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Tadount F, Doyon-Plourde P, Rafferty E, et al. Is there a Difference in the Immune Response, Efficacy, Effectiveness and Safety of Seasonal Influenza Vaccine in Males and Females? – A Systematic Review. Vaccine 2020; 38: 444-459.
Children's Hospital (Vancouver, B.C.). Vaccine Evaluation Center
Children's Hospital (Vancouver, B.C.). Research Institute
University of British Columbia. Division of Infectious Diseases
Tadount, Fazia
Doyon-Plourde, Pamela
Rafferty, Ellen
MacDonald, Shannon
Sadarangani, Manish
Quach, Caroline
Introduction: Seasonal influenza is an important cause of morbidity and mortality, despite being vaccine-preventable. Sex factors (genes and hormones) seem to impact individuals’ susceptibility to infectious diseases and their response to vaccination. However, most vaccine studies do not explicitly assess sex differences in vaccine response, but rather adjust for sex. Methods: We conducted a systematic review to analyze immunogenicity, efficacy, effectiveness and/or safety of seasonal influenza vaccine data stratified by sex. We searched PubMed, EMBASE, CINAHL, Web of Science and clinicaltrials.gov for observational studies and phase III/IV trials from January 1990 to June 2018, published in English or French. Two reviewers independently screened all references, then proceeded to data extraction and quality assessment using the Cochrane tools (RoB and ROBINS-I) on included studies. Results: Of the 5,745 citations retrieved, 46 studies were included in the SR. Overall, 18 studies assessed immunogenicity, 1 estimated efficacy, 6 measured effectiveness and 25 evaluated safety of seasonal influenza vaccine in females and males (four studies reported on two sex-stratified outcomes concomitantly). Conclusion: No clear conclusion could be drawn regarding the effect of sex on the immunogenicity and effectiveness of seasonal influenza vaccine, but higher rates of adverse events following immunization (AEFIs) were reported in females. The heterogeneity of data and studies’ low quality prevented us from conducting a meta-analysis. There is a need to emphasize on the appropriate use of the terms sex and gender in biomedical research. Evidence of higher quality is needed to better understand sex differences in response to influenza vaccine.
1 "This is the peer reviewed version of the following article: Tadount F, Doyon-Plourde P, Rafferty E, et al. Is there a Difference in the Immune Response, Efficacy, Effectiveness and Safety of Seasonal Influenza Vaccine in Males and Females? – A Systematic Review. Vaccine 2020; 38., which has been published in final form at 10.1016/j.vaccine.2019.10.091. This article may be used for non-commercial purposes in accordance with Elsevier Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Elsevier or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Elsevier’s version of record on Science Direct and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Science Direct must be prohibited.1 Is there a Difference in the Immune Response, Efficacy, 2 Effectiveness and Safety of Seasonal Influenza Vaccine in 3 Males and Females? – A Systematic Review 4 5 Fazia Tadount, M.Sc. 1,2 6 Pamela Doyon-Plourde, B.Sc. 1,2 7 Ellen Rafferty3 8 Shannon MacDonald3 9 Manish Sadarangani4,5 10 Caroline Quach, MD, M.Sc., FRCPC 1,2,6,7 11 12 1Department of Microbiology, Infectious Diseases, and Immunology, Faculty of Medicine, 13 University of Montreal (QC) Canada 14 2Research Institute – CHU Sainte Justine, Montreal (QC) Canada 15 3Faculty of Nursing, University of Alberta, Edmonton (AB) Canada 16 4Vaccine Evaluation Center, BC Children’s Hospital Research Institute, Vancouver (BC) Canada 17 5Division of Infectious Diseases, Department of Pediatrics, University of British Columbia, 18 Vancouver (BC) Canada 19 6Department of Pediatric Laboratory Medicine, CHU Sainte-Justine, Montreal (QC) Canada 20 7Infection Prevention & Control, CHU Sainte-Justine, Montreal (QC) Canada 21 Corresponding author: 22 Caroline Quach, MD MSc FRCPC FSHEA, 23 Professor, Dept. of Microbiology, Infectious Diseases & Immunology, University of 24 Montreal 25 Centre Hospitalier Universitaire Sainte-Justine 26 3175 ch. Côte-Sainte-Catherine 27 Montréal, Québec, Canada 28 H3T 1C5 2 29 Tel 514-345-4931, 7430 30 Fax 514-345-2358 31 Email : c.quach@umontreal.ca 32 33 Keyword: Influenza, Vaccines, Sex differences, Immunity, Safety. 34 Word count: 3555 35 Abstract word count: 250 36 3 30 Abstract: 31 Introduction: Seasonal influenza is an important cause of morbidity and mortality, 32 despite being vaccine-preventable. Sex factors (genes and hormones) seem to impact 33 individuals’ susceptibility to infectious diseases and their response to vaccination. 34 However, most vaccine studies do not explicitly assess sex differences in vaccine 35 response, but rather adjust for sex. 36 Methods: We conducted a systematic review to analyze immunogenicity, efficacy, 37 effectiveness and/or safety of seasonal influenza vaccine data stratified by sex. We 38 searched PubMed, EMBASE, CINAHL, Web of Science and clinicaltrials.gov for 39 observational studies and phase III/IV trials from January 1990 to June 2018, published 40 in English or French. Two reviewers independently screened all references, then 41 proceeded to data extraction and quality assessment using the Cochrane tools (RoB and 42 ROBINS-I) on included studies. 43 Results: Of the 5,745 citations retrieved, 46 studies were included in the SR. Overall, 18 44 studies assessed immunogenicity, 1 estimated efficacy, 6 measured effectiveness and 25 45 evaluated safety of seasonal influenza vaccine in females and males (four studies reported 46 on two sex-stratified outcomes concomitantly). 47 Conclusion: No clear conclusion could be drawn regarding the effect of sex on the 48 immunogenicity and effectiveness of seasonal influenza vaccine, but higher rates of 49 adverse events following immunization (AEFIs) were reported in females. The 50 heterogeneity of data and studies’ low quality prevented us from conducting a meta- 51 analysis. There is a need to emphasize on the appropriate use of the terms sex and gender 4 52 in biomedical research. Evidence of higher quality is needed to better understand sex 53 differences in response to influenza vaccine. 54 55 Keyword: Influenza, Vaccines, Sex differences, Immunity, Safety. 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 5 79 Introduction: 80 Despite being vaccine-preventable, influenza still has an important burden of illness, 81 causing important morbidity and mortality annually, with up to 5 million cases of severe 82 illness and 650 000 deaths worldwide.