Oral Polio Vaccine Campaigns May Reduce the Risk of Death from Respiratory Infections.

Oral polio vaccine (OPV) campaigns, but not other campaigns, have been associated with major reductions in child mortality. Studies have shown that OPV reduces the risk of respiratory infections. We analysed the causes of death at 0-2 years of age in Chakaria, a health and demographic surveillance Systems in Bangladesh, in the period 2012-2019 where 13 national campaigns with combinations of OPV (n = 4), vitamin A supplementation (n = 9), measles vaccine (MV) (n = 2), and albendazole (n = 2) were implemented. OPV-only campaigns reduced overall mortality by 30% (95% confidence interval: -10-56%). Deaths from respiratory infections were reduced by 62% (20-82%, p = 0.01) in the post-neonatal period (1-35 months), whereas there was as slight increase of 19% (-37-127%, p = 0.54) for deaths from other causes. There was no benefit of other types of campaigns. Hence, the hypothesis that OPV may have beneficial non-specific effects, protecting particularly against respiratory infections, was confirmed.

National Immunization Campaigns With Oral Polio Vaccine May Reduce All-cause Mortality: An Analysis of 13 Years of Demographic Surveillance Data From an Urban African Area.

BACKGROUND: Between 2002 and 2014, Guinea-Bissau had 17 national campaigns with oral polio vaccine (OPV) as well as campaigns with vitamin A supplementation (VAS), measles vaccine (MV), and H1N1 influenza vaccine. We examined the impact of these campaigns on child survival. METHODS: We examined the mortality rate between 1 day and 3 years of age of all children in the study area. We used Cox models with age as underlying time to calculate adjusted mortality rate ratios (MRRs) between "after-campaign" mortality and "before-campaign" mortality, adjusted for temporal change in mortality and stratified for season at risk. RESULTS: Mortality was lower after OPV-only campaigns than before, with an MRR for after-campaign vs before-campaign being 0.75 (95% confidence interval [CI], .67-.85). Other campaigns did not have similar effects, the MRR being 1.22 (95% CI, 1.04-1.44) for OPV + VAS campaigns, 1.39 (95% CI, 1.20-1.61) for VAS-only campaigns, 1.32 (95% CI, 1.09-1.60) for MV + VAS campaigns, and 1.13 (95% CI, .86-1.49) for the H1N1 campaign. Thus, all other campaigns differed significantly from the effect of OPV-only campaigns. Effects did not differ for trivalent, bivalent, or monovalent strains of OPV. With each additional campaign of OPV only, the mortality rate declined further (MRR, 0.86 [95% CI, .81-.92] per campaign). With follow-up to 3 years of age, the number needed to treat to save 1 life with the OPV-only campaign was 50 neonates. CONCLUSIONS: OPV campaigns can have a much larger effect on child survival than otherwise assumed. Stopping OPV campaigns in low-income countries as part of the endgame for polio infection may increase child mortality.

Vaccinology: time to change the paradigm?

The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.

Lessons Learned from the Testing of Neonatal Vitamin A Supplementation.

A total of 12 trials have tested the effect of neonatal vitamin A supplementation (NVAS) on mortality. Overall, NVAS had no effect on mortality, but results were heterogeneous. Two competing hypotheses have been put forward to explain the divergent effects: A) NVAS works by preventing vitamin A deficiency (VAD) and not all countries have VAD; B) NVAS interacts negatively with subsequent diphtheria-tetanus-pertussis (DTP) vaccine, increasing mortality in females; in countries with low DTP coverage NVAS may have a beneficial effect. Only hypothesis A was tested in a recent meta-analysis; there is no strong empirical support for hypothesis A and it would not explain observed negative effects in some settings. Hypothesis B accounts for most observations. However, so far it has only been tested properly in a few trials. If hypothesis B is correct, it has major consequences for the understanding of the effects of vitamin A, and for the VAS policy in older children. As a WHO priority, the DTP coverage is bound to increase, and therefore hypothesis B urgently needs to be tested.

Does India Need a Universal High-Dose Vitamin A Supplementation Program?

