Eff ects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival:an observational study

Background In 2008, the GAVI Alliance funded the introduction of new vaccines (including pentavalent diphtheriatetanus- pertussis [DTP] plus hepatitis B and Haemophilus infl uenzae type b antigens) in Guinea-Bissau. The introduction was accompanied by increased vaccination outreach services and a more restrictive wastage policy, including only vaccinating children younger than 12 months. We assessed coverage of all vaccines in the Expanded Program on Immunizations before and after the new vaccines’ introduction, and the implications on child survival. Methods This observational cohort study used data from the Bandim Health Project, which has monitored vaccination status and mortality in randomly selected village clusters in Guinea-Bissau since 1990. We assessed the change in vaccination coverage using cohort data from children born in 2007 and 2009; analysed the proportion of children who received measles vaccine after 12 months of age using data from 1999–2006; and compared child mortality after age 12 months in children who had received measles vaccine and those who had not using data from 1999 to 2006. Findings The proportion of children who were fully vaccinated by 12 months of age was 53% (468 of 878) in the 2007 cohort and 53% (467 of 879) in the 2009 cohort (relative risk [RR] 1·00, 95% CI 0·89–1·11). Coverage of DTP-3 and pentavalent-3 increased from 73% (644 of 878) in 2007 to 81% (712 of 879) in 2009 (RR 1·10, 95% CI 1·04 –1·17); by contrast, the coverage of measles vaccination declined from 71% (620 of 878) to 66% (577 of 879; RR 0·93, 0·85–1·01). The eff ect of the changes was signifi cantly diff erent for DTP-3 coverage compared with measles vaccine coverage (p=0·002). After 12 months of age, the adjusted mortality rate ratio was 0·71 (95% CI 0·56–0·90) for children who had received measles vaccine compared with those who had not (0·59 [0·43–0·80] for girls and 0·87 [0·62–1·23] for boys). Interpretation The introduction of the new vaccination programme in 2008 was associated with increased coverage of DTP, but decreased coverage of measles vaccine. In 1999–2006, child mortality was higher in children who had not received measles vaccine than in those who had

Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine.

BACKGROUND: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV). METHODS: During an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial. SETTING: MV RCT conducted in urban Guinea-Bissau 2003-2009. INTERVENTIONS: Natural experiments with OPV due to missing vaccine and the implementation of OPV campaigns. MAIN OUTCOME MEASURE: Changes in the mortality rate ratio (MRR) for 2-dose MV versus 1-dose MV. RESULTS: First, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2-dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before-enrolment, respectively. CONCLUSIONS: Bissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2-dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed

Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival.

BACKGROUND: Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. METHODS: To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4-6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. RESULTS: In trial I (1993-1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0-.52). In trial II (2003-2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09-.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4-6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07-.64) between 4-6 months and 5 years. CONCLUSIONS: Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4-6 months (earlier than currently recommended) and a booster dose at 9-12 months of age. CLINICAL TRIALS REGISTRATION: NCT00168558

Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau.

BACKGROUND: In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines. OBJECTIVE: We investigated whether there were interactions between NVAS and early MV. DESIGN: We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR). RESULTS: A total of 5141 children were randomized to NVAS (N=3015) or placebo (N=2126) and were later randomized to early MV (N=1700) or no early MV (N=3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR=30 versus MR=0, p=0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV=0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio=5.39 (95% confidence interval: 1.62, 17.99)). CONCLUSIONS: These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs

Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment

Background: Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. Methods and Findings: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. Conclusions: This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine

The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau

<p>Abstract</p> <p>Background</p> <p>Vitamin A supplementation (VAS) given to children between 6 months and 5 years of age is known to reduce mortality in low-income countries. We have previously observed that girls benefit more from a lower dose of VAS than the one recommended by WHO, the effect being strongest if diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccination. We aimed to test these observations.</p> <p>Methods</p> <p>During national immunisations days in Guinea-Bissau, West Africa, combining oral polio vaccination and VAS, we randomised 8626 children between 6 months and 5 years of age to receive the dose of VAS recommended by WHO or half this dose. Mortality rate ratios (MRRs) were assessed after 6 and 12 month.</p> <p>Results</p> <p>The overall mortality rate among participants was lower than expected. There was no significant difference in mortality at 6 months and 12 months of follow up between the low dose VAS group and the recommended dose VAS group. The MRRs were 1.23 (0.60-2.54) after 6 months and 1.17 (0.73-1.87) after 12 months. This tendency was similar in boys and girls. The low dose was not associated with lower mortality in girls if the most recent vaccine was DTP (MRR = 0.60 (0.14-2.50) after 6 months).</p> <p>Conclusion</p> <p>Our sample size does not permit firm conclusions since mortality was lower than expected. We could not confirm a beneficial effect of a lower dose of VAS on mortality in girls.</p> <p>Trial registration</p> <p>The study was registered under clinicaltrials.gov, number <a href="http://www.clinicaltrials.gov/ct2/show/NCT00168636">NCT00168636</a></p

Adverse pregnancy outcome disclosure and women's social networks: a qualitative multi-country study with implications for improved reporting in surveys.