[1, 2] Although data are rarely disaggregated by 83 sex and age, several reports outlined a higher incidence of seasonal influenza infections 84 and hospitalization rates in males compared to females of different ages.[3-5] 85 “Sex” refers to the biological difference between males and females, while the term 86 “gender” is used in a sociocultural and behavioral context.[6] Susceptibility to and 87 severity of diverse infectious diseases is thought to be male-biased, mainly due to the 88 biological differences between sexes.[7-9] Sex factors (i.e. genes and hormones) 89 influence both innate and adaptive immunity in the course of viral infections, with males 90 having in general, a lower immune response than females.[8, 10-12] This sexual 91 dimorphism has also been observed following immunization against several pathogens, 92 and females tend to exhibit a greater immune response accompanied by a higher 93 incidence of adverse events.[13] 94 Additionally, it has been demonstrated that adverse events following immunization 95 (AEFIs) are barriers to influenza vaccine uptake in different population groups. 96 Interestingly, female sex was associated with higher vaccine hesitancy.[14] 97 Furthermore, sex is considered as a confounder in epidemiological studies, i.e. a covariate 98 associated with both exposure and outcome.[15] Statistical adjustment is necessary to 99 generate more accurate estimates: multivariate analysis as well as stratification are 100 appropriate methods to control for confounding.[15, 16] Although multivariate models 101 are mostly used, doing so provides a unique adjusted effect measure from which the 6 102 effect of sex has been eliminated. Stratification, on the other hand, provides an effect 103 measure for each sex stratum, and thus enables a comparison of the effect between 104 sexes.[17] 105 It has been suggested that the hypothesized higher immunogenicity in females may 106 logically be accompanied by an increase in the incidence of AEFIs, which in turn, may be 107 linked to vaccine hesitancy.[14, 18] Moreover, an improved quantification of sex 108 differences in influenza vaccine outcomes would enable more targeted use of the various 109 vaccine formulations for different sub-groups in the population.[19] 110 There is currently a knowledge gap in sex-related vaccine outcomes as data are rarely 111 stratified by sex [20]. We therefore conducted a systematic review to assess the 112 consensus of the published literature on sex differences in immunogenicity, efficacy, 113 114 effectiveness and safety of the seasonal influenza vaccine in adults. 115 Methods: 116 Protocol registration, search strategy and study selection 117 The research question for this systematic review was adapted in a PICOT format 118 (Population, Intervention, Comparator, Outcomes, Time). “P” consisted of healthy adults 119 18 years of age and older, “I” was seasonal influenza vaccine, “C” included any other 120 intervention (i.e. influenza vaccine, placebo or no intervention), “O” were defined as 121 immunogenicity, efficacy, effectiveness and safety of the vaccine that occurred during 122 the influenza season “T”, as defined by surveillance data for each study area. 7 123 A search strategy was developed in collaboration with a research librarian. We searched 124 five electronic databases: PubMed, EMBASE, CINAHL, Web of Science and 125 ClinicalTrials.gov, using a combination of the following terms and their derivatives: 126 “influenza” OR “seasonal influenza”; “vaccine” OR “immunization”; “immunogenicity” 127 OR “efficacy” OR “effectiveness” OR “safety” OR “AEFI” OR “SAE”; “sex factors” OR 128 “gender factors”. The initial strategy was created on PubMed, then adapted for the other 129 databases. The full search strategy is shown in Appendix I. Once retrieved and 130 deduplicated, unique citations were screened at the title and/or abstract level, then 131 selected ones were assessed for eligibility at the full-text level. The screening and 132 selection process were independently carried out by two reviewers (FT and PDP). We 133 evaluated the inter-observer agreement between both reviewers at each level by 134 computing a Kappa statistic. 135 The protocol for this systematic review was registered on the National Institute for Health 136 Research international prospective register of scientific reviews (PROSPERO - ID: 137 CRD42018097380) 138 Study eligibility 139 Eligible studies were phase III randomized-controlled trials (RCTs), observational and 140 phase IV post-licensure studies published between January 1st, 1990 and June 1st, 2018 in 141 English or French. We included studies for which data were stratified by sex (i.e. 142 comparing females vs. males). Study populations consisted of adults ≥ 18 years old. If 143 data were not stratified by age, at least 90% of the population had to be 18 years and 144 older for the study to be eligible. We did not restrict on health status or setting. As we 145 focused our research question on seasonal influenza vaccine, studies on the H5N1 and 8 146 pandemic 2009 H1N1 vaccines as well as those conducted during 2009-2010 were 147 excluded. Our primary outcome was Influenza vaccine immunogenicity; efficacy, 148 effectiveness and safety were secondary outcomes. 149 We included studies that evaluated influenza vaccine immunogenicity during the 2-4 150 weeks following immunization using the hemagglutination inhibition (HAI) or 151 microneutralization (MN) assay. Vaccine efficacy or effectiveness (VE) were defined 152 against RT-PCR or viral culture confirmed influenza infections. Adverse events 153 following immunization (AEFIs) were recorded during the first month following vaccine 154 administration. AEFIs were local reactions, systemic reactions or any AEFIs. Influenza 155 vaccine-related serious adverse events (SAEs) such as Guillain-Barré syndrome (GBS) 156 were also reported. (Supplementary 2) 157 Data Extraction 158 Data were independently extracted by FT and PDP on an electronic form with the 159 following items: study characteristics, population characteristics, season, type of 160 influenza vaccine, statistical methods, type of outcome assessed and effect measures for 161 each outcome, as follows: pre and post vaccination geometric mean titres (GMTs) and 162 geometric mean fold rise (GMFR) for influenza vaccine immunogenicity. We log- 163 transformed HAI titres to compute GMTs, when they were not initially provided in the 164 study. We also computed GMFRs when both pre and post vaccinations GMTs were 165 available. Odds ratio (OR), risk ratio (RR) and/or vaccine efficacy/effectiveness (VE) 166 estimates were extracted. Finally, safety measures as reported in each study were 167 collected (proportions, incidence rates, attack rates, RR and ORs comparing females to 168 males). 