High dose vitamin A (HDVA) concentrate began to be distributed in India in 1970 as a short-term, stop-gap approach to reduce clinical signs of vitamin A deficiency. As this problem declined globally, the purpose of distributing them changed to the reduction of young child mortality. However, their impact on this has also declined, if not disappeared, as suggested in India by the enormous DEVTA study. This may be because of improved protection against and treatment of the main morbidity involved, measles and diarrhea. At the same time, semi-annual provision of mega-doses of vitamin A is not without risks, in particular linked to children's vaccination status. While a single dose is inexpensive, large-scale implementation of HDVA programs is expensive, particularly the opportunity cost involved in reducing the time health workers involved have to deal with their other commitments. Balancing potential benefits, risks and costs leads us to recommend an immediate cessation of the distribution of HDVA in India.

Impact of H1N1 Influenza Vaccination on Child Morbidity in Guinea-Bissau.

BACKGROUND: In addition to vaccines' specific effects, vaccines may have non-specific effects (NSEs) altering the susceptibility to unrelated infections. Non-live vaccines have been associated with negative NSEs. In 2010, a campaign with the non-live H1N1-influenza vaccine targeted children 6-59 months in Guinea-Bissau. METHODS: Bandim Health Project runs a health and demographic surveillance system site in Guinea-Bissau. Using a Cox proportional hazards model, we compared all-cause consultation rates after vs. before the campaign, stratified by participation status. RESULTS: Among 10 290 children eligible for the campaign, 60% had participated, 18% had not and for 22% no information was obtained. After the H1N1 campaign, the consultation rates tended to decline less for participants [HR = 0.80 (95% confidence interval, CI: 0.75; 0.85)] than for non-participants [HR = 0.68 (95% CI: 0.58; 0.79)], p = 0.06 for same effect. CONCLUSION: The decline in the vaccinated group may have been smaller than the decline in the non-vaccinated group consistent with H1N1-vaccine increasing susceptibility to unrelated infections.

[Limited knowledge of the effect on child mortality of vaccinations and vitamin A supplementation].

Preventive health interventions, including the vaccination and vitamin A supplementation programmes, are implemented in low-income countries with little assessment of the real-life effects on child mortality. Nevertheless, the programmes are frequently credited with large, finite numbers of deaths prevented. Forty years of demographic surveillance in Guinea-Bissau indicates, that vaccines and vitamin A supplementation have effects beyond what can be explained by preventing the target infections and vitamin A deficiency. Taking these effects into account would substantially improve child health.

National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials.

BACKGROUND: A recent WHO review concluded that live BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs) reducing mortality from non-targeted diseases. NSEs of oral polio vaccine (OPV) were not examined. If OPV vaccination campaigns reduce the mortality rate, it would suggest beneficial NSEs. SETTING: Between 2002 and 2014, Guinea-Bissau had 15 general OPV campaigns and other campaigns with OPV plus vitamin A supplementation (VAS), VAS-only, MV, and H1N1 vaccine. In this period, we conducted seven randomized controlled trials (RCTs) with mortality as main outcome. METHODS: Within these RCTs, we assessed whether the mortality rate was lower after-campaign than before-campaign. We used Cox models with age as underlying time and further adjusted for low birth-weight, season and time trend in mortality. We calculated the adjusted mortality rate ratio (MRR) for after-campaign vs before-campaign. RESULTS: The mortality rate was lower after OPV-only campaigns than before, the MRR being 0.81 (95% CI = 0.68-0.95). With each additional dose of campaign-OPV the mortality rate declined further (MRR = 0.87 (95% CI: 0.79-0.96) per dose) (test for trend, p = 0.005). No other type of campaign had similar beneficial effects. Depending on initial age and with follow-up to 3 years of age, the number needed to treat with campaign-OPV-only to save one life was between 68 and 230 children. CONCLUSION: Bissau had no case of polio infection so the results suggest that campaign-OPV has beneficial NSEs. Discontinuation of OPV-campaigns in low-income countries may affect general child mortality levels negatively.

Long-term sex-differential effects of neonatal vitamin A supplementation on in vitro cytokine responses.

