Short communicationNon-live pentavalent vaccines after live measles vaccine may increase mortality
Introduction
The Expanded Programme on Immunizations (EPI) in many low income countries includes Bacillus Calmette-Guérin vaccine (BCG) with oral polio vaccine (OPV) at birth, 3 doses of diphtheria-tetanus-pertussis (DTP)-containing vaccine with OPV at 6, 10 and 14 weeks of age and measles vaccine (MV) at 9 months of age [1]. Since three doses of DTP-containing vaccines are scheduled, delays in DTP-vaccinations frequently accumulate and cause DTP-containing vaccines to be given after MV. The actual sequence of vaccinations receives little focus in the present monitoring of the EPI. EPI performance is assessed by coverage for specific antigens; administrative data reported to donors and WHO focus on the number of doses given to infants [2]. It is assumed that providing missing vaccine doses will always leave the child better off than not providing them. However, this may be wrong.
In addition to preventing targeted infections, vaccines may have non-specific effects (NSEs) affecting susceptibility to unrelated infections. In the recent WHO-commissioned review of the NSEs of the live attenuated BCG and MV and the non-live DTP-vaccine, there were strong contrasts between the live vaccines, which were associated with 40–50% lower mortality, and the non-live DTP vaccine, which tended to be associated with higher mortality [3]. The review also indicated that sequence of vaccines was important: compared with the recommended sequence (MV after DTP), DTP after MV was associated with 2.66 (95%CI: 1.04–6.81) times higher mortality and DTP with MV was associated with a 2.29 (1.55–3.37) times higher mortality [3]. A new study of vaccination sequence and mortality from Ghana found that mortality for children who received DTP-containing vaccines after MV was 1.61 (1.07–2.44) times higher than for children vaccinated in-sequence [4].
We took advantage of the continuous data collection of the Bandim Health Project (BHP) to assess associations between vaccination sequence and subsequent mortality. Higher mortality of children receiving vaccines out-of-sequence could be due to an inherent bias, the mothers being less compliant with the health care system. In the present study, we could assess mortality of children who received out-of-sequence vaccination, and mortality of children who were eligible for out-of-sequence vaccination but did not receive missing doses of DTP-containing vaccines.
Section snippets
Methods
Setting: BHP runs a Health and Demographic Surveillance System (HDSS), covering 182 village clusters in Guinea-Bissau [5]. All households in the HDSS are visited every 6 months by field teams collecting information on women and children < 5 years. At all visits, pregnancies, births and deaths are registered; children are followed with registration of vital status, nutritional status (mid-upper-arm circumference) and vaccination status. A team nurse provides vaccines according to the national
Results
Among 25,831 children first visited at 9–18 months of age between 1 September 2008 and 22 June 2015, 7094 had received MV without co-administered VAS through the national EPI (Supplementary Fig. 1, Supplementary Table 1). The majority of the children (6458 (91%)) had already received Penta3 and among these 5426 (85%) had received Penta3 before MV, thus being vaccinated in-sequence (Table 1, Group 1). The 1032 children who were fully vaccinated but received vaccines out-of-sequence mainly had
Discussion
In the present small observational study, confounders may explain part of the excess mortality in the group of children receiving Penta after MV. However, it is unlikely to explain the whole difference. First, mortality tended to be higher among children who received vaccines out-of-sequence, both among fully vaccinated children and among children receiving Penta after MV on the date of visit. In contrast, mortality was not higher among children missing Penta3 who were not vaccinated with Penta
Conflicts of interest and source of funding
This work was supported by DANIDA [grant: 104.Dan.8-920], European Union FP7 support for OPTIMUNISE [grant: Health-F3-2011-261375] and Danish Council for Independent Research [DFF-1333-00192]. The Bandim Health Project received support from Danish National Research Foundation via support to CVIVA [grant: DNRF108]. The funding agencies had no role in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication.
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