9 169 In some studies, the authors only described observed sex differences for their outcomes 170 of interest. Precise estimates were requested from the contact author of each study, after 171 three follow-up emails, if data were not available or authors did not respond, we included 172 qualitative findings. 173 Quality Assessment 174 Once data were abstracted, both reviewers independently assessed the quality of each 175 study using the Cochrane tools (RoB2.0 for randomized studies and ROBINS-I for non- 176 randomized studies).[21, 22] We did not evaluate the risk of bias for qualitative 177 outcomes. 178 Most included studies were not primarily designed to investigate sex differences in the 179 response to influenza vaccine, therefore the estimated immunogenicity and VE were not 180 adequately adjusted for some important confounders. This led us to evaluate the risk of 181 bias (for non-randomized studies) with respect to the outcomes we collected, 182 independently of those for which the study was designed. For example, studies that 183 assessed sex differences in the immunogenicity of the vaccine without considering the 184 effect of age (i.e. not adjusted or stratified by age group) and the immune history of 185 participants were deemed at serious risk of bias. This judgment was driven by the several 186 studies that demonstrated how sex hormones and their differential expression across ages 187 affect the immune system,[23-25] and the impact of vaccination history on the immune 188 response to novel exposures.[26]. Sex stratified VEs had to be at least adjusted for age, 189 health status and vaccination history to be deemed at low or moderate risk of 190 confounding bias. 10 191 Finally, we evaluated the quality of evidence and strength of recommendations for each 192 clinical outcome using the GRADE tool.[27] 193 Screening, data extraction and quality assessment were conducted using DistillerSR 194 (Evidence Partners, Ottawa, Canada). Disagreements between reviewers were resolved 195 by consensus. If a consensus could not be reached, a third reviewer (CQ) arbitrated. 196 Data Analysis 197 We performed a descriptive analysis of the included studies. We summarized principal 198 studies characteristics and major findings into tables. We created forest plots for VEs and 199 stratified them by study design. Immunogenicity data were analyzed according to four 200 subgroups: healthy young adults (18 to 49 years old), medically-stable adults (with wider 201 age ranges), older adults (50 years of age and older) and unhealthy cohorts. 202 Results: 203 We retrieved 8789 records from all searched databases. After deduplication, 5745 unique 204 citations remained, and the screening revealed 46 eligible studies that were included in 205 our systematic review.[28-72] Overall, 18 studies assessed immunogenicity [29, 31, 32, 206 34, 39, 40, 42, 45, 46, 50, 51, 55, 58, 63, 67, 68, 72, 73], 1 estimated efficacy [31], 6 207 measured effectiveness [30, 38, 41, 48, 49, 66] and 25 evaluated safety [28, 33, 35-37, 208 42-44, 47, 51-57, 59-62, 64, 65, 69-71] of seasonal influenza vaccine in females and 209 males (four studies reported on two sex-stratified outcomes concomitantly [31, 42, 51, 210 211 212 55]). (Figure 1) 11 213 Study Characteristics: 214 Overall, 31 observational studies, 11 phase III RCTs and 4 phase IV randomized studies 215 were included in our systematic review. They were carried out between the 1991-1992 216 and the 2016-2017 influenza seasons in North America (50%), Europe (30.4%), Asia 217 (15.2%) and Australia (4.3%). 218 Identified populations were adults 18 years of age and older. Nineteen studies (41.3%) 219 included medically stable adults of all ages, seventeen (37%) were exclusively conducted 220 on elderly populations, six (13%) comprised patients with underlying medical conditions, 221 and finally four studies (8.7%) focused on predominantly healthy young adults with age 222 ranging from 18 to 49 years of age. (Table 1) 223 Within-study risk of bias: 224 Overall, seven (15.2%) studies were deemed at low risk of bias, fifteen (32.6%) at 225 moderate, fifteen (32.6%) at serious risk of bias and five (10.9%) at critical risk of bias. 226 Four studies were qualitative, and thus were not assessed for risk of bias. (Table 2) 227 In observational designs, eight studies were deemed at serious and critical risk of 228 confounding bias, as estimates were crude or not adjusted for all known confounding 229 variables. No information on adjustment was available for ten studies. Selection bias was 230 strongly suspected in five studies, mainly safety studies where participants may be more 231 inclined to return questionnaires if they experienced AEFIs compared to those who did 232 not. Finally, five studies were at risk of outcome measurement errors principally when 233 recall bias was suspected in self-reported outcomes. Three randomized trials had unclear 12 234 randomization and/or concealment processes and five were subject to outcome 235 measurement errors. (Supplementary 4) 236 Summary of findings: 237 Immunogenicity: 238 Seventeen studies assessed sex differences in the immunogenicity of seasonal influenza 239 vaccine (Table 2). We extracted 444 effect measures: pre, post vaccination GMTs and/or 240 GMFR for each influenza strain, as available. (Supplementary 2) 241 In the young healthy adults subgroup, Jackson et al. reported lower immune response in 242 females compared to males for influenza H1N1 strain in the 2005-2006 season but 243 noticed no differences in the following season (2006-2007)[31], whereas Barrett et al. 244 and Rivera et al. observed no sex differences.[29, 50] 245 In a cohort of medically stable adults, with wider age groups, Looker et al. outlined 246 higher immunogenicity for influenza B strain in males [45]. Furman et al. reported 247 greater antibody response in females compared to males for H3N2 and B influenza 248 strains, while adjusting for the effect of age[73]. However, no differences between males 249 and females were noticed in similar studies.[39, 42, 51, 68] 250 Cook et al. reported a significantly higher immunogenicity in females for all influenza 251 strains in the intramuscular injection group of an elderly participants cohort, but no 252 differences were found in the subcutaneous injection group.[55] A higher antibody 253 response was also observed in females by Falsey et al. in both high and standard vaccine 254 dose groups.