High-dose vitamin A supplementation (VAS) may affect mortality to infectious diseases in a sex-differential manner. Here, we analysed the long-term immunological effects of neonatal vitamin A supplementation (NVAS) in 247 children, who had been randomly allocated to 50 000 or 25 000 IU vitamin A (15mg and 7·5mg retinol equivalents, respectively) or placebo at birth. At 4-6 months of age, we assessed bacille Calmette-Guérin (BCG) scarification, and we analysed in vitro responses of TNF-α, IL-5, IL-10, IL-13 and IFN-γ in whole blood stimulations to phytohaemagglutinin (PHA), purified protein derivative (PPD), tetanus toxoid and lipopolysaccharide. There were no differences between the two doses of NVAS, and thus they were analysed combined as NVAS (any dose) v. placebo. All analyses were performed unstratified and by sex. NVAS increased the chance of having a scar after BCG vaccination in females (NVAS v. placebo: 96 v. 71 %, proportion ratio: 1·24; 95 % CI 1·09, 1·42), but not in males (P for interaction=0·012). NVAS was associated with significant sex-differential effects on the pro- to anti-inflammatory cytokine ratios (TNF-α:IL-10) to PPD, tetanus toxoid and medium alone, which were increased in females but decreased in males. In addition, IL-17 responses tended to be increased in NVAS v. placebo recipients in males but not in females, significantly so for the PHA stimulation. The study corroborates sex-differential effects of VAS on the immune system, emphasising the importance of analysing VAS effects by sex.

We Need Studies of the Mortality Effect of Vitamin A Supplementation, Not Surveys of Vitamin A Deficiency.

It is usually acknowledged that high-dose vitamin A supplementation (VAS) provides no sustained improvement in vitamin A status, and that the effect of VAS on mortality is more likely linked to its immunomodulating effects. Nonetheless, it is widely assumed that we can deduce something about the need for continuing or stopping VAS programs based on studies of the biochemical prevalence of vitamin A deficiency (VAD). This is no longer a tenable assumption. The justification for using VAS is to reduce child mortality, but there is now doubt that VAS has any effect on overall child mortality. What we need now are not surveys of VAD, but proper randomized trials to evaluate whether VAS has beneficial effects on overall child survival.

The effects of vitamin A supplementation with measles vaccine on leucocyte counts and in vitro cytokine production.

As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP ≥ 5 mg/l (28 v. 12%; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95% CI 1·44, 10·90) but not in males (GMR 0·44; 95% CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS.

Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life: a randomised controlled trial.

BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants. METHODS: Two-thousand three hundred forty-three LBW infants were randomly allocated 1:1 to "early BCG" (intervention group) or "late BCG" (current practice). Furthermore, a subgroup (N = 1717) were included in a two-by-two randomised trial in which they were additionally randomised 1:1 to vitamin A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth in Guinea-Bissau, early BCG had no negative effect on infant growth and may have had a beneficial effect for girls. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT00146302).

Neonatal vitamin A supplementation associated with a cluster of deaths and poor early growth in a randomised trial among low-birth-weight boys of vitamin A versus oral polio vaccine at birth.

BACKGROUND: The effect of oral polio vaccine administered already at birth (OPV0) on child survival was not examined before being recommended in 1985. Observational data suggested that OPV0 was harmful for boys, and trials have shown that neonatal vitamin A supplementation (NVAS) at birth may be beneficial for boys. We set out to test this research question in a randomised trial. METHODS: The trial was carried out at the Bandim Health Project, Guinea-Bissau. We planned to enrol 900 low-birth weight (LBW) boys in a randomised trial to investigate whether NVAS instead of OPV0 could lower infant mortality for LBW boys. At birth, the children were randomised to OPV (usual treatment) or VAS (intervention treatment) and followed for 6 months for growth and 12 months for survival. Hazard Ratios (HR) for mortality were calculated using Cox regression. We compared the individual anthropometry measurements to the 2006 WHO growth reference. We compared differences in z-scores by linear regression. Relative risks (RR) of being stunted or underweight were calculated in Poisson regression models with robust standard errors. RESULTS: In the rainy season we detected a cluster of deaths in the VAS group and the trial was halted immediately with 232 boys enrolled. The VAS group had significantly higher mortality than the OPV0 group in the rainy season (HR: 9.91 (1.23 - 80)). All deaths had had contact with the neonatal nursery; of seven VAS boys enrolled during one week in September, six died within two months of age, whereas only one died among the six boys receiving OPV (p = 0.05). Growth (weight and arm-circumference) in the VAS group was significantly worse until age 3 months. CONCLUSION: VAS at birth instead of OPV was not beneficial for the LBW boys in this study. With the premature closure of the trial it was not possible to answer the research question. However, the results of this study call for extra caution when testing the effect of NVAS in the future. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00625482. Registered 18 February 2008.

