ABSTRACT
Vaccines may alter the ability to combat infections unrelated to the target disease, i.e. have “nonspecific effects.” The non-live Diphtheria-Tetanus-Pertussis vaccine (DTP) has been associated with increased child mortality, especially for females. In 2008, the DTP-containing Pentavalent vaccine replaced DTP vaccine in Guinea-Bissau. We investigate female relative to male mortality after Penta vaccination. In Guinea-Bissau, Bandim Health Project (BHP) registered children’s vaccination and vital status at biannual village visits and provided vaccines. Among children Penta-vaccinated by BHP, we compared mortality of males and females in Cox proportional hazards models. Children aged 6 weeks to 8 months entered the analysis at the date of vaccination and were followed for up to 6 months. Between September 2008 and December 2017, 33,989 children aged 6 weeks to 8 months were under surveillance. Of these 12,753 (females: 6,363; males: 6,390) received Penta by the BHP and entered the study contributing with 19,667 observations. The mortality rate following Penta vaccination was 25.2 per 1,000 person years for females and 26.6 for males, resulting in an adjusted Female/Male mortality rate ratio of (F/M aMRR) 1.01 (0.82–1.25). The association between sex and mortality differed by timeliness of vaccination, F/M aMRR: 0.62 (0.41–0.93) for children vaccinated below median age, and F/M aMRR: 1.38 (0.90–2.13) for children vaccinated above median age. We did not find higher overall mortality in females than males after Penta vaccination. Our findings suggest that mortality differences between males and females following Penta vaccination may depend on timeliness of Penta vaccination.
Introduction
Vaccines have played a major role in the decline in child mortality during the past decades. In addition to protecting against specific diseases, vaccines may alter the ability to combat unrelated infections, i.e. have “non-specific effects” (NSE).Citation1 NSEs can decrease or increase the susceptibility to unrelated infections. Research indicates that live vaccines have beneficial NSEsCitation1–5 and non-live vaccines have negative NSEs,Citation1,Citation6–10 and that NSEs are often sex-differential.Citation1,Citation7,Citation8,Citation11 Such contrasting patterns between different vaccines are important especially in observational studies, where self-selection could produce biased estimates. E.g., ‘healthy vaccinee bias’ would lead to comparing healthy (and therefore vaccinated) children with frail (unvaccinated) children.
In 2014, the World Health Organization (WHO) commissioned a review of the literature on NSEs of measles (MV), Bacillus Calmette-Guérin (BCG), and whole cell Diphtheria-Tetanus-Pertussis (DTP) vaccines. For MV and BCG the review indicated beneficial effects. For DTP, the review identified 17 observational studies of which 10 studies were used to compare DTP versus no DTP. In the included studies, DTP was associated with a tendency toward higher child mortality.Citation12 The review concluded that the results regarding DTP were inconclusive yet ‘a cause for concern’.Citation12 However, some of the DTP studies included data where vaccination status was updated retrospectively. As vaccination status is more likely to be updated for surviving children than for children who have died, this introduces survival bias, which would tend to produce a more positive effect estimate of any vaccine.Citation6,Citation13 In a follow-up on the WHO review, 5 studies with poorly defined control groups and survival bias were excluded. Limiting the analysis to studies with prospective follow-up and well-defined control groups, DTP vaccination was associated with a mortality rate ratio (MRR) of 2.00 (1.50–2.67) compared with no DTP.Citation6
The apparent higher mortality following DTP vaccination is more evident among females (MRR 2.54 (1.68–3.86) for DTP vs no DTP) and results in higher female than male mortality after DTP vaccination, Female/Male (F/M) MRR 1.53 (1.21–1.93).Citation11 The findings of higher overall mortality among DTP-vaccinated versus not DTP-vaccinated children, in particular for girls, were later corroborated by two studies using older data from the introduction of the DTP vaccine in Guinea-Bissau.Citation14,Citation15
In September 2008, the DTP vaccine was replaced by the Pentavalent (DTP-H). influenzae type B-Hepatitis B) vaccine (Penta) in the vaccination programme in Guinea-Bissau.Citation16 Only one study has compared the mortality of Penta-vaccinated versus Penta-unvaccinated children, and did not find excess mortality among the vaccinated children.Citation17 Nevertheless, studies also indicate that Penta is also associated with higher female relative to male mortality.Citation18–20 Moreover, a meta-analysis of the F/M MRR following DTP-containing vaccines (Penta included) found higher F/M MRR with increasing number of DTP doses.Citation21 These studies are all from high mortality settings, the majority being from Guinea-Bissau, but the meta-analysis includes studies from Ghana, Senegal, Malawi, Bangladesh, and India.Citation21
Using data from rural Guinea-Bissau, we assessed mortality among Penta vaccinated children to test the hypothesis that females have 50% higher mortality than males after Penta vaccination and assessed whether the F/M MRR after Penta increased from Penta1 to Penta3.