[32] No sex differences were reported in other studies conducted in older 255 adults.[34, 40, 72] 13 256 Finally, Hara et al. reported significantly higher antibody titres for the H1N1pdm09 strain 257 in females with severe motor and intellectual disability.[67] Further studies conducted on 258 unhealthy cohorts observed no sex differences.[46, 58, 63] 259 Heterogeneity of studies’ populations, absence of stratification by age groups and the 260 lack of precision in reported effect measures (i.e. CIs) prevented us from conducting a 261 meta-analysis. 262 Efficacy and effectiveness: 263 Efficacy was measured in one phase III RCT while effectiveness was assessed in five 264 observational studies. (Figure 2) 265 Jackson et al. outlined a significantly higher average influenza vaccine efficacy in healthy 266 young males compared to females: VEM = 89% (97.5% CI lower band 53.0%); VEF = 267 19.4% (97.5% CI lower band -42.8%) (p = 0.0123).[31] 268 The test-negative design (TND) was used to estimate VE in elderly groups. We extracted 269 two adjusted VE measures: Talbot et al. and Kwong et al. reported no sex differences 270 between males and females [aVEM = 63.7% (-48.9%, 91.2%), aVEF = 60.1% (1.8%, 271 83.8%)] and [aVEM = 43% (22% - 58%), aVEF = 44% (25% - 58%)], respectively. [30, 272 49] Crude VE estimates were computed in four studies [38, 41, 48, 66] and no sex 273 difference was observed. (Table 2) 274 Effectiveness studies’ low quality (66.7% were crude VE estimates) hindered generation 275 276 277 of pooled sex-stratified VE estimates. 14 278 Safety: 279 Overall, measures from twenty-five studies were collected (Appendix II.2). Local 280 reactions were recorded in ten studies, systemic reactions were measured in thirteen and 281 any AEFIs reported in twelve. Two studies assessed SAEs. (Table 2) 282 Influenza vaccine seems to cause more local reactions in females compared to males. 283 Indeed, of ten studies that evaluated local reactions, nine reported significantly higher 284 rates in females. [28, 33, 42, 51, 54, 55, 60, 64, 70] Differences were mainly seen in site 285 injection pain, soreness, tenderness and redness/swelling. However, Robb et al. observed 286 no sex differences in injection site soreness reactions.[65] 287 Systemic reactions were recorded in thirteen studies. Females experienced more systemic 288 reactions in five studies, including headache and fatigue.[28, 42, 43, 47, 55] Three other 289 studies investigated risk factors for the occurrence of oculo-respiratory syndrome (ORS). 290 While Boulianne et al. [71] observed a 2-fold higher risk for ORS in females [aORF = 2.1 291 (1.1 – 4.2)], De Serres et al. and Scheifele et al. reported no sex differences in the 292 incidence of ORS.[57, 59]. Studies were carried out in different seasons: Boulianne’s in 293 2000-2001 and the two others in the 2001-2002 season, which may explain part of the 294 difference. No differences between males and females were found in the other studies 295 investigating systemic reactions.[33, 35, 64, 65, 70] 296 When comparing the incidence of any AEFI in males and females, Scheifele, et al. 297 described a higher incidence of AEFIs in females [59], Govaert et al. also reported a 30% 298 rate of adverse events in elderly females and 15% in older males in their phase III 299 RCT.[36] In a healthcare workers (HCW) cohort, Hajiabdolbaghi, et al. reported an OR 300 (95% CI) of 1.97 (1.13 – 3.46) for females.[33] Similar findings were reported by 15 301 McEvoy et al. and Spila-Alegiani et al. and van Balveren-Slingerland et al. with an OR 302 (95% CI) of 1.64 (1.22 – 2.22), 1.9 (1.8 - 2.0) and 2.55 (1.98 – 3.27) for females, 303 respectively.[62, 69, 70] Phengxay et al. recorded 13.6% (11.1 – 16.2) AEFIs in females 304 and 9.3% (6.0 – 12.6) in males.[44] Conversely, Zheng et al. observed greater rates of 305 AEFIs in males, however, results were not statistically significant as the study was 306 underpowered, and females were underrepresented.[37] Further studies found no sex 307 differences in safety of seasonal influenza vaccine.[52, 54, 56, 65] (Figure 3) 308 Guillain-Barré syndrome (GBS) is a rare serious event following influenza vaccine. Two 309 studies assessed sex differences in the occurrence of GBS. Burwen et al. observed higher 310 incidence of definite, probable or possible GBS cases in males compared to females.[53] 311 However, Lasky et al. reported equal incidence of GBS in both sexes.[61] 312 Due to heterogeneity of collected effect measures, data were not pooled in a meta- 313 analysis. 314 Risk of Bias Across Studies 315 We used the GRADE approach to evaluate the quality of evidence provided for each 316 clinical outcome included in our systematic review. We recorded moderate certainty for 317 immunogenicity when measures were extracted from randomized trials and very low 318 certainty in those recorded in observational studies. We did not evaluate certainty for 319 vaccine efficacy, as only one RCT was included. However, certainty was very low for 320 vaccine effectiveness. Finally, randomized trials provided moderate certainty for safety 321 outcomes while observational studies provided very low certainty. These findings were 322 mainly due to the risk of bias in included studies and the strongly suspected publication 323 bias, as seldom studies do stratify findings by sex. (Table 3) 16 324 Discussion 325 Females and males are different, and so is their immune system. There is growing 326 evidence showing sex differences in both humoral and cellular response to infections and 327 vaccines. [7-12, 74] 328 This is the first systematic review to investigate sex differences in response to seasonal 329 influenza vaccine in adults. Forty-six studies were included to assess differences in the 330 immunogenicity, efficacy, effectiveness and safety of influenza vaccine, between males 331 and females. 332 Several studies reported significantly higher immunogenicity in females compared to 333 males in healthy young adult, adults of all ages and older adult cohorts. These results 334 were consistent with the findings of a large phase II trial published by Engler et al. that 335 demonstrated that in healthy adults, 18 to 49 years of age receiving full and half dose of 336 the 2004-05 TIV, females had an almost 2-fold higher HI antibody GMT compared to 337 males. The same trend was also observed in older adults after the administration of a full 338 dose of TIV.[75] Yet, two studies in our systematic review described a greater immune 339 response in males. 