Sanne Marie Thysen

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.

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.

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.

Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study

ABSTRACT Background: Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. Methods: Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). Results: From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52–5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal <3 mm were more likely to not develop a scar (RR = 9.05 (3.69–22.20) and RR = 4.74 (1.96–11.45), respectively). Nutritional status and socioeconomic status were not associated with scarification. Conclusion: Vaccination technique and vaccine strain were associated with BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.

Cost-effectiveness of providing measles vaccination to all children in Guinea-Bissau

ABSTRACT Background: Measles vaccination is associated with major reductions in child mortality and morbidity. In Guinea-Bissau, to limit vaccine wastage, children are only measles-vaccinated if at least six children aged 9–11 months are present at a vaccination session. Objective: To estimate the incremental cost-effectiveness of providing measles vaccine (MV) to all children regardless of age and number of children present. Methods: We estimated MV coverage among children living in villages cluster-randomized to MV for all children and among children cluster-randomized to the current restrictive MV policy (status quo). Prices of MV and injection equipment were obtained from the United Nations Children’s Fund (UNICEF). Cost savings of hospital admissions averted were collected from a sample of health facilities. The non-specific mortality effects of MV were estimated and presented as deaths averted and life years gained (LYG) from providing MV-for-all. Results: MV coverage at 36 months was 97% in MV-for-all clusters and 84% in restrictive MV policy clusters. Conservatively assuming 90% wastage of MV under the MV-for-all policy and 40% under the restrictive MV policy, cost per child vaccinated was USD 3.08 and USD 1.19, respectively. The incremental costs per LYG and death averted of the MV-for-all policy were USD 5.61 and USD 148, respectively. The MV-for-all policy became cost-saving at 88% wastage. Conclusions: Taking the low cost of MV and the beneficial non-specific effects of MV into consideration, a 10-dose MV vial should be reclassified as a ‘1+ dose vial’. The vial should be opened for a single child, irrespective of age, but can vaccinate up to 10 children.

Changes in BCG Vaccination Policy Should Consider the Effect on Child Health

TO THE EDITOR—Tchakoute et al [1] assessed the BCG-specific T-cell proliferation and responsiveness following BCG vaccination at birth versus BCG vaccination at 8 weeks of age in human immunodeficiency virus (HIV)–exposed, uninfected infants. The authors concluded that the 8-week delay did not compromise the immunogenicity of BCG vaccination; in fact, the immunogenicity may have been even higher [1].This is important because according to currentWorld Health Organization (WHO) recommendations, whereas HIV-exposed children without symptoms should receive BCG vaccine at birth, HIV-infected infants and HIV-exposed infants with symptoms of HIV infection should not receive BCG vaccination, because of the risk of disseminated BCG disease (Table 1) [2]. Giving BCG vaccination to HIV-infected children is associated with an estimated risk of 417–992 cases of disseminated BCG disease per 100 000 vaccinations; with a case-fatality rate of 75% [3] this could mean around 1 death in 200 BCG vaccinations of HIV-infected children. Thus, if BCG administration to HIV-exposed infants can be delayed to 8 weeks, it would be possible to exclude many HIV-infected children and reduce the risk of disseminated BCG disease without compromising immunogenicity. The authors should be commended for studying how BCG vaccination recommendations forHIV-exposed infantsmaybe improved. However, neither the authors [1] nor the editorial commentary [3] consider the potential nonspecific effects of BCG. Many observational studies have shown that BCG may have very positive heterologous nonspecific effects, increasing the general resistance to infectious diseases early in life. In randomized trials among lowbirth-weight infants, administration of BCG vaccine at birth versus delayed vaccination as usual was associated with a 48% reduction in neonatal mortality [4, 5]. In 2014, the WHO Strategic Advisory Group of Experts on Immunization acknowledged that BCG vaccination may have beneficial nonspecific effects and recommended further research [6]. From a tuberculosis-prevention perspective, delaying BCG vaccination of HIV-exposed infants until 8 weeks of age may be a limited problem, and as shown by the authors, it may result in even improved immune response to the vaccine [1]. However, neonatal mortality constitutes a great proportion of deaths among children aged <5 years [7]. If BCG vaccination reduces neonatal mortality by around 40%, it is clear that, a delay in BCG vaccination to 8 weeks of age, among HIV-exposed children and irrespective of their symptoms, would yield >1 death among 200 recipients, compared with the mortality rate if they had received BCG vaccine at birth (Table 1). This difference will be even more pronounced with time: with reduced rates of mother-to-child transmission of HIV [8] and better treatment [3], disseminated BCG disease will be responsible for a decreasing fraction of deaths. BCG vaccination is alreadymarkedly delayed in most African countries [9], preventing many children from benefitting from the nonspecific effects of BCG vaccination early in life. Emphasis on the immunological safety of delayed BCG vaccination may lead to further delays in BCG vaccination of HIV-exposed children and possibly also other children and may therefore do more harm than good. Larger studies assessing the impact on overall child survival are needed before recommending delayed BCGvaccination forHIV-exposed children.