Participants and methods
Setting
The study was conducted within the Bandim Health Project’s (BHP) rural Health and Demographic Surveillance System (HDSS),Citation22 which covers all nine rural health regions in Guinea-Bissau. The cohort consists of women of fertile age and children below 5 years of age in 182 village clusters. Villages are visited every 6 months. Between 2012 and 2015, monthly visits were conducted in 71 village clusters as part of a randomized trial investigating the effect of an additional dose of MV after 4.5 months.Citation23 Since 2016 visits were conducted every two months in 51 of these village clusters.
Upon registration of a woman, information on ethnicity, maternal age, and schooling was collected. At first registration of a child, information on socioeconomic status (type of roof, toilet facilities, possession of a radio, mobile phone, and generator)Citation22 was recorded. At all visits, vaccination status and survival status of all children were recorded by field assistants who copied vaccination dates from the child’s vaccination card.Citation22 The field teams (in all regions until late 2016, subsequently in three regions) were accompanied by a nurse who set up a vaccination post. Children who lacked one or more vaccines were referred to the nurse who administered missing vaccines, weighed the child, and recorded vaccines given, date of vaccination and dose number.
Children aged 6 weeks to 8 months who received Penta by the BHP team at a village visit between September 1, 2008 and December 31, 2017 were included in the analyses. Children were followed for survival from the date of vaccination until a subsequent visit where a vaccine was given or was registered to have been given based on the child’s vaccination card or for a maximum of 6 months. We excluded observations, where other non-routine interventions were administered together with the Penta vaccine, e.g. vitamin A. Children, who were not vaccinated by the BHP team, and hence, not included in the analyses included both Penta-unvaccinated children, and children who had received their Penta vaccine elsewhere.
Vaccination of children
From September 2008 to June 2015 the vaccination schedule in Guinea-Bissau consisted of BCG and oral polio vaccine (OPV) at birth, Penta and OPV at 6, 10 and 14 weeks, and MV and yellow fever vaccine (YF) at 9 months. 13-valent pneumococcal conjugate vaccine (PCV; 6, 10, and 14 weeks) was added June 2015, Rotavirus vaccine (Rota; 6 and 10 weeks) was added November 2015, and inactivated polio vaccine (IPV; 14 weeks) was added June 2016.
Vaccination campaigns, where children are vaccinated regardless of prior vaccination status, are common in Guinea-Bissau. During the study period there were national vaccination campaigns with OPV (n = 14), MV (n = 4), H1N1-influenza vaccine (n = 1) and Meningitis A vaccine (n = 1) (Full list of vaccination campaigns, Appendix A).
Follow-up
At the village visits by the BHP team, new children are registered and information on vital status obtained for all children already registered in the HDSS. For children, who presented a vaccination card, information on vaccination status was registered. Children who did not have a vaccination card were provided with one. Children who were present at the BHP visit had their mid-upper-arm circumference assessed. For deaths, information on the reported cause of death including whether the death was due to accident, and the symptoms of illness prior to death was collected.
