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Open Access Research article

A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

Michael T White1*, Philip Bejon23, Ally Olotu2, Jamie T Griffin1, Kalifa Bojang4, John Lusingu5, Nahya Salim6, Salim Abdulla6, Nekoye Otsyula7, Selidji T Agnandji89, Bertrand Lell89, Kwaku Poku Asante10, Seth Owusu-Agyei10, Emmanuel Mahama10, Tsiri Agbenyega11, Daniel Ansong11, Jahit Sacarlal1213, John J Aponte1214 and Azra C Ghani1

Author Affiliations

1 MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK

2 KEMRI-Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya

3 Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK

4 Medical Research Council Unit, Fajara, The Gambia

5 National Institute for Medical Research, Tanga Centre, Tanga, Tanzania

6 Ifakara Health Institute, Bagamoyo, Tanzania

7 Kenya Medical Research Institute, and US Army Medical Research Unit–Kenya, Nairobi, Kenya

8 Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon

9 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany

10 Kintampo Health Research Centre, Kintampo, Ghana

11 School of Medical Sciences, Kumasi, Ghana

12 Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique

13 Faculdade de Medicina, Universidade Eduardo Mondlane, Avenida do Zimbabwe, Maputo, Mozambique

14 Barcelona Centre for International Health Research (CRESIB), Universitat de Barcelona, Barcelona, Spain

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BMC Medicine 2014, 12:117  doi:10.1186/s12916-014-0117-2

Published: 10 July 2014

Abstract

Background

The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria.

Methods

Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.

Results

Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.

Conclusions

Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.

Keywords:
Malaria; Vaccine; Circumsporozoite protein; Antibody; RTS,S; Phase 2 clinical trials; Mathematical model; Clinical immunity