation leads to widespread thrombosis and secondary thrombocytopenia.

BNT162b2 (BioNTech/Pfizer) and VITT/VIPITT

Since the mass vaccination campaign began with the BNT162b2 vaccine, several case reports have been published regarding the combination of thrombotic events together with thrombocytopenia, in a form of cerebral venous sinus thrombosis, VITT/VIPITT, and acquired thrombotic thrombocytopenic purpura (TTP) several days following vaccination with the BNT162b2 vaccine ( 153 – 162 ). In a large-scale study based on national data made up of 29,121,633 vaccinated individuals with the first dose of BNT162b2 vaccine ( 163 ), the association between VITT/VIPITT occurring as post-vaccine and post-infection was investigated. Among the enrollees, 9,513,625 were vaccinated with the BNT162b2 vaccine, and 1,758,095 were in the post-infection group as they were previously infected with COVID-19. An increased risk of arterial thromboembolism, cerebral venous sinus thrombosis, and ischemic stroke after the BNT162b2 vaccine was found however, an even higher risk of these associations was documented following COVID-19 infection. The study concluded an increased risk of hematological and vascular events for short-time intervals following the BNT162b2 vaccine. Still, most of these events were substantially higher and more prolonged after COVID-19 infection than after vaccination in the same population. In contrast, in another large-scale study using a national prospective cohort in Scotland with regard to hematologic and vascular events following vaccination with various vaccine types, no positive correlations were found between BNT162b2 and thrombocytopenic, thromboembolic, and hemorrhagic events ( 164 ).

mRNA-1273 (Moderna) and VITT7VIPITT

Cases of ITP and TTP after mRNA-1273 COVID-19 vaccine have been documented since the early vaccination campaign ( 165 – 168 ). A flare of familial thrombocytopenia has been reported as well ( 169 ). In addition, 13 cases of thrombocytopenia following 16 million doses of mRNA-1273 were found in the USA, suggesting a rate of 0.8 cases per million ( 170 ). Lee et al. ( 171 ) discussed 20 cases of thrombocytopenia among 20 million people who were vaccinated by at least one dose of the BNT162b2 or the mRNA1273 vaccines. A total of 17 cases considered new-onset ITP, and 11 out of the 20 cases received mRNA-1273. Furthermore, in a study based on the WHO Vigibase which includes 361 million COVID-19 vaccinated people, 2161 thrombotic events were noted, 325 of the cases appeared after the mRNA-1273 vaccine ( 172 ). Among the 325 thrombotic events, only 8 had associated thrombocytopenia. Regarding VITT/VIPITT, a German study assessed the rate of cerebral sinus and venous thrombosis (CVT) within 1 month of the first dose of the BNT162b2, ChAdOx1 and mRNA‐1273 COVID-19 vaccines and the frequency of VITT/VIPITT as the causing mechanism ( 173 ). The authors identified 45 cases of CVT, none of the cases occurred after the administration of mRNA-1273. Similar findings were shown by Krzywicka et al. ( 174 ) as out of 213 European patients with CVT, only one patient received the mRNA-1273 vaccine. According to the same study, out of 107 patients who had CVT alongside thrombocytopenia, no patient received the mRNA-1273 vaccine. In addition, only 5 possible cases of CVT were reported in Europe among 4 million subjects who received the mRNA-1273 vaccine ( 175 ). In summary, the risk of thrombocytopenia and thrombotic events in mRNA-1273 vaccinated people appears to be very low. In fact, the incidence of CVT among people vaccinated with the mRNA COVID-19 vaccines, both the BNT162b2 and mRNA-1273, was shown to be lower than that among people infected with COVID-19 (4.1 vs 39 per million) ( 176 ).

Other Autoimmune Side Effects

Immune thrombocytopenia.

ITP is a well-known autoimmune hematological condition characterized by a substantial reduction in peripheral platelet count to less than <100,000/microL due to platelet destruction by antiplatelet antibodies ( 177 ). Patients generally asymptomatic, may have minor mucocutaneous bleeding, and not uncommonly progress to life-threatening hemorrhages in severe cases ( 178 ). ITP was reported in correlation to COVID-19, COVID-19 vaccines, as well as other vaccines ( 179 , 180 ).

Minimal Change Disease

Minimal change disease (MCD) is a histologically based renal pathology which is the leading cause of idiopathic nephrotic syndrome in adults and children ( 181 ). As cases of MCD were described after vaccination in the past ( 182 – 184 ), the reporting of cases following COVID-19 vaccines were not unforeseen.

BNT162b2 (BioNTech/Pfizer) and MCD

Several case reports have been published regarding new-onset or relapse of MCD following vaccination with the BNT162b2 vaccine. A 50-year-old healthy male presented with nephrotic syndrome and acute kidney injury four days following the first dose of the BNT162b2 vaccine ( 185 ). The diagnosis was confirmed by kidney biopsy. Renal function returned to normal within few days following treatment with corticosteroids. Following this report, similar cases in older people were presented ( 186 , 187 ). The symptoms appeared seven days following the first dose of the vaccine. MCD was confirmed by kidney biopsy as well. In addition, a relapse of MCD was also described in a patient diagnosed with MCD 20 years prior to vaccination, developed proteinuria after vaccination, which resolved within 2 weeks following corticosteroids and cyclosporine treatment ( 188 ).

mRNA-1273 (Moderna) and MCD

Though autoimmune renal AEFIs of the mRNA-1273 COVID-19 vaccine were reported, MCD was not common among them. For instance, Thappy et al. ( 189 ) presented a case of 43-year-old man who developed symptoms of minimal change disease 7 days after receiving the first dose of the mRNA-1273 vaccine. The biopsy confirmed concomitant MCD and IgA nephropathy. The patient responded well to oral steroid treatment. In addition, biopsy proven IgA nephropathy, both as new onset and flare, was previously described following the mRNA-1273 COVID-19 vaccine, manifesting as hematuria ( 190 , 191 ). Interestingly, the symptoms appeared 1-2 days after the second dose of the vaccine.

