Stine Byberg

Reduced All-cause Child Mortality After General Measles Vaccination Campaign in Rural Guinea-Bissau.

Background: Randomized trials have shown that measles vaccine (MV) prevents nonmeasles deaths. MV campaigns are conducted to eliminate measles infection. The overall mortality effect of MV campaigns has not been studied. Methods: Bandim Health Project (BHP) surveys children aged 0–4 years in rural Guinea-Bissau through a health and demographic surveillance system. A national MV campaign in 2006 targeted children aged 6 months to 15 years. In a Cox proportional hazards model with age as the underlying timescale, we compared mortality of children aged 6–59 months after the campaign with mortality in the same age group during the 2 previous years. Results: Eight thousand one hundred fifty eight children aged 6–59 months were under BHP surveillance during the 2006 campaign and 7999 and 8108 during similar periods in 2004 and 2005. At least 90% of the eligible children received MV in the campaign. There were 161 nonaccident deaths in 12 months after the campaign compared with 203 and 206 deaths in the 2 previous years, the adjusted mortality rate ratio (aMRR) comparing all children in 2006 with all children in 2004 to 2005 being 0.80 (95% confidence interval: 0.66–0.96). Censoring deaths caused by measles infection, the aMRR was 0.83 (0.69–1.00). The mortality reduction was separately significant for girls [aMRR = 0.74 (0.56–0.97)] and for children who also had received routine MV [MRR = 0.59 (0.36–0.99)]. Conclusions: Mortality levels were stable during 2004 and 2005, but a significant drop occurred after the 2006 MV campaign and was not explained by the prevention of measles deaths. If MV campaigns reduce nonmeasles-related mortality, the policies for measles vaccination should take this into account.

Neonatal vitamin A supplementation associated with increased atopy in girls

Neonatal vitamin A supplementation (NVAS) is currently being considered as policy in countries at risk of deficiency. A previous study suggested that NVAS may be associated with increased atopy. We examined the effect of NVAS on atopy by conducting long‐term follow‐up of a previous randomized controlled trial in Guinea‐Bissau.

BCG coverage and barriers to BCG vaccination in Guinea-Bissau: an observational study

BackgroundBCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination (“restricted vial-opening policy”). BCG coverage is usually reported as 12-month coverage, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau.MethodsBandim Health Project (BHP) runs a health and demographic surveillance system covering women and their children in 182 randomly selected village clusters in rural Guinea-Bissau. BCG coverage was assessed for children born in 2010, when the restricted vial-opening policy was universally implemented, and in 2012–2013, where BHP provided BCG to all children at monthly visits in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios.ResultsAmong 3951 children born in 2010, vaccination status was assessed for 84%. BCG coverage by 1 week of age was 11%, 38% by 1 month, and 92% by 12 months. If BCG had been given at first contact with the health system, 1-week coverage would have been 35% and 1-month coverage 54%. When monthly visits were introduced in intervention regions, 1-month coverage was higher in intervention regions (88%) than in control regions (51%), the prevalence ratio being 1.74 (1.53-2.00). Several factors, including socioeconomic factors, were associated with delayed BCG vaccination in the 2010-birth cohort. When BCG was available at monthly visits these factors were no longer associated with delayed BCG vaccination, only region of residence was associated with delayed BCG vaccination.ConclusionBCG coverage during the first months of life is low in Guinea-Bissau. Providing BCG at monthly vaccination visits removes the risk factors associated with delayed BCG vaccination.

A general measles vaccination campaign in urban Guinea-Bissau: Comparing child mortality among participants and non-participants

BACKGROUND Measles vaccination campaigns targeting children aged 9-59months are conducted every three years in Guinea-Bissau. Studies have demonstrated beneficial non-specific effects of measles vaccine. We compared mortality one year after the December 2012 measles vaccination campaign in Bissau city for children who received campaign measles vaccine with children who did not receive campaign measles vaccine. METHODS Field workers from Bandim Health Project registered all children living in the Bandim Health Projects study area who received measles vaccination at the campaign posts. Children not seen during the campaign were visited at home and campaign participation status was assessed. We compared mortality rates of participants vs. non-participants in Cox regression models. RESULTS 5633 children aged 9-59months (85%) received campaign measles vaccination and 1006 (15%) did not. During the subsequent year 16 children died. Adjusted for background factors, the hazard ratio (HR) comparing measles vaccinated versus unvaccinated was 0.28 (95% CI: 0.10-0.77). The benefit was larger for girls (HR: 0.17 (0.05-0.59)) and for children who had received routine measles vaccine before the campaign (HR: 0.15 (0.04-0.63)). CONCLUSIONS We found indications of strong beneficial non-specific effects of receiving measles vaccine during the 2012 campaign, especially for girls and children with previous routine measles vaccination. Measles vaccination campaigns may be an effective way of improving child survival.