Statistical analyses
We compared available background characteristics by sex using chi2 tests, t-tests, and Kruskal Wallis test. Weight for age Z-scores (WAZ) were calculated using the WHO macro for Stata®.Citation24 We estimated F/M MRR using Cox proportional hazards models with age as underlying timescale and with village cluster-robust variance estimates. We stratified the F/M MRR by Penta dose to assess whether the association differed according to number of doses. Background characteristics were included individually in the model one-by-one. Unadjusted and adjusted estimates were compared among the children with information on the assessed background characteristic. Characteristics that changed the estimate by more than 5%, among observations with full information, were included in the adjusted analysis. In the adjusted analyses, missing WAZ values were set to the mean WAZ among children with same sex and number of dose of Penta.
In planned secondary analyses, we stratified by vaccines co-administered with Penta and by timeliness of Penta vaccination: Classifying records as before or equal to the median age vs after for each of the given doses of Penta separately.
During the study period more frequent visits were implemented in some regions and thus availability of Penta vaccination by the BHP team was increased. We therefore stratified the analyses by period of administering the Penta vaccine (2008–2011, 2012–2015, and 2016–2017). We conducted three further sensitivity analyses to limit interference from other vaccines 1) children were censored after 3 months of follow-up, 2) children were censored at subsequent vaccination campaigns if they were eligible for participation or at 9 months of age when they became MV eligible, whichever came first, 3) we stratified data by OPV campaign eligibility prior to Penta vaccination (not pre-specified). Furthermore, we assessed the sensitivity of using different WAZ values for imputation of missing values (using a WAZ of −2 and +2, respectively).
To assess whether mortality of children included in the study differed from children not Penta-vaccinated by the BHP, we performed an additional analysis (not pre-specified). In this we included children aged 6 weeks to 8 months, who were present and had their vaccination card inspected at a visit during the same time period but never received a Penta vaccine by the BHP. Follow-up end was defined as in the main analysis.
Median age of Penta vaccination was the pre-specified proxy of timeliness of Penta vaccination, but we assessed the robustness of results, by performing the analysis (not pre-specified) with cutoffs of median ±14 days.
Ethics approval and consent to participate
The data collection by the Bandim Health Project was initiated in 1978 at request by the Ministry of Health in Guinea-Bissau. The National Guinean Ethics Committee granted approval for the HDSS platform. No further administrative approvals were sought for the present study. Oral consent was obtained from all participants prior to registration in the HDSS. Written informed consent has been obtained for all participants in the HDSS since 2018.
Results
Between September 1, 2008 and December 31, 2017, 33,989 children aged 6 weeks to 8 months were under surveillance in rural Guinea-Bissau. Of these we excluded 2,015 (6%) never present at a BHP visit, 18,895 (56%) present at a BHP visit, but who never received Penta by the BHP team, and 326 (1%) who received Penta with other non-routine interventions (vitamin A or MV) (). We included 12,753 children in the analyses. Background characteristics at first Penta vaccination by the BHP team were similar between females and males, and statistically significant differences corresponded to small absolute differences (). Median age at first Penta dose was 2 days lower for males than for females (p = .02), WAZ was 0.05 z-scores lower for males than for females (p = .01), and 2% more females than males did not receive BCG vaccine prior to entry or during follow-up.
Figure 1. Flowchart of study subjects.
Table 1. Background factors by sex of included Penta-vaccinated children.