ChAdOx1 (AstraZeneca) and MCD

Several cases of MCD were described in the context of the ChAdOx1 vaccine ( 192 – 194 ). All these cases presented with a clinical picture of nephrotic syndrome that started up to 15 days after the first dose of the vaccine. The fairly short period from vaccination to presentation could be attributed to cytokine release by activated T-cells, as the ChAdOx1 vaccine has been shown to induce a robust T-cell response in most individuals ( 195 ). However, as the reported cases were limited, a definite conclusion could not be drawn. The number of cases of MCD following the vaccine was small, thus a strong association could not be inferred.

As for vasculitis, two cases of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis after the second dose of the mRNA-1273 COVID-19 vaccine were reported. As a result of the new onset ANCA vasculitis, one patient became dependent on dialysis ( 196 ), while in the other case renal improvement was achieved after plasma exchange, pulse steroid and cyclophosphamide therapy ( 197 ). Additional case of ANCA vasculitis which manifested as renal failure together with pulmonary hemorrhage 3 weeks after the first dose of mRNA-1273 was also described ( 198 ).

Miscellaneous

Autoimmune hepatitis was reported as well among individuals vaccinated with various types of COVID-19 vaccines ( 199 – 202 ). In a multicenter study conducted in several countries during the early implementation of the program of vaccination against the COVID-19, Watad and colleagues ( 203 ) investigated the association between new-onset or flares of immune-mediated diseases 28-days following mRNA COVID-19 vaccination. The authors detected 27 cases; 17 (63%) had flares of their illnesses whereas 10 (37%) cases had a new-onset disease. In total, 23 (85%) patients received the BNT162b2 vaccine, 2 (7.5%) received the mRNA-1273 vaccine, and 2 (7.5%) received the ChAdOx1 vaccine. Taking into consideration the great proportion of people vaccinated, the authors concluded that immune-mediated diseases flares or new-onset temporally associated with COVID-19 vaccination are rare. Furthermore, Ishay et al. ( 204 ) presented a case series of patients with new-onset or flares of autoimmune AEFIs after the BNT162b2 vaccine. Eight patients presented with either symmetric polyarthritis, panuveitis, pericarditis, temporal arteritis-like disease, fever of unknown origin (FUO), oligoarthritis, and myocarditis following either the first dose (62.5%) or the second dose (37.5%) of the vaccine. Based on their findings, the authors concluded that immune AEFIs might occur following vaccination however, they usually follow a mild course.

A brief summary of the studies addressing autoimmune AEFIs of the most utilized COVID-19 vaccines, including the study population and the conclusion of the works, is presented in Table 1 .

Table 1

A brief summary of studies addressing immune and autoimmune side effects of COVID-19 vaccines.

Immune and autoimmune AEFIs after COVID-19 vaccines are rare and mostly non-life-threatening. Their rate follows 1 out of 3 possibilities, either it is very low, or similar to the occurrence rate in the general population, or even much lower in comparison to the COVID-19 infection itself. Of AEFIs mentioned, Bell’s palsy and myocarditis seemingly have the greatest risk when it comes to the mRNA-based COVID-19 vaccines however, in addition to their rarity, the disease course is mild and full recovery is the rule. In turn, GBS and VITT/VIPITT were found to be associated mainly with the adenovirus vector based COVID-19 vaccines, still with a low rate. Addressing this sort of AEFIs, their severity, and long-term effects of the COVID-19 vaccines while fighting against vaccine hesitancy is of great importance. Doubtlessly, such efforts will decrease public concern, increase vaccination coverage rate, and guide physicians towards the rapid identification of AEFIs, reassuring patients, and applying appropriate treatment in a timely manner.

Author Contributions

NM: Supervision, Writing- Review and Editing. NL: Writing - Original Draft, Software. AO: Writing - Original Draft. RS: Writing - Original Draft. AA: Writing - Original Draft. MA: Writing - Original Draft. MZ: Writing - Original Draft. NB: Conceptualization, Writing- Review and Editing. All authors contributed to the article and approved the subitted version.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Literature review of HPV vaccine delivery strategies: considerations for school- and non-school based immunization program

Affiliations.

• 1 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: [email protected].
• 2 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
• PMID: 24295804
• DOI: 10.1016/j.vaccine.2013.11.070

School-based vaccination is becoming a more widely considered method of delivering HPV immunizations to an adolescent population; however, many countries do not have experience with delivering adolescent vaccines or school-based programs. This literature review will summarize the experiences from countries implementing non-health facility-based and health facility-based vaccination programs and assess HPV vaccine coverage. In October 2012, a systematic search in PubMed for studies related to the evaluation of national/regional, pilot, or demonstration HPV immunization programs that worked within existing health system yielded nine articles, representing seventeen countries. School-based programs achieved high HPV vaccination coverage rates in 9 to 13-year-old girls across the different studies and geographic locations, suggesting non-health facility-based programs are possible for HPV vaccine introduction. Grade-based, compared to age-based, eligibility criteria may be easier to implement in school settings. More studies are needed to explore the methods to standardize estimates for HPV vaccine coverage so that programs can be appropriately evaluated.

Keywords: HPV vaccine; School-based vaccination; Vaccine delivery strategies.

Copyright © 2013 Elsevier Ltd. All rights reserved.

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