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The effect of Plasmodium falciparum exposure and maternal anti-circumsporozoite protein antibodies on responses to RTS,S/AS01E vaccination in infants and children: an ancillary observational immunological study to a phase 3, randomised clinical trial - 24/10/24

Doi : 10.1016/S1473-3099(24)00527-9 
Dídac Macià, PhD a, b, c, Joseph J Campo, PhD d, Chenjerai Jairoce, MSc b, e, Maximilian Mpina, PhD f, Hermann Sorgho, PhD g, David Dosoo, PhD h, Selidji Todagbe Agnandji, PhD i, j, Kwadwo Asamoah Kusi, PhD k, Luis M Molinos-Albert, PhD a, b, Simon Kariuki, PhD l, Claudia Daubenberger, PhD m, n, Benjamin Mordmüller, MD c, j, o, Gemma Moncunill, PhD a, b, c, , Carlota Dobaño, ProfPhD a, b, c, ,
a ISGlobal, Barcelona, Catalonia, Spain 
b Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain 
c CIBER de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain 
d Antigen Discovery, Irvine, CA, USA 
e Centro de Investigação em Saúde de Manhiça (CISM), Cambeve, Vila de Manhiça, Maputo, Mozambique 
f Ifakara Health Institute, Bagamoyo Research and Training Centre, Bagamoyo, Tanzania 
g Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso 
h Kintampo Health Research Centre, Kintampo, Brong-Ahafo, Ghana 
i Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon 
j Institute of Tropical Medicine and German Center for Infection Research, University of Tübingen, Tübingen, Germany 
k Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana 
l Kenya Medical Research Institute/Centre for Global Health, Kisumu, Kisumu, Kenya 
m Swiss Tropical and Public Health Institute, Basel, Switzerland 
n University of Basel, Basel, Switzerland 
o Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands 

* Correspondence to: Prof Carlota Dobaño, ISGlobal, Hospital Clínic–Universitat de Barcelona, Barcelona, Catalonia, Spain ISGlobal Hospital Clínic–Universitat de Barcelona Barcelona Catalonia Spain
Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 24 October 2024

Summary

Background

The RTS,S/AS01E malaria vaccine showed lower antibody response and protective efficacy in infants aged 6–12 weeks compared with children aged 5–17 months (for whom this vaccine is recommended). We aimed to study the effect of previous Plasmodium falciparum exposure on the antibody responses to RTS,S/AS01E vaccination in infants and children, and the mediating effect of baseline (including maternal) anti-circumsporozoite protein (CSP) antibodies.

Methods

In this observational study, we included children and infants from six African countries (Burkina Faso, Gabon, Ghana, Kenya, Mozambique, and Tanzania) enrolled in the MAL067 immunology ancillary study of the RTS,S/AS01E phase 3 clinical trial from March 27, 2009, to Jan 21, 2011. We used comparator-vaccinated infants and children to identify antibody-based signatures of previous P falciparum exposure, which were later applied to RTS,S/AS01E-vaccinated infants and children. In these participants, we explored the relationship between vaccine antibody immunoglobulin G (IgG) responses measured by ELISA and pre-vaccination serological markers of malaria exposure by assessing the IgG levels against 1000 P falciparum antigens using partial proteome microarrays.

Findings

We included 718 comparator-vaccinated infants (348 [48%]) and children (370 [52%]) and 606 RTS,S/AS01E-vaccinated infants (329 [54%]) and children (277 [46%]). Anti-CSP IgG responses to primary vaccination did not correlate with a baseline signature of previous exposure in children, suggesting that prior P falciparum exposure does not significantly affect antibody immunogenicity in children (Pearson’s r=–0·02 [95% CI –0·13 to 0·10]). By contrast, high P falciparum exposure signature levels at the time of vaccination in infants, presumably driven by maternally transferred antibodies and declining within the initial 6–12 months of life, correlated with reduced RTS,S/AS01E responses (r=–0·17 [–0·27 to –0·06]). This negative correlation was stronger for anti-CSP IgG than for the exposure signature or any other more immunogenic blood stage P falciparum antigens (r=–0·42 [–0·50 to –0·33]), persisted after adjustment by baseline levels of the exposure signature (semi-partial correlation r=–0·44 [–0·55 to –0·33]), and involved antibodies to the central NANP region (r=–0·39 [–0·49 to –0·28]) but not the C-terminal region (r=0·02 [–0·10 to 0·15]) of CSP. The negative effect of maternal anti-CSP IgG in infants did not appear to be confounded by other malaria transmission-dependent variables.

Interpretation

Interference between passive immunity and vaccine response is clinically significant and might affect the implementation of next-generation CSP-based vaccines for young infants and mothers as well as passive immunisation with human monoclonal antibodies.

Funding

US National Institutes of Health, National Institute of Allergy and Infectious Diseases; PATH–Malaria Vaccine Initiative; Spanish Ministerio de Economía y Competitividad (Instituto de Salud Carlos III), European Regional Development Fund and European Social Fund; Fundación Ramón Areces; Spanish Ministry of Science and Innovation; and Generalitat de Catalunya (CERCA Program).

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