Main results
The 6,363 (50%) females contributed with 2,901 person years (PYRS) in the survival analysis, and 6,390 (50%) males with 2,930 PYRS. During follow-up 151 children died, 73 (48%) females and 78 (52%) males. The mortality rate (MR) per 1,000 PYRS following Penta vaccination was 25.2 for females and 26.6 for males, resulting in a crude F/M MRR of 0.95 (0.77–1.17) (). Including the background factors one-by-one, only WAZ changed the estimate by more than 5% and was included in the adjusted analysis, resulting in an adjusted F/M MRR (F/M aMRR) of 1.01 (0.82–1.25) (). Among the 151 deaths, 2 deaths (1 male, 1 female) were registered to be caused by accident. Censoring the two deaths resulted in an adjusted HR of 1.01 (0.81–1.26).
Table 2. Female relative to male mortality after any dose of Penta and stratified by dose number.
Stratifying by number of Penta dose, females tended to have higher mortality than males following Penta1 (F/M aMRR 1.08 (0.74–1.56)) and Penta3 (F/M aMRR 1.13 (0.71–1.81)). Whereas females tended to have lower mortality than males after Penta 2 (F/M aMRR 0.76 (0.31–1.86)) ().
Delays in vaccination age increased with higher dose numbers the median age at Penta vaccination being, Penta1: 70 days, Penta2: 116 days, and Penta3: 156 days. Stratifying by timeliness of vaccination revealed a lower mortality in females (MR 20.3/1,000 PYRS) than males (MR 32.4/1,000 PYRS) among the children vaccinated on or before the median age for the relevant dose, F/M aMRR 0.62 (0.41–0.93). Among the late vaccinated children, there was a tendency toward higher female (MR 28.5/1,000 PYRS) than male mortality (MR 22.2/1,000 PYRS), F/M aMRR 1.38 (0.90–2.13) (test of no difference between early and late vaccinated children: p-value: 0.02).
The pattern was similar when stratifying by number of dose of Penta (). Median age at vaccination and period were correlated: 62% in period 1, 45% in period 2, and 59% in period 3 were vaccinated after the median age. Further, follow-up time varied with period and timeliness of vaccination. Thus, we could not fully disentangle period, age at vaccination, and follow-up time. However, adjusting for period in analyses stratified by median age at vaccination did not alter conclusions.
Table 3. F/M MRR by dose number of Penta vaccine stratified by age (above or below mediana).
Receiving Penta co-administered with any vaccine resulted in an F/M aMRR of 1.01 (0.83–1.23). Only few children received Penta alone with only two deaths (1 female, 1 male) (). The F/M MRR differed by type of co-administered vaccines, however, with the many new vaccines introduced during the study period, there were many combinations and no clear pattern depending on whether the co-administered vaccines were live or non-live ().
Table 4. F/M MRR after any dose of Penta stratified by co-administering other vaccines.
Sensitivity analyses
Stratifying by period, females tended to have higher mortality than males (F/M aMRR 1.36 (0.92–2.02) in the early period (2008–2011) (). In later periods with more frequent visits, females tended to have lower mortality than males (2012–2015: F/M aMRR 0.88 (0.71–1.10) and 2016–2017: F/M aMRR 0.86 (0.52–1.43)) (). In 2012, the visit frequency by the BHP increased resulting in more frequent and earlier Penta vaccinations, and most of the follow-up time in the present study (58%, ) is during 2012–2015.
Table 5. F/M MRR after any Penta stratified by period (2008–2011, 2012–2015, 2016–2017).
Censoring follow-up after three months, the crude mortality rates for both males and females were slightly lower than in the main analysis and the F/M aMRR for any Penta was 0.98 (0.78–1.25) (Appendix B). Censoring at subsequent campaign eligibility and at 9 months of age the mortality rates among females were lower than during the full follow-up period and the F/M aMRR was 0.90 (0.68–1.18) (Appendix C).
Stratifying by eligibility for OPV campaigns prior to Penta vaccination, females eligible for OPV campaigns tended to have higher mortality than males, F/M aMRR 1.33 (0.65–2.72). Among children not eligible, females tended to have lower mortality than males 0.90 (0.73–1.09) (test of no difference, p = 0.32). This was mainly driven by differences in mortality for eligible males (MR 18.2 per 1000 PYRS) compared with not eligible males (MR 32.1 per 1000 PYRS), whereas there was little difference between eligible females (MR 22.9 per 1000 PYRS) and not eligible females (MR 26.6 per 1000 PYRS) (Appendix D).
