Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial

Sebastian Nielsen, Ane B Fisker, Isaquel da Silva, Stine Byberg, Sofie Biering-Sørensen, Carlitos Balé, Amarildo Barbosa, Morten Bjerregaard-Andersen, Nadja Skadkær Hansen, Vu An Do, Ole Bæk, Stine Møller Rasmussen, Lone Damkjær, Sophus Hvidt, Olga Baltzersen, Amabelia Rodrigues, Cesario Martins, Kristoffer J Jensen, Hilton C Whittle, Gaby Smits, Fiona van der Klis, Peter Aaby, Christine S Benn, Sebastian Nielsen, Ane B Fisker, Isaquel da Silva, Stine Byberg, Sofie Biering-Sørensen, Carlitos Balé, Amarildo Barbosa, Morten Bjerregaard-Andersen, Nadja Skadkær Hansen, Vu An Do, Ole Bæk, Stine Møller Rasmussen, Lone Damkjær, Sophus Hvidt, Olga Baltzersen, Amabelia Rodrigues, Cesario Martins, Kristoffer J Jensen, Hilton C Whittle, Gaby Smits, Fiona van der Klis, Peter Aaby, Christine S Benn

Abstract

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%.

Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355.

Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028].

Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further.

Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

Keywords: Heterologous effecs; Maternal antibody; Maternal priming; Measles; Mortality; Non-specific effects; Vaccines.

Conflict of interest statement

OB received a scholarship from the Lundbeck Foundation. All other authors declare no competing interests.

© 2022 The Authors.

Figures

Figure 1
Figure 1
Trial design for the 2-dose versus 1-dose measles vaccine (MV) trial.
Figure 2
Figure 2
Levels of maternal measles antibodies by Study Period (before and after August 15, 2012).
Figure 3
Figure 3
Trial diagram for the 2-dose versus 1-dose measles vaccine (MV) trial in Guinea-Bissau, 2011–2019.
Figure 4
Figure 4
Kaplan-Meier curves of accumulated mortality in children randomised to 2-dose versus 1-dose measles vaccine (MV).
Figure 5
Figure 5
Kaplan-Meier curves of accumulated mortality in children randomised to 2-dose measles vaccine (MV) (A) and in children randomised to 1-dose MV (B) by maternal measles antibody (MatAb) levels.
Figure 6
Figure 6
Meta-analysis: Comparing overall survival of children with vs. without maternal measles antibody (MatAb) in measles-vaccinated children and in control children unvaccinated against measles, respectively.

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Source: PubMed

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