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

doi:10.1016/j.eclinm.2022.101467

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

EClinicalMedicine. 2022 May 27:49:101467. doi: 10.1016/j.eclinm.2022.101467. eCollection 2022 Jul.

Authors

Sebastian Nielsen^{1

2}, Ane B Fisker^{1

2}, Isaquel da Silva¹, Stine Byberg¹, Sofie Biering-Sørensen¹, Carlitos Balé¹, Amarildo Barbosa¹, Morten Bjerregaard-Andersen¹, Nadja Skadkær Hansen¹, Vu An Do¹, Ole Bæk¹, Stine Møller Rasmussen¹, Lone Damkjær¹, Sophus Hvidt¹, Olga Baltzersen¹, Amabelia Rodrigues¹, Cesario Martins¹, Kristoffer J Jensen^{1

2}, Hilton C Whittle³, Gaby Smits⁴, Fiona van der Klis⁴, Peter Aaby^{1

2}, Christine S Benn^{1

2}

Affiliations

¹ Bandim Health Project, Indepth Network, Apartado 861, Bissau, Guinea-Bissau.
² Bandim Health Project, OPEN, Odense Patient data Explorative Network, Institute of Clinical Research, and Danish Institute of Advanced Science, Odense University Hospital/ University of Southern Denmark, Denmark.
³ London School of Hygiene and Topical Medicine, Keppel Street, London, UK.
⁴ National Institute of Public Health and the Environment, Bilthoven, The Netherlands.

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[n_2-dose=4,397; n_1-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: n_2-dose=90; n_1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n_2-dose=21; n_1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n_2-dose=10/2,801; n_1-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: n_2-dose=27/1,602; n_1-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: n_MatAb=51/3,132; n_noMatAb=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.

Associated data

ClinicalTrials.gov/NCT01486355