340 It is important to stress that most of the included studies did not look at GMTs by age 341 group nor did they adjust for it. Although not very well investigated, males and females’ 342 immune system likely evolve differently with age and thus, their response to vaccines 343 may differ.[23] Other variables such as the previous vaccination history may interfere[26, 344 76]. For example, if in a given study females were more exposed to influenza virus 345 antigens (whether after vaccination or natural infection) compared to males, sex 346 differences can be muted. This can explain the weakened immune response observed by 17 347 Jackson et al. in females, the latter having slightly higher previous immunization rates for 348 the two previous years, compared to males.[26, 31] 349 We collected sex-stratified VE estimates against laboratory confirmed influenza 350 infections. Whereas Jackson et al. observed in their RCT a higher efficacy in males, 351 along with greater immune response, effectiveness measured in test-negative design 352 studies, did not appear to differ between males and females. However, most of these 353 findings were crude estimates, and hence were at high risk for confounding bias. In 354 observational studies, the test-negative design is widely used to evaluate vaccines 355 effectiveness as it allows to minimize selection bias that arises from differential health- 356 seeking behaviours in vaccinated and non-vaccinated individuals. Yet, when 357 investigating sex differences through this design, caution is warranted. Some gender 358 differences may interfere. There is evidence that men show a delayed help and health 359 seeking behaviour when experiencing illness compared to women, [77] which may 360 introduce a selection bias as cases and controls in the test-negative design are originally 361 derived from a population of subjects who seek care for acute respiratory illness (ARI). 362 [78] Men with mild symptoms may not consult for ARI and thus, would not be tested for 363 influenza whereas those seeking healthcare – sicker – are more likely to test positive for 364 influenza. Gender could interfere in the evaluation of sex-stratified VE when studied 365 through a test-negative design. 366 Finally, significantly higher rates of AEFIs were mainly observed in females, particularly 367 local reactions. These findings are supported by Cook et al. who outlined higher rates of 368 injection site reactions in females in their narrative review.[79] 18 369 Nonetheless, we noticed while screening citations that most authors used sex (i.e. females 370 and males) and gender-related terms (i.e. men and women) interchangeably or used 371 “gender” terms while describing or reporting on sex as a biological phenomenon. 372 Limitations 373 The present systematic review has several limitations. First, a small number of studies 374 were eligible for inclusion for each outcome of interest and only studies in English and 375 French were selected. 376 Second, we only included studies assessing the humoral response to influenza vaccine. 377 Investigating the cellular response would help better understand the sexual dimorphism in 378 response to vaccines. 379 Third, many of the identified studies were at high risk of bias, mainly confounding bias 380 since not initially designed to investigate sex differences in their outcomes of interest. 381 Hence, effect measures were not adequately adjusted. For example, studies reporting on 382 sex differences in the immune response to influenza vaccine were downgraded if no 383 adjustment or stratification were made for age. Also, using a test-negative design to 384 estimate sex-stratified VE needs some caution, as gender differences may bias findings. 385 Further RCTs and observational studies need to address these limitations by using 386 appropriate designs and statistical methods. 387 Finally, very heterogeneous effect measures were collected, which prevented us from 388 389 390 conducting a meta-analysis. 19 391 Conclusion 392 Whereas influenza vaccination seems to be associated with more AEFIs in females 393 compared to males, the available evidence on sex differences in the immunogenicity and 394 effectiveness of seasonal influenza vaccine in adults is heterogeneous. Identified studies 395 were at risk of bias and heterogeneity of data prevented us from drawing clear 396 conclusions. An individual patient data meta-analysis of phase III RCTs would help 397 better assess and understand sex difference in response to influenza vaccines 398 (PROSPERO – ID: CRD42018112260). 399 Conflicts of interest 400 The authors have no conflicts of interest to disclose. 401 Funding 402 This work was funded by a grant from the Canadian Institutes of Health Research 403 (CIHR). 404 Contribution: 405 FT and CQ conceived and designed the research protocol. All authors drafted the 406 manuscript and approved the final version submitted for publication. 407 Acknowledgment: 408 409 410 411 We thank Monique Clar for assistance in the literature search strategy. 20 412 References 413 [1] Centers for Disease Control and Prevention. Estimated Influenza Illnesses, Medical visits, 414 Hospitalizations, and Deaths in the United States–2017–2018 Influenza Season 2018. 415 [2] WHO. Influenza (Seasonal). 2018. 416 [3] Klein SL, Pekosz, A., Passaretti, C., Anker, M., Olukoya, P. 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The test-negative design for estimating influenza vaccine 622 effectiveness. Vaccine. 2013;31:2165-8. 623 [79] Cook IF. Sex differences in injection site reactions with human vaccines. Human Vaccines. 624 2009;5:441-9. 1 1 2 Figure 1. Study selection flowchart 2 3 4 Figure 2. Sex stratified vaccine efficacy (A) and effectiveness (B) against laboratory- 5 confirmed influenza infections in adults. 6 a Average efficacy (2005-2006 and 2006—2007 seasons) 7 b Propensity score–adjusted VE: adjusted for age in y, race, smoking status, home oxygen use, underlying 8 medical conditions, immunosuppression, timing of admission relative to onset of influenza season, and 9 specific influenza season (2006–2007, 2007–2008, or 2008–2009) 10 c VE adjusted for age, rural residence, neighborhood income quintile, healthcare utilization factors 11 (number of outpatient visits and prescriptions in the past year, number of hospitalizations in the past 3 12 years, and receipt of home care services in the past year), comorbidities that increase the risk for 13 influenza complications, and month of influenza testing; 14 d mid-season estimates 3 15 16 Figure 3. Summary of reported sex differences in the occurrence of adverse events 17 following seasonal influenza vaccine. 