Differential Patterns of IgG Subclass Responses to Plasmodium falciparum Antigens in Relation to Malaria Protection and RTS,S Vaccination.

Carlota Dobaño,Gemma Moncunill,Alfons Jiménez,Deepak Gaur,David Dosoo,Kwaku Poku Asante,Itziar Ubillos,Ruth Aguilar,Clarissa Valim,Ross L Coppel,Nana Aba Williams,Núria Díez-Padrisa,Rebeca Santano,Ben Gyan,Marta Vidal,David Cavanagh,Linda Reiling,Joseph J Campo,Chenjerai Jairoce,James G Beeson,Evelina Angov,B Gamain ,David E Lanar ,Seth Owusu‐Agyei ,Chetan E Chitnis ,Virander S Chauhan ,Augusto Nhabomba ,Ana Ayestarán ,Sandeep Dutta

doi:10.3389/fimmu.2019.00439

Abstract

Naturally acquired immunity (NAI) to Plasmodium falciparum malaria is mainly mediated by IgG antibodies but the subclasses, epitope targets and effector functions have not been unequivocally defined. Dissecting the type and specificity of antibody responses mediating NAI is a key step toward developing more effective vaccines to control the disease. We investigated the role of IgG subclasses to malaria antigens in protection against disease and the factors that affect their levels, including vaccination with RTS,S/AS01E. We analyzed plasma and serum samples at baseline and 1 month after primary vaccination with RTS,S or comparator in African children and infants participating in a phase 3 trial in two sites of different malaria transmission intensity: Kintampo in Ghana and Manhiça in Mozambique. We used quantitative suspension array technology (qSAT) to measure IgG1−4 responses to 35 P. falciparum pre-erythrocytic and blood stage antigens. Our results show that the pattern of IgG response is predominantly IgG1 or IgG3, with lower levels of IgG2 and IgG4. Age, site and RTS,S vaccination significantly affected antibody subclass levels to different antigens and susceptibility to clinical malaria. Univariable and multivariable analysis showed associations with protection mainly for cytophilic IgG3 levels to selected antigens, followed by IgG1 levels and, unexpectedly, also with IgG4 levels, mainly to antigens that increased upon RTS,S vaccination such as MSP5 and MSP1 block 2, among others. In contrast, IgG2 was associated with malaria risk. Stratified analysis in RTS,S vaccinees pointed to novel associations of IgG4 responses with immunity mainly involving pre-erythrocytic antigens upon RTS,S vaccination. Multi-marker analysis revealed a significant contribution of IgG3 responses to malaria protection and IgG2 responses to malaria risk. We propose that the pattern of cytophilic and non-cytophilic IgG antibodies is antigen-dependent and more complex than initially thought, and that mechanisms of both types of subclasses could be involved in protection. Our data also suggests that RTS,S efficacy is significantly affected by NAI, and indicates that RTS,S vaccination significantly alters NAI.

Highlights

Malaria caused by Plasmodium falciparum is a significant health problem in children under 5 years old in subSaharan Africa, with about 219 million cases and 435,000 deaths worldwide [1]
We aimed to better understand the differential role that IgG1−4 subclass responses to P. falciparum antigens considered as targets of naturally-acquired immunity (NAI) might have in protection against clinical malaria disease in children who are naturally exposed to the parasite and who receive a primary immunization course with three doses of RTS,S/AS01E or a comparator vaccine
Our study found that malaria protective immunity is mostly associated with the cytophilic subclasses IgG1 and IgG3 and, in spite of the low levels, with IgG4, to certain PE and blood stage (BS) P. falciparum antigens, whereas IgG2 responses were mostly associated with malaria risk

Summary

Introduction

Malaria caused by Plasmodium falciparum is a significant health problem in children under 5 years old in subSaharan Africa, with about 219 million cases and 435,000 deaths worldwide [1]. NAI is mediated by IgG antibodies mainly to antigens of the parasite asexual blood stage (BS) [2, 3] but the specific epitope targets, subclasses and effector functions have not been unequivocally defined. Elucidating these knowledge gaps is important for the development and improvement of vaccines to control and eliminate malaria. RTS,S/AS01E has already undergone a phase 3 trial in Africa, where it showed partial protection with overall vaccine efficacy of 25.9% in infants and 36.3% in children [4]. NAI is mainly directed against BS antigens, a natural response to CSP exists [5] and immunization with irradiated sporozoites confers sterile immunity [6]

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