A randomized trial of an early measles vaccine at 4½ months of age in Guinea-Bissau: sex-differential immunological effects.

BACKGROUND: After measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females. OBJECTIVE: We aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality. METHODS: Within a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A. RESULTS: Overall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction. CONCLUSIONS: In this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects. TRIAL REGISTRATION: clinicaltrials.gov number NCT 00168545.

Vitamin A supplementation and risk of atopy: long-term follow-up of a randomized trial of vitamin A supplementation at six and nine months of age.

BACKGROUND: The World Health Organization recommends high-dose vitamin A supplementation (VAS) for children above six months of age in low-income countries. VAS has been associated with up-regulation of the Th2 response. We aimed to determine if VAS is associated with atopy in childhood. METHODS: Infants in Guinea-Bissau were randomly allocated VAS or placebo, either at six and nine months of age, or only at nine months of age. At six months of age, children were furthermore randomized to measles vaccine or inactivated polio vaccine. At nine months of age all children received measles vaccine. Children were revisited seven years later and skin prick testing was performed. Atopy was defined as a skin prick reaction ≥ 3 mm. RESULTS: 40 of 263 children (15%) were atopic. Overall VAS had no significant effect on the risk of atopy (Prevalence Ratio 1.23; 95% CI 0.69-2.18). The Prevalence Ratio was 1.60 (0.66-3.90) for males and 1.00 (0.46-2.15) for females. CONCLUSIONS: There was no significant effect of VAS in infancy on atopy later in childhood. The role of infant VAS in the development of atopy is still unclear.

The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial.

BACKGROUND: Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG. METHODS: We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion. RESULTS: Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p = 0.07 and head circumference-for-age: p = 0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP. CONCLUSION: The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed. TRIAL REGISTRATION: www.ClinicalTrials.gov (NCT00168610).

High-dose vitamin A supplementation administered with vaccinations after 6 months of age: sex-differential adverse reactions and morbidity.

BACKGROUND: WHO recommends vitamin A supplementation (VAS) at vaccination contacts after six months of age. The effect of this recommendation on mortality has not been evaluated. METHODS: We tested the effect of VAS at vaccination contacts on mortality in a randomised trial in Guinea-Bissau. In a subgroup within this trial we studied adverse reactions to VAS and whether VAS modified known adverse reactions to live and inactivated vaccines and general morbidity during the first month after supplementation overall and by sex. Children aged 6-17 months were randomised to VAS or placebo at the day of vaccination (day 0). We interviewed the caretaker, assessed the fontanel and measured temperature and local reaction at the injection site at home visits on day 1, 2, 3, 7, 14, 21, and 31. We defined systemic adverse reactions to inactivated and live vaccines as fever on day 1 and 2 and on 4-14 respectively. Clinical symptoms associated with increased intracranial pressure (ICP) on day 1 were considered possible adverse reactions to VAS. RESULTS: In 1673 children VAS had no overall effect on clinical symptoms associated with increased ICP (Relative Risk(RR)=1.07 (95%CI: 0.85-1.35)). However, VAS was associated with such clinical symptoms in boys RR=1.38 (1.00-1.91)) but not in girls (p=0.03 for interaction between VAS and sex). VAS had no effect on fever after inactivated vaccines. VAS had no overall effect on fever after live vaccines (RR=0.86 (0.53-1.39)), but tended to reduce the prevalence of fever in boys (RR=0.58 (0.30-1.14)), but not in girls (RR=1.37 (0.66-2.84)) (p=0.09 for interaction between VAS and sex). VAS was associated with increased local reactions to measles vaccine in both sexes (RR=3.65 (1.20-11.12)). CONCLUSION: Adverse reactions were rare, mild and transient and may not in their own right cause concern. However, VAS caused sex-differential adverse reactions and may have sex-differential effects on adverse reactions to vaccines.