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

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.

Antibody responses to the RTS,S/AS01E vaccine and Plasmodium falciparum antigens after a booster dose within the phase 3 trial in Mozambique

“…It has been shown that antibody levels are involved in the vaccine-induced immunity, but they do not fully explain the protective effect of the vaccine 5,6 . Thus far, the study of antibody response in trials performed in endemic areas has been largely focused on IgG levels against the NANP repeat region of CSP, with the exception of our previous work assessing more generally subclass responses to NANP and to other antigens after primary vaccination in the phase 3 trial [7][8][9] .…”

“…We evaluated total IgM, IgG and IgG 1-4 subclasses to vaccine and vaccine-unrelated P. falciparum blood stage antigens. Data were combined with those from the primary vaccine response previously assessed [7][8][9] to display the kinetics from baseline (M0) until M32.…”

The immune response to malaria in utero

“…113 However, this analysis was based on measurement of total IgG levels and did not take into account more recent evidence indicating that cytophilic IgG subclasses, particularly IgG3, may play a more important role in protection, likely due to their ability to fix complement and/or engage of FcR-bearing lymphocytes and phagocytes. 114 Future studies should carefully address the role of antibody subclass, glycosylation, and FcR-mediated engagement of cellular immunity in infant protection from malaria.…”

IgG abnormalities in HIV-positive Malawian women initiating antiretroviral therapy during pregnancy persist after 24 months of treatment

“…The polarization of immunoglobulins towards the IgG1 and IgG3 subclasses is a characteristic of HIV-induced B-cell dysregulation (Raux et al, 2000), but we cannot exclude that the predominance of the cytophilic isotype in women could also be a consequence of exposure to malaria infection, which in Malawi has a prevalence of around 24% in the general population (National Malaria Control Programme (NMCP) and ICF, 2018). Cytophilic antibodies mediate parasite-killing responses (Scopel et al, 2006), and their increase in populations living in areas endemic for Plasmodium falciparum has been widely reported (Rouhani et al, 2015;Dobaño et al, 2019).…”