Different effects of BCG strains – A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau

BACKGROUND Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. METHODS During 2011-2013, infants in the Bandim Health Projects urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. RESULTS Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74-2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. CONCLUSION BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost.

A two-centre randomised trial of an additional early dose of measles vaccine: Effects on mortality and measles antibody levels.

Background In addition to protecting against measles, measles vaccine (MV) may have beneficial nonspecific effects. We tested the effect of an additional early MV on mortality and measles antibody levels. Methods Children aged 4-7 months at rural health and demographic surveillance sites in Burkina Faso and Guinea-Bissau were randomized 1:1 to an extra early standard dose of MV (Edmonston-Zagreb strain) or no extra MV 4 weeks after the third diphtheria-tetanus-pertussis-hepatitis B-Haemophilus influenzae type b vaccine. All children received routine MV at 9 months. We assessed mortality through home visits and compared mortality from enrollment to age 3 years using Cox proportional hazards models, censoring for subsequent nontrial MV. Subgroups of participants had blood sampled to assess measles antibody levels. Results Among 8309 children enrolled from 18 July 2012 to 3 December 2015, we registered 145 deaths (mortality rate: 16/1000 person-years). The mortality was lower than anticipated and did not differ by randomization group (hazard ratio, 1.05; 95% confidence interval, 0.75-1.46). At enrollment, 4% (16/447) of children in Burkina Faso and 21% (90/422) in Guinea-Bissau had protective measles antibody levels. By age 9 months, no measles-unvaccinated/-unexposed child had protective levels, while 92% (306/333) of early MV recipients had protective levels. At final follow-up, 98% (186/189) in the early MV group and 97% (196/202) in the control group had protective levels. Conclusions Early MV did not reduce all-cause mortality. Most children were susceptible to measles infection at age 4-7 months and responded with high antibody levels to early MV. Clinical Trials Registration NCT01644721.

Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.

Background Measles vaccine (MV) may have non-specific beneficial effects for child health and particularly seems to prevent respiratory infections. Streptococcus pneumoniae is the leading cause of bacterial pneumonia among children worldwide, and nasopharyngeal colonization precedes infection. Objective We investigated whether providing early MV at 18 weeks of age reduced pneumococcal colonization and/or density up to 9 months of age. Method The study was conducted in 2013–2014 in Guinea-Bissau. Pneumococcal vaccine was not part of the vaccination program. Infants aged 18 weeks were block-randomized 2:1 to early or no early MV; at age 9 months, all children were offered MV as per current policy. Nasopharyngeal swabs were taken at baseline, age 6.5 months, and age 9 months. Pneumococcal density was determined by q-PCR. Prevalence ratios of pneumococcal colonization and recent antibiotic treatment (yes/no) by age 6.5 months (PR6.5) and age 9 months (PR9) were estimated using Poisson regression with robust variance estimates while the pneumococcal geometric mean ratio (GMR6.5 and GMR9) was obtained using OLS regression. Results Analyses included 512 children; 346 early MV-children and 166 controls. At enrolment, the pneumococcal colonization prevalence was 80% (411/512). Comparing early MV-children with controls, the PR6.5 was 1.02 (95%CI = 0.94–1.10), and the PR9 was 1.04 (0.96–1.12). The GMR6.5 was 1.02 (0.55–1.89), and the GMR9 was 0.69 (0.39–1.21). Early MV-children tended to be less frequently treated with antibiotics prior to follow up (PR6.5 0.60 (0.34–1.05) and PR9 0.87 (0.50–1.53)). Antibiotic treatment was associated with considerably lower colonization rates, PR6.5 0.85 (0.71–1.01) and PR9 0.66 (0.52–0.84), as well as lower pneumococcal density, GMR6.5 0.32 (0.12–0.86) and GMR9 0.52 (0.18–1.52). Conclusion Early MV at age 18 weeks had no measurable effect on pneumococcal colonization prevalence or density. Higher consumption of antibiotics among controls may have blurred an effect of early MV. Trial registration clinicaltrials.gov NCT01486355

Household experience and costs of seeking measles vaccination in rural Guinea-Bissau.