Non-live pentavalent vaccines after live measles vaccine may increase mortality

Live measles vaccine (MV) may have beneficial off-target/non-specific effects (NSEs) reducing child mortality beyond prevention of measles infection. In contrast, the non-live pentavalent (Diphtheria-Tetanus-Pertussis-H. influenzae Type B-Hepatitis B) vaccine has no beneficial NSEs. The NSEs are strongest for the most recent vaccine. Hence, sequence of vaccination may affect survival. In Guinea-Bissau, we followed 7094 measles-vaccinated children prospectively from first home visit after 9 months (when MV is scheduled) to 5 years of age. We compared survival by sequence of MV and third Pentavalent vaccine (Penta3; scheduled at 3½ months) in Cox proportional-hazards models. Compared with being vaccinated in-sequence (Penta3-then-MV), having received out-of-sequence Penta3-after-MV before the visit was associated with an adjusted Hazard Ratio (aHR) of 1.19 (95%CI: 0.84-1.69); Receiving missing Penta doses on the visit date tended to be associated with higher mortality (aHR = 1.87 (0.96-3.65)) while not receiving missing doses of Penta was not (aHR = 0.93 (0.57-1.54)), test for interaction p = 0.09.

Selecting the right indicators to ensure optimised implementation of BCG vaccination policy

At the latest Strategic Advisory Group of Experts (SAGE) on Immunization meeting, the working group discussed an extensive review of the evidence of BCG vaccine use for protection against mycobacterial infections including tuberculosis, leprosy, and other nontuberculous mycobacteria infections. We fear that these policy recommendations will not translate into the warranted changes in implementation unless they are accompanied by appropriate indicators. In this commentary, we suggest that BCG coverage should be reported as both coverage at 1 month and 12 months.

Implementation and assessment of vaccination programmes: the importance of vaccination sequence for overall health outcomes

ABSTRACT In addition to their effect on the target infections, accumulating evidence indicates that vaccines have non-specific effects. Live measles vaccine (MV) has beneficial NSEs reducing mortality by more than can be explained by preventing measles infection. In contrast, non-live diphtheria-tetanus-pertussis vaccine (DTP) has negative NSEs; in spite of protecting against diphtheria, tetanus and pertussis, it is associated with increased mortality. The most recent vaccine has the strongest effect on child health, and therefore sequence of vaccines is important. There is consistent evidence that DTP with or after MV is associated with increased mortality compared with having MV as the most recent vaccine, but the sequence of vaccines is not considered in the current evaluation and implementation of vaccination programmes. To maximise the impact of current vaccination programmes on child health, increased emphasis should be placed on receiving MV after DTP. Increasing time with live MV as the most recent vaccine through better adherence to the schedule, and modified recommendations for catch-up vaccinations for children who do not follow the recommended schedule are likely to result in improvements in child health.