14 12 10 8 F=M 6 M>F F>M 4 2 0 Local reactions (N = 10) Systemic reactions (N = 13) Any AEFIs (N=12) 1 Table 1. Key Characteristics of Studies included in the Systematic Review Study Country Design Season Vaccine Participants Age (in years) [Range] Sample size (% males) Outcomes Assessed‡ Immunogenicity Efficacy Effectiveness Safety Barrett, et al. [29] USA Phase III RCT (TIV vs placebo) 2008-2009 TIV-IM Healthy Young Adults 31 [18-49] 3623 (50.3%) HAI assay Day 0 Day 18-24 Cook, et al. [55] Australia Phase III RCT (IM vs SC routes) 2004 TIV-IM TIV-SC Elderly 65 of age and older, 55 and older with underlying medical condition IM group: 72.9 ±8.9 SC group: 72.4 ±8.6 Immunogenicity set: IM: 344 (48.5%); SC: 349 (51%) Safety set: IM: 356 (48%); SC: 353 (50.4%) HAI assay Day 0 Day 28-31 AEFIs: 7 days Dunkle, et al. [28] USA Phase III RCT (RIV4 vs IIV4) 2014-2015 RIV4 IIV4 Ambulatory medically- stable young adults [18-50] RIV4 : 33.3, [18- 50] IIV4 : 34 [18-49] 1330 (35.3%): RIV4: 998 (36%); IIV4: 332 (33.1%) AEFIs: 0 – 28 days SAEs: 6 months Falsey, et al. [32] USA Phase III RCT (HD vs SD) 2006-2007 2007-2008 TIV-IM (HD) TIV-IM (SD) Medically stable elderly Predominantly with chronic conditions. 73 ±6 HD group: 2576 (48.7%); SD group: 1275 (45.3%) HAI assay Day 28 Gorse, et al. [42] USA Phase III RCT (IIV4-ID vs licensed IIV3-ID1 vs investigational IIV3- ID2) 2012-2013 IIV4-ID IIV3-ID1 Lic. IIV3-ID2 Inv. Healthy adults [18-64] IIV4-ID: 41.6 ±13.2 IIV3-ID1: 41.2 ±13.5 IIV3-ID2: 41.9 ±13.3 Immunogenicity set: IIV4-ID: 1092 (38%); IIV3-ID1: 548 (38.7%); IIV3-ID2: 554 (39%) Safety set: IIV4-ID: 1672 (38.9%); IIV3-ID1: 837 (39.7%); IIV3-ID2: 846 (37.6%) HAI assay Day 0 Day 28 AEFIs: 28days SAEs: 6 months Govaert, et al.[36] Netherlands Phase III RCT (TIV vs placebo) 1991-1992 TIV Patients older than 60 from GPs practices. Heart condition: 13.5%; Lung condition: 11.3%; Diabetes mellitus: 2.3% 67 ±5.6 Median : 66 927 (45.3%) AEFIs : 48h – 4 weeks Govaert, et al.[72] Netherlands Phase III RCT (QIV vs placebo) 1991-1992 QIV Older adults 67 ±6 Median: 66 Vaccinated in 1989 and 1990: 118 (39.8%) Not vaccinated in 1989 and 1990: 788 (46.3%) HAI assay Day 0 Day 21 Jackson, et al. [60] USA Phase III RCT (standard or reduced TIV dosage by jet injector or IM) 1998-1999 TIV, Jet injector/I M Healthy adult volunteers Mean : 26.7 (95% CI 25.8-27.5) 294 (34%) AEFIs : 7 days Jackson, et al. [31] USA Phase III RCT (TIV vs placebo) 2005-2006 Good match 2006-2007 Good match TIV-IM Healthy young adults 32.7 ±9.19 [18-49] Immunogenicity Set: 1298 (37.1%) Efficacy set: 3783 (38.7%) HAI assay Day 21 Vaccine matched, culture- confirmed influenza (VMCCI) 2 Rivera, et al.[50] Dominican Republic Phase III RCT (Agrippal® vs Fluvirin®) 2007-2008 TIV-IM Healthy young adults Agrippal® : 31.2 ±8.8 Fluvirin® : 31.3 ±8.7 1507 (29.9%) HAI assay Day 1 Day 22 Scheifele, et al. [59] Canada Phase III RCT (TIV vs placebo) 2001-2002 TIV Healthy government and healthcare workers Mean: 45.7 [30-59] 651 (35%) ORS: 24h - 48h; AEFIs: 6 days Ambrose and Wu [47] USA Randomized Phase IV (LAIV vs placebo) 1997-1998 LAIV Predominantly healthy working adults [18-64] 2831 (44.3%) AEFIs: 7 days Coleman, et al. [51] Canada Randomized Phase IV (Self vs nurse administered TIV) 2010-2011 TIV-ID Medically stable adults Mean: 36.6 Median: 34 [18- 59] [18-34 yo]: 115 (22.6%) [35-59 yo]: 113 (37.2%) HAI assay Day 0 Day 21 AEFIs: 0 - 6 days Coleman, et al. [43] Canada Randomized Phase IV (Self vs nurse administered TIV) 2012-2013 TIV (IM/ID) Hospital workers Median : 42 [19- 69] 808 (28.6%) AEFIs : 7 days Gauthey, et al.[64] Switzerland Randomized Phase IV (SC vs IM) 1991-1992 TIV-IM TIV-SC Individuals over 60 years old, residing in long-term care facilities 84±8 [60 - 103] 1959 (22.2%) AEFIs : 3 days Boulianne, et al. [71] Canada Cohort 2000-2001 NA “Public servants in the Quebec Region who had received the influenza vaccine in the workplace on 24, 26 and 31 October 2000, and individuals who had been immunized at CLSCs (local community service centres), doctor’s offices or home-care centres between 27 October and 22 November.’’ 17.5% with history of allergy NA 1218 (NA) ORS: 24h Bragstad, et al. [48] Denmark TNCC 2012-2013 TIV Elderly adults ≥ 65 1443 (53%) RT-PCR confirmed Influenza Burwen, et al. [53] USA Cohort 2000-2001 2001-2002 TIV People with a Medicare claim for influenza vaccination during September–December in 2000 or 2001 NA 22.2 Million (40%) GBS: Weeks 0–6 and Weeks 9 –14 D'Alessandro, et al. [56] Italy Cohort 1999-2000 TIV Patients over 65 years old 34.2% had at least 1 comorbidity 74.5 ±6.8 16601 (44.2%) AEFIs : 72h De Serres, et al. [57] Canada Cohort 2001-2002 TIV Healthcare workers in Quebec hospitals Predominantly healthy Mean : 43 2070 (27.1%) ORS : 24h 3 Emborg, et al. [66] Denmark TNCC 2015-2016 Mismatch (B) TIV Elderly patients from Danish Microbiology Database, swabbed for Influenza A or B at GPs or hospitals. Predominantly with comorbidities. ≥ 65 3831 (51.3%) RT-PCR confirmed Influenza Fraund, et al. [63] Germany Cohort 1996-1997 TIV-IM Stable cardiac transplant recipients and healthy controls 92.4% under IS treatment Transplant Recipients: 53.6 ±10.4 Healthy controls: 50.7 ±15.19 Transplant Recipients: 79 (88.7%) Healthy controls: 109 (45%) HAI assay Day 0 Week 4 Week 8 Furman, et al. [73] USA Cohort 2008-2009 TIV-IM “Ambulatory and generally healthy adults’’ M: 63 [20 – 89] F: 68 [20 – 89] 91 (40.7%) MN assay Day 0 Day 28 Gilca, et al. [41] Canada TNCC 2014-2015 Mismatch (A/H3N2) TIV, MF-59 Elderly patients admitted to hospitals for respiratory symptoms. Predominantly with comorbidities. 81.5 [65 - 101] 314 (46.5%) RT-PCR confirmed Influenza Hagihara, et al. [46] Japan Cohort 2010-2011 TIV-SC Inflammatory Bowel Disease (IBD) patients 66% under immunosuppressive treatment 44.4 ±14.4 88 (58%) HAI assay Day 0 Day 21 Hajiabdolbaghi, et al. [33] Iran Cohort 2006-2007 TIV Healthy HCW adults 9.9% had allergy 35.9 ±8 [19-58] M: 37.4 ±7.8 F: 33.9 ±8 897 (57.1%) AEFIs : 48h – 10 days Hajiabdolbaghi, et al. [54] Iran Cohort 2006-2007 TIV-IM/SC HIV-infected adults 36.9±7.9 [21-59] F: 37.6±7.7 M: 34.2±8.6 203 (89.7%) AEFIs: 15 days Hara, et al. [67] Japan Cohort 2010-2011 TIV, 2 doses Subjects with severe motor and intellectual disability 41.7 (±10.4) 103 (54.4%) HAI assay Day 0 Day 21 Honkanen, et al. [35] Finland Cohort 1992-1993 TIV “Persons aged 65 years or older living in 29 administrative districts in Northern Finland who accepted the free vaccine” 73.6 ±6.7 4581 (39%) AEFIs : 4 days Kwong, et al.