Children younger than 12 months of age are eligible for childhood vaccines through the public health system in Guinea‐Bissau. To limit open vial wastage, a restrictive vial opening policy has been implemented; 10‐dose measles vaccine vials are only opened if six or more children aged 9–11 months are present at the vaccination post. Consequently, mothers who bring their child for measles vaccination can be told to return another day. We aimed to describe the household experience and estimate household costs of seeking measles vaccination in rural Guinea‐Bissau.

Placebo use in vaccine trials: Caution when using active vaccines as placebo.

Recently, a WHO expert panel published its recommendations egarding placebo use in vaccine trials [1]. The expert panel conludes that the use of placebo vaccines can be acceptable in certain ituations. The panel proposes that “Rather than using a true placebo ontrol (i.e. an inert substance), it may be appropriate to use a vaccine gainst a disease that is not the focus of the trial” [1]. It is stated that The motivation for using these types of “placebos” is to benefit paricipants in the control arm”. The panel notes that “this motivation nderscores the importance of ensuring that the comparator vaccine(s) re proven to be beneficial in the study population” and “It is imporant to recognize that trials using such “placebos” may provide a less erfect control if the effects of the comparator vaccine(s) confound the valuation of the risk-benefit profile of the experimental vaccine”. The concept of non-specific heterologous effects of vaccines is ot mentioned. However, many studies have shown that vaccines, part from protecting against the target disease, have non-specific ffects on the immune system. In brief, these studies have sugested that live attenuated vaccines train the immune system nd increase resistance towards infections in general. In contrast, nactivated vaccines have been associated with increased susceptiility to unrelated infections [2]. A recently conducted WHO/SAGE eview of BCG, measles, and DTP-containing vaccines, concluded hat though the evidence mostly came from observational studes which were regarded as being at risk of bias, the results with egard to the live BCG and measles vaccine indicated a “beneficial ffect on overall mortality” with estimated effects for both vaccines eing “in the region of a halving of mortality risk”. In contrast, for TP-containing vaccine it was noted that “The majority of studies ndicated a deleterious effect of DTP on mortality” [3]. SAGE conluded that “the non-specific effects on all-cause mortality of DTP arrant further research” [3]. Thus, if vaccines in addition to their specific effects also have on-specific effects there are reasons to question whether it will e possible to meet the two conditions set up by the panel when sing a placebo vaccine: that the placebo vaccine is beneficial in he study population and that it does not confound the evaluation f the experimental vaccine. Based on existing evidence, an inactivated placebo vaccine may e harmful to the control group and may lead to a falsely overestiated safety and efficacy of the experimental vaccine. For example, n early measles vaccine trials in Guinea-Bissau, inactivated polio accine (IPV) was used as a comparator vaccine. However, IPV was

Randomized Trial of 2 Versus 1 Dose of Measles Vaccine: Effect on Hospital Admission of Children After 9 Months of Age

Background Two doses of measles vaccine (MV) might reduce the nonmeasles mortality rate more than 1 dose of MV does. The effect of 2 versus 1 dose on morbidity has not been examined. Within a randomized trial of the effect of 2 doses versus 1 dose of MV on mortality in Guinea-Bissau, we investigated the effect on hospital admissions. Methods Children were randomly assigned 1:2 to receive MV at 4.5 and 9 months of age or the currently recommended dose at 9 months. We compared hospital admission rates among children between 9 and 18 months of age in a Cox regression model with age as the underlying time scale. Half of the children had received neonatal vitamin A supplementation (NVAS) in another trial. The beneficial effect of MV at 4.5 and 9 months on mortality was limited to children who had not received NVAS; therefore, we investigated the interaction of MV with NVAS on admission rates. Results Among 5626 children (2 doses of MV, 1960 children; 1 dose of MV, 3666), we identified 311 hospital admissions of children between 9 and 18 months of age. Overall, compared to 1 dose of MV, 2 doses reduced the risk of hospital admission for children who had not received NVAS (hazard ratio [HR], 0.66 [95% confidence interval (CI), 0.47-0.93]), but we found no effect among NVAS recipients (HR, 1.16 [95% CI, 0.82-1.63]) (P = .02 for interaction). Conclusions The benefit of 2 doses of MV was limited to children who had not received NVAS. NVAS is not generally recommended; hence, an early 2-dose measles vaccination policy might reduce hospital admissions more than the current policy of providing the first MV at 9 months of age. Trial registration ClinicalTrials.gov identifier NCT00168558.