Evaluating mortality among children not Penta-vaccinated by the BHP, but surviving to have their vaccination card inspected, revealed that females had a lower mortality rate (MR: 22.8 per 1000 PYRS) than females who were Penta-vaccinated by BHP (MR: 25.2 per 1000 PYRS). In contrast, the males who were not Penta-vaccinated by BHP had similar mortality rates to those who were Penta-vaccinated by BHP (MR: 26.7 per 1000 PYRS and MR: 26.6 per 1000 PYRS, respectively) (Appendix E).
Altering WAZ values used for imputation did not alter conclusions (Appendix F). Changing the proxy for timeliness of Penta vaccination to median age ±14 days revealed the same pattern (Appendix G).
Discussion
Main results
Overall, female mortality was similar to male mortality after Penta vaccination, the F/M aMRR was 1.01 (0.82–1.25). The F/M aMRR was lower for children vaccinated timely (0.62 (0.41–0.93) for children vaccinated below median age) and tended to be higher for children vaccinated late (F/M aMRR: 1.38 (0.90–2.13) for children vaccinated above median age, p = 0.02).
Strengths and weaknesses
Vaccinations were performed by BHP nurses and follow-up data was collected by experienced field assistants. Both were intensely supervised and the risk of misclassification of vaccination status was low.Citation22 In our study, Penta was almost always co-administered with other vaccines making it difficult to disentangle the effect of Penta from the effect of co-administered vaccines. The study design cannot capture if Penta (and co-administered vaccines) decreases or increases mortality for both sexes. However, opposed to studies comparing mortality of vaccinated with unvaccinated children, our study design focusing on the F/M MRR, limits the risk of confounding due to self-selection to vaccination.Citation6 From the many years of data collection at the BHP, we have no indications that males and females are treated differentially regarding vaccination. In the pre-vaccination era in West Africa mortality was similar for males and females, or slightly lower for females.Citation25 Nevertheless, as in any observational study, we cannot rule out confounding: Although we have assessed some potential confounders, the results might still be affected by unmeasured confounding.
The study group is a selected population, as children were only included in the analysis, if they received Penta vaccine by BHP, thus they had reached the eligible age, but not yet been vaccinated. Comparing mortality rates between children included in this study, and children in the same age group, who did not receive Penta by BHP, revealed that males had similar mortality, whereas mortality seemed higher for females who received Penta by BHP, compared with females who did not receive Penta by BHP. As visit frequency changed during the study period, children contributed with more follow-up time after Penta in the early period than in later periods.
Comparison with other studies
We found similar mortality among females and males following Penta vaccination. This finding does not correspond with the literature on the effect of DTP-containing vaccines on mortality. In 2016, a meta-analysis found that DTP vaccination was associated with 53% higher female than male mortalityCitation11 and other studies have also found Penta vaccination to be associated with higher female than male mortality in Guinea-Bissau,Citation18 Burkina FasoCitation19 and Bangladesh.Citation20 In these studies, Penta was usually co-administered with OPV. In the early period (2008–11) where Penta was co-administered with OPV only, we found a F/M aMRR of 1.36 (0.92–2.02). Female mortality was high in the early period (MR: 35.3 per 1000 PYRS), and lower in later periods (2012–2015: 22.5 per 1000 PYRS, and 2016–17: 19.9 per 1000 PYRS), whereas male mortality was stable across periods.