[49] Canada TNCC 2010-2011 TIV “Community-dwelling adults aged >65 years tested for influenza using a nucleic acid amplification test between 1 December 2010 and 30 April 2011 and admitted to an acute care hospital at the time of testing.” Test positive: 80.62 ±7.91 Test negative: 78.87 ±7.56 2230 (50.3%) RT-PCR confirmed Influenza 4 Lasky, et al. [61] USA Case-control 1992-1993 1993-1994 NA ‘’Patients discharged with code 357.0 (ICD-9) and with GBS onset between September 1, 1992, and February 28, 1993, or between September 1, 1993, and February 28, 1994’’ Mean : 54 [18 to 90] GBS : 6 weeks Looker, et al. [45] USA Cohort 2010-2011 TIV Predominantly Healthy adults previously exposed to Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) 51.3% were over 51 years old 411 (51.3%) HAI assay Day 0 Day 21 ±3 McEvoy [70] Australia Cohort 2010 TIV Healthcare workers. Predominantly healthy Mean: 46 [15 - 83] b 2245 (20.9%) AEFIs: 48h Moynihan, et al. [34] USA Cohort 2002-2003 TIV Nursing home elderly residents 84±7.1 37 (27%) HAI assay Day 0 Day 21 Nakaya, et al. [68] USA Cohort 2007-2011a Consecutive seasons TIV Healthy Adults 2007-2008 (F: 27.4 ± 3.6 - M: 31±10.13) 2008-2009 (F: 33.1±8.1; M: 28.1 ± 3.01) 2010-2011 (F: 57±20.4; M: 59 ±18.03) 2007-2008: 9 (44.4%) 2008-2009: 28 (32.1%) 2010-2011: 58 (44.8%) 65% were ≥ 65 years HAI assay Day 0 Day 28 Naz, et al. [52] Turkey Cohort 2006-2007 TIV-IM Healthcare workers Mean : 34.48 ±8.85 [18-63] 547 (45.9%) AEFIs : 10 days Olafsdottir, et al. [39] Iceland Cohort 2012-2013 2013-2014 2015-2016 TIV-IM Predominantly Healthy Adults 2012-2013: 55 [20-103] 2013-2014: 50 [21-93] 2015-2016: 47 [21-70] 2012-2013: 565 (33.3%) 2013-2014: 711 (48.9%) 2015-2016: 576 (53.3%) HAI and MN assays Day 0 Day 28 ±3 Phengxay, et al. [44] Laos Cohort 2012 TIV High risk individuals: pregnant women, persons aged >50 years, persons with chronic disease, and all healthcare personnelc 35% with underlying medical conditions (F: 74% - M: 26%) 47 [5-94] 2080 (26%) AEFIs : 7 days Rapezzi, et al. [58] Italy Cohort 1999-2000 TIV-IM Patients with chronic lymphoproliferative 69 [34 – 78] 34 (50%) HAI assay Day 0 1 month 5 disorders (CLPD) and multiple myeloma (MM) 41.67% of females and 58.33% of males under IS treatment (94.1% females and 88% males were older adults) Robb, et al. [65] USA Cohort 1992-1993 TIV Annually vaccinated Air National Guard members Mean age in the early 30- to 39 years old [18 - 59] 209 (87.6%) AEFIs: 2 weeks Spila-Alegiani, et al. [62] Italy Cohort 1996-1997 TIV Individuals ≥ 65 years presenting at the local health unit for their first seasonal influenza vaccination 67% had chronic medical conditions 73 [65-101] 16637 (0.9 male to female ratio) AEFIs : 72h Strindhall, et al. [40] Sweden Cohort 2011-2012 TIV-IM Elderly subjects who from an ongoing longitudinal study. They were selected to optimise the proportion of individuals with a CD4/CD8 ratio <1. All were 69 years old 88 (50%) HAI assay Day 0 Day 30 Talbot, et al. [30] USA TNCC 2006-2007 Good match 2007-2008 Poor match 2008-2009 Poor match TIV Elderly patients hospitalized with respiratory symptoms or nonlocalizing fever. Predominantly with underlying comorbidities 67 [58 - 78] 438 (47%) RT-PCR confirmed Influenza Trebbien, et al. [38] Denmark TNCC 2016-2017 TIV Elderly patients from Danish Microbiology Database, swabbed for Influenza A or B at GPs or hospitals. Predominantly with comorbidities. ≥ 65 5514 (49.7%) RT-PCR confirmed Influenza van Balveren- Slingerland, et al. [69] Netherlands Cohort 2013-2014 NA ‘’Patients who were vaccinated (GPs) and had access to internet and were literate in Dutch’’ Predominantly heathy elderly 71.1% were over 60 years old 1384 (47.2%) AEFIs: 5 - 15 and 30 days SAEs: 30 days Zheng, et al. [37] China Cohort 2016-2017 TIV Medically stable adults or clinically cured leprosy patients from leprosarium (leprosy group) and healthy controls Leprosy group : 70.3±8.3 Control group : 72.7 ±5.1 Leprosy group: 37 (75.7%) Control group: 97 (42.3%) AEFIs : 0 – 7 days SAEs : 28 days ‡ Only reporting sex-stratified outcomes. a The pandemic 2009-2010 season was excluded and data for the 2011-2012 season were not available. 6 b Only 3/2245 people were under 18 years old c Less than 10% of the total population were pregnant women or under 18 years old AEFIs: adverse events following immunization; F: Females; GBS: Guillain-Barré syndrome; GMFR: geometric mean fold rise; HD: high dose; HAI: hemagglutination inhibition; ID: intradermal; IIV3: trivalent inactivated influenza vaccine; IIV4: quadrivalent inactivated influenza vaccine; IM: intramuscular; IS: immunosuppressive therapy; LAIV: live attenuated influenza vaccine; M: Males; MM: multiple myeloma; MN: microneutralization; NA: not available; ORS: Oculo-respiratory syndrome; QIV: quadrivalent influenza vaccine; RCT: randomized-controlled trial; RIV4: quadrivalent recombinant influenza vaccine; RT-PCR: Reverse transcription polymerase chain reaction; SAEs: serious adverse events; SC: subcutaneous; SD: standard dose; TIV: trivalent inactivated vaccine 7 409 Table 2. Summary of Findings and Quality Assessment Study Age (in years) [Range] Outcomes Assessed† Notes Risk of Bias‡ * Immunogenicity Efficacy Effectiveness Safety Barrett, et al. [29] 31 [18-49] No significant sex NA differences Cook, et al. [55] Dunkle, et al. [28] IM group: 72.9 ±8.9 SC group: 72.4 ±8.6 [18-50] RIV4 : 33.3, [18-50] IIV4 : 34 [18-49] F>M for all strains, IM group only. Local reactions (IM and SC): F>M Systemic reactions (IM and SC): F>M Local reactions: F>M Systemic reactions: F>M Low Low Falsey, et al. [32] 73 ±6 F>M (HD and SD groups) Differences were more pronounced for H1N1 and H3N2 strains. Low Gorse, et al. [42] [18-64] IIV4-ID: 41.6 ±13.2 IIV3-ID1: 41.2 ±13.5 IIV3-ID2: 41.9 ±13.3 No significant sex differences Local reactions: F>M Systemic reactions: F>M (significant for pruritus, erythema, induration, myalgia, headache, and malaise) Some Concerns Govaert, et al. [36] 67 ±5.6 Median : 66 Any AEFIs: F>M Some concerns Govaert, et al. [72] 67 ±6 Median : 66 No significant sex differences ‘’A strikingly lower immune response was found in this trial between those who had previously been vaccinated and those who had not ... In the case of those who had been previously vaccinated, this reduced immune response was independent of gender and risk factors.’’ Some concerns Jackson, et al. [60] Mean : 26.7 (95% CI 25.8-27.5) Moderate to severe tendereness: F>M Moderate to severe pain: F>M >1’’ redness and/or swelling: F>M Some concerns Jackson, et al. [31] Rivera, et al. [50] Scheifele, et al. [59] 32.7 ±9.19 [18-49] Agrippal® : 31.2 ±8.8 Fluvirin® : 31.3 ±8.7 Mean: 45.7 [30-59] 2005-2006 F<M (H1N1) 2006-2007 No significant sex differences No significant sex differences F: 19.4% (97.5% CI lower bound - 42.8%) M: 89.0% (97.5% CI lower bound 53.0%) F<M (p = 0.0123) - - Average efficacy (2005- 06 and 2006-07 seasons). ‘’Women in this trial had a slightly higher rate than men of recent (within ≤ 2 years) previous influenza vaccine (women, 21%; men, 16%; p < 0.0001) in both placebo and TIV groups.’’ Vaccine attribuatable-risk for ORS: F=M Any AEFIs 24h after vaccination: F>M (injection-site redness, swelling and pain, reduced arm mobility, headache, and fatigue.) Low Low Low Ambrose and Wu [47] [18-64] Systemic reactions: F>M High Coleman, et al. [51] Mean: 36.6 Median: 34 [18-59] No significant sex differences Site injection pain: F>M Low Coleman, et al. [43] Median : 42 [19-69] Moderate to severe systemic reactions: F>M Some concerns Gauthey, et al. [64] 84±8 [60 - 103] Local reactions: F>M Systemic reactions: F=M Some concerns Boulianne, et al. [71] Bragstad, et al. [48] Burwen, et al. [53] NA Incidence of ORS in Quebec population: F>M ≥ 65 F: 4,4 (-32,21 – 30,87) M: -25,77 (-76,2 – 10,23) NA Incidence of definite, probable or possible GBS: M>F Serious Crude VE estimates Critical Serious 8 D'Alessandro, et al. [56] 74.5 ±6.8 Any AEFIs: F=M Moderate De Serres, et Mean : 43 ORS attack rate: F=M Serious al. [57] Emborg, et al. ≥ 65 12,36 (-16,2 – 33,89) Crude VE estimates Critical [66] M: 25,04 (1,79 – 42,78) Fraund, et al. Transplant Recipients: 53.6 ±10.4 No significant sex ‘’None of the NA [63] Healthy controls: 50.7 ±15.19 differences vaccinees had a history of influenza vaccination over a period of three years before vaccination.’’ Furman, et al. M: 63 [20 – 89] H1N1 strain: no significant The difference was Serious [73] F: 68 [20 – 89] sex differences greater for the H3N2 H3N2 strain: F>M strain (P = 0.0027) B strain: F>M compared to the B strain (P = 0.02)d Gilca, et al. 81.5 [65 - 101] F: -8,06 (-118,05 – 46,45) Crude mid-season VE Critical [41] M: -24,4 (-130,81 – 32,95) estimates Hagihara, et al. 44.4 ±14.4 No significant sex Serious [46] differences Hajiabdolbaghi 35.9 ±8 Local reactions: F>M Moderate , et al. [33] [19-58] Systemic reactions: F=M M: 37.4 ±7.8 Any AEFIs: F>M F: 33.9 ±8 Hajiabdolbaghi 36.9±7.9 [21-59] Any AEFIs : F=M NA , et al. [54] F: 37.6±7.7 M: 34.2±8.6 Hara, et al. [67] 41.7 (±10.4) H1N1: F>M Moderate (p=0.04) Honkanen, et 73.6 ±6.7 Local reactions: F>M Moderate al. [35] Fever: F=M Kwong, et al. Test positive: 80.62 ±7.91 Test F: 44% (25% - 58%) Adjusted VE estimates a Moderate [49] negative: 78.87 ±7.56 M : 43% (22% - 58%) Lasky, et al. Mean : 54 Risk for GBS: F=M Moderate [61] [18 to 90] Looker, et al. 51.3% were over 51 years old B strain: M>F Serious [45] McEvoy [70] Mean: 46 [15 - 83] Any AEFIs: F>M Serious (Only 3/2245 people were under 18 Local reactions: F>M years old) Systemic reactions: F=M Moynihan, et 84±7.1 No significant sex NA al. [34] differences Nakaya, et al. 2007-2008 (F: 27.4 ± 3.6 - M: No significant sex Serious [68] 31±10.13) differences 2008-2009 (F: 33.1±8.1; M: 28.1 ± 3.01) 2010-2011 (F: 57±20.4; M: 59 ±18.03) Naz, et al. [52] Mean : 34.48 ±8.85 Any AEFIs: F=M Serious [18-63] Olafsdottir, et 2012-2013: 55 [20-103] No significant sex Post-vaccination Serious al. [39] 2013-2014: 50 [21-93] differences antibody titres were 2015-2016: 47 [21-70] adjusted for pre- vaccination titres and year of immunization. Phengxay, et 47 [5-94] Any AEFIs: F>M Serious al. [44] Rapezzi, et al. 69 [34 – 78] No significant sex Serious [58] (94.1% of females were older differences adults) Robb, et al. Mean age was in the early 30- to 39 Any symptom : F=M Serious [65] years old [18 - 59] Spila-Alegiani, 73 [65-101] Any AEFIs: F>M Moderate et al. [62] Strindhall, et All were 69 years old No significant sex Serious al. [40] differences Talbot, et al. 67 [58 - 78] F : 60.1% (1.8%, 83.8%) Adjusted VE estimatesb Moderate [30] M : 63.7% (-48.9%, 91.2%) Trebbien, et al. ≥ 65 F: 8,14 (-8,57 – 22,28) Crude VE estimates Critical [38] M: 15,6 (0,43 – 28,46) van Balveren- 71.1% aged over 60 years At least 1 AEFI: F>M Critical Slingerland, et al. [69] Zheng, et al. Leprosy group Any AEFI: Moderatec [37] 70.3±8.3 Leprosy group: M>F Control group Control group: M>F 72.7 ±5.1 410 CI: Confidence Interval; F: Females; M: Males 411 †Only reporting sex-stratified outcomes 9 412 ‡Risk of bias was assessed with respect to sex-stratified outcomes 413 * Qualitative studies were not assessed for risk of bias 414 a VE adjusted for age, rural residence, neighborhood income quintile, healthcare utilization factors 415 (number of outpatient visits and prescriptions in the past year, number of hospitalizations in the past 3 416 years, and receipt of home care services in the past year), comorbidities that increase the risk for 417 influenza complications, and month of influenza testing 418 b Propensity score–adjusted VE: adjusted for age in years, race, smoking status, home oxygen use, 419 underlying medical conditions, immunosuppression, timing of admission relative to onset of influenza 420 season, and specific influenza season (2006–2007, 2007–2008, or 2008–2009). 421 c Study was underpowered, and females were underrepresented 422 d Logistic regression analysis to compute antibody changes for each strain was adjusted for age. 423 10 424 Table 3. Evaluation of the quality and the strength of recommendation of the clinical 425 outcome using the GRADE approach Certainty assessment Certainty Importance № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Immunogenicity 8 randomized trials not serious not serious not serious not serious publication bias strongly suspected a ⨁⨁⨁◯ MODERATE IMPORTANT 10 observational studies serious b not serious not serious serious c publication bias strongly suspected a ⨁◯◯◯ VERY LOW IMPORTANT Vaccine effectiveness 6 observational studies serious d not serious not serious serious publication bias strongly suspected a ⨁◯◯◯ VERY LOW IMPORTANT Safety 10 randomized trials not serious not serious not serious not serious publication bias strongly suspected a ⨁⨁⨁◯ MODERATE IMPORTANT 14 observational studies serious e not serious not serious not serious publication bias strongly suspected a ⨁◯◯◯ VERY LOW IMPORTANT 426 a Only few studies assessed sex differences 427 b Most studies were deemed at high risk of bias. GMTs were not stratified by age. 428 c Most studies did not compute confidence intervals for GMTs 429 d 4 out of 6 studies were deemed at critical risk of bias. Crude estimates. 430 e Most studies were deemed at serious risk of bias
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Is there a Difference in the Immune Response, Efficacy, Effectiveness and Safety of Seasonal Influenza Vaccine in Males and Females? : A Systematic Review
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