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

Dídac Macià; Joseph J Campo; Chenjerai Jairoce; Maximilian Mpina; Hermann Sorgho; David Dosoo; Selidji Todagbe Agnandji; Kwadwo Asamoah Kusi; Luis M Molinos-Albert; Simon Kariuki; Claudia Daubenberger; Benjamin Mordmüller; Gemma Moncunill; Carlota Dobaño

doi:10.1016/S1473-3099(24)00527-9

The effect of Plasmodium falciparum exposure and maternal anti-circumsporozoite protein antibodies on responses to RTS,S/AS01_E vaccination in infants and children: an ancillary observational immunological study to a phase 3, randomised clinical trial

Lancet Infect Dis. 2024 Oct 23:S1473-3099(24)00527-9. doi: 10.1016/S1473-3099(24)00527-9. Online ahead of print.

Authors

Affiliations

¹ ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain.
² Antigen Discovery, Irvine, CA, USA.
³ Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain; Centro de Investigação em Saúde de Manhiça (CISM), Cambeve, Vila de Manhiça, Maputo, Mozambique.
⁴ Ifakara Health Institute, Bagamoyo Research and Training Centre, Bagamoyo, Tanzania.
⁵ Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso.
⁶ Kintampo Health Research Centre, Kintampo, Brong-Ahafo, Ghana.
⁷ Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon; Institute of Tropical Medicine and German Center for Infection Research, University of Tübingen, Tübingen, Germany.
⁸ Department of Immunology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, Legon, Ghana.
⁹ ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain.
¹⁰ Kenya Medical Research Institute/Centre for Global Health, Kisumu, Kisumu, Kenya.
¹¹ Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
¹² CIBER de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain; Institute of Tropical Medicine and German Center for Infection Research, University of Tübingen, Tübingen, Germany; Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, Netherlands.
¹³ ISGlobal, Barcelona, Catalonia, Spain; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Barcelona, Spain. Electronic address: carlota.dobano@isglobal.org.

PMID: 39461358
DOI: 10.1016/S1473-3099(24)00527-9

Abstract

Background: The RTS,S/AS01_E 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/AS01_E 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/AS01_E 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/AS01_E-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/AS01_E-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/AS01_E 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).