OPV campaigns have been associated with reduced mortality.Citation26,Citation27 In our study, we found lower mortality for males eligible for OPV campaigns prior to Penta vaccination compared with males not eligible. In contrast, mortality was similar for females eligible and not eligible for OPV campaigns. This resulted in an F/M aMRR of 1.33 (0.65–2.72) among children eligible for OPV campaigns prior to Penta and F/M aMRR of 0.90 (0.73–1.09) among children not eligible. While this observation is consistent with OPV campaigns especially lowering the mortality for males,Citation28,Citation29 it does not explain the results of studies conducted before the OPV campaigns were introducedCitation30–32 or in periods with few/no OPV campaigns.Citation33
Unlike previous studies that have found a higher female than male mortality with increasing number of DTP containing vaccines,Citation18,Citation30–31,Citation33–36 this pattern was not evident here.
Interpretation and implications
In the present study, we found no evidence of an increased female relative to male mortality after Penta vaccination in the combined cohort. Nevertheless, female mortality tended to be higher than male mortality among children vaccinated late. Median age at vaccination was used as a proxy for the timeliness of vaccination, and our data suggest that among children with delayed vaccination, females tended to have higher mortality than males. However, timeliness of vaccination, period, and follow-up time were correlated, and we were not able to disentangle the impact of these.
A higher female than male mortality after Penta vaccination was observed during the first years (2008–2011) while no excess female mortality was seen after 2012. In trials of measles vaccination during the same time period (after 2011),Citation23,Citation37,Citation38 we have also observed that providing MV after Penta did not lower overall female mortality as hypothesized and observed in prior trials.Citation39,Citation40 Also, a recent observational study within a randomized trial using data from 2010 to 2014 found no excess mortality when comparing Penta with no Penta.Citation17 Whether the explanation should be sought in a changed disease burden or in interactions with other interventions, we are not able to establish based on the present data. However, consistent with change in mortality patterns and contrary to previous findings, the mortality in our study was not higher when censoring the later follow-up period, indicating that a declining mortality with increasing age was not evident in the present cohort.
Conclusion
Contrary to existing literature, our study does not support an overall higher female relative to male mortality after Penta vaccination. While there was some indication of this in the early period, further studies are needed to assess whether a potential sex-differential mortality after Penta vaccination is dependent on timeliness of vaccination, disease burden/level of mortality, or co-administered vaccines.
Authors’ contribution
ABF conceived the idea for the study. ABF and SMT designed the study with input from CCJ. ABF, CC, MF, and SMT supervised the data collection. TA, ABF, CC, and MF cleaned the data. TA conducted the data analysis under the supervision of ABF and SMT. TA drafted the manuscript with help from SMT. All authors read and approved the final manuscript.
Abbreviations
| BCG | = | Bacillus Calmette-Guérin vaccine |
| BHP | = | Bandim Health Project |
| DTP | = | Diphtheria-Tetanus-Pertussis vaccine |
| F/M aMRR | = | Female/Male mortality rate ratio |
| HDSS | = | Health and Demographic Surveillance System |
| IPV | = | Inactivated polio vaccine |
| IQR | = | Interquartile range |
| MR | = | Mortality rate |
| MRR | = | Mortality rate ratio |
| MV | = | Measles vaccine |
| NSE | = | Non-specific effects |
| OPV | = | Oral polio vaccine |
| PCV | = | 13-valent pneumococcal conjugate vaccine |
| Penta | = | Pentavalent (DTP-H. influenzae type B-Hepatitis B) vaccine |
| PYRS | = | Person years |
| Rota | = | Rotavirus vaccine |
| SD | = | Standard deviation |
| WAZ | = | Weight for age Z-scores |
| WHO | = | World Health Organization |
| YF | = | Yellow fever vaccine |
Appendix_031123.pdf
Download PDF (635.3 KB)Acknowledgments
We would like to thank all our research assistants who have contributed to the data collection. We would also like to thank all the women and children who participated in the study. We are indebted to Peter Aaby for setting up the HDSS and for a pre-submission review of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
Data are available from the corresponding author on a collaborative basis.
Supplementary data
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2288297.
Additional information
Funding
References
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