BACKGROUND: Globally, approximately 6,700 newborn deaths and 5,400 stillbirths occur daily. The true figure is likely higher, with under reporting of adverse pregnancy outcomes (APOs) noted. Decision-making in health is influenced by various factors, including one's social networks. We sought to understand APOs disclosure within social networks in Uganda, Ghana, Guinea-Bissau and Bangladesh and how this could improve formal reporting of APOs in surveys.  METHODS: A qualitative, exploratory multi-country study was conducted within four health and demographic surveillance system sites. 16 focus group discussions were held with 147 women aged 15-49 years, who had participated in a recent household survey. Thematic analysis, with both deductive and inductive elements, using three pre-defined themes of Sender, Message and Receiver was done using NVivo software. RESULTS: Disclosure of APOs was a community concern, with news often shared with people around the bereaved for different reasons, including making sense of what happened and decision-making roles of receivers. Social networks responded with comfort, providing emotional, in-kind and financial support. Key decision makers included men, spiritual and traditional leaders. Non-disclosure was usually to avoid rumors in cases of induced abortions, or after a previous bad experience with health workers, who were frequently excluded from disclosure, except for instances where a woman sought advice on APOs. CONCLUSIONS: Communities must understand why they should report APOs and to whom. Efforts to improve APOs reporting could be guided by diffusion of innovation theory, for instance for community entry and sensitization before the survey, since it highlights how information can be disseminated through community role models. In this case, these gatekeepers we identified could promote reporting of APOs. The stage at which a person is in decision-making, what kind of adopter they are and their take on the benefits and other attributes of reporting are important. In moving beyond survey reporting to getting better routine data, the theory would be applicable too. Health workers should demonstrate a more comforting and supportive response to APOs as the social networks do, which could encourage more bereaved women to inform them and seek care

Stillbirth maternity care measurement and associated factors in population-based surveys: EN-INDEPTH study.

BACKGROUND: Household surveys remain important sources of maternal and child health data, but until now, standard surveys such as Demographic and Health Surveys (DHS) have not collected information on maternity care for women who have experienced a stillbirth. Thus, nationally representative data are lacking to inform programmes to address the millions of stillbirths which occur annually. METHODS: The EN-INDEPTH population-based survey of women of reproductive age was undertaken in five Health and Demographic Surveillance System sites in Bangladesh, Ethiopia, Ghana, Guinea-Bissau and Uganda (2017-2018). All women answered a full birth history with additional questions on pregnancy losses (FBH+) or full pregnancy history (FPH). A sub-sample, including all women reporting a recent stillbirth or neonatal death, was asked additional maternity care questions. These were evaluated using descriptive measures. Associations between stillbirth and maternal socio-demographic characteristics, babies' characteristics and maternity care use were assessed using a weighted logistic regression model for women in the FBH+ group. RESULTS: A total of 15,591 women reporting a birth since 1 January 2012 answered maternity care questions. Completeness was very high (> 99%), with similar proportions of responses for both live and stillbirths. Amongst the 14,991 births in the FBH+ group, poorer wealth status, higher parity, large perceived baby size-at-birth, preterm or post-term birth, birth in a government hospital compared to other locations and vaginal birth were associated with increased risk of stillbirth after adjusting for potential confounding factors. Regarding association with reported postnatal care, women with a stillbirth were more likely to report hospital stays of > 1 day. However, women with a stillbirth were less likely to report having received a postnatal check compared to those with a live birth. CONCLUSIONS: Women who had experienced stillbirth were able to respond to questions about pregnancy and birth, and we found no reason to omit questions to these women in household surveys. Our analysis identified several potentially modifiable factors associated with stillbirth, adding to the evidence-base for policy and action in low- and middle-income contexts. Including these questions in DHS-8 would lead to increased availability of population-level data to inform action to end preventable stillbirths

Barriers and enablers to reporting pregnancy and adverse pregnancy outcomes in population-based surveys: EN-INDEPTH study.

BACKGROUND: Risks of neonatal death, stillbirth and miscarriage are highest in low- and middle-income countries (LMICs), where data has most gaps and estimates rely on household surveys, dependent on women reporting these events. Underreporting of pregnancy and adverse pregnancy outcomes (APOs) is common, but few studies have investigated barriers to reporting these in LMICs. The EN-INDEPTH multi-country study applied qualitative approaches to explore barriers and enablers to reporting pregnancy and APOs in surveys, including individual, community, cultural and interview level factors. METHODS: The study was conducted in five Health and Demographic Surveillance System sites in Guinea-Bissau, Ethiopia, Uganda, Bangladesh and Ghana. Using an interpretative paradigm and phenomenology methodology, 28 focus group discussions were conducted with 82 EN-INDEPTH survey interviewers and supervisors and 172 women between February and August 2018. Thematic analysis was guided by an a priori codebook. RESULTS: Survey interview processes influenced reporting of pregnancy and APOs. Women found questions about APOs intrusive and of unclear relevance. Across all sites, sociocultural and spiritual beliefs were major barriers to women reporting pregnancy, due to fear that harm would come to their baby. We identified several factors affecting reporting of APOs including reluctance to speak about sad memories and variation in recognition of the baby's value, especially for APOs at earlier gestation. Overlaps in local understanding and terminology for APOs may also contribute to misreporting, for example between miscarriages and stillbirths. Interviewers' skills and training were the keys to enabling respondents to open up, as was privacy during interviews. CONCLUSION: Sociocultural beliefs and psycho-social impacts of APOs play a large part in underreporting these events. Interviewers' skills, careful tool development and translation are the keys to obtaining accurate information. Reporting could be improved with clearer explanations of survey purpose and benefits to respondents and enhanced interviewer training on probing, building rapport and empathy