Baseline exposure, antibody subclass, and hepatitis B response differentially affect malaria protective immunity following RTS,S/AS01E vaccination in African children

Abstract

BackgroundThe RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure.MethodsWe measured total IgM, IgG, and IgG1–4 subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them.ResultsRTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified.ConclusionsCytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1186-4) contains supplementary material, which is available to authorized users.

A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

“…Clinical trials on RTS,S showed that the protective response induced by the vaccine fades rapidly; however, whether this is related to specific features of the CSP antigen, or of the HBsAg carrier, or both has not yet been elucidated. Recent analyses of phase III trials suggest that lots of factors are at play in determining the efficacy of RTS,S-induced protection and antibodies levels and decay, such as age, malaria exposure, IgG subclasses, all of which might have different impact on different antigens (50,51). An interesting observation from Ubillos et al (50) was that higher anti-HBsAg antibody levels were associated with less malaria disease risk in RTS,S vaccinees, and further investigation will be needed to explain such a finding.…”

Antibody feedback limits the expansion of cognate memory B cells but drives the diversification of vaccine-induced antibody responses

“…In contrast no relationship was observed between antibody titer and the magnitude of boosting for C-terminal antibodies at any timepoint (Figure 7F). It is notable that C-terminal antibodies have been associated with protection by the RTS, S vaccine 42, 43 . Overall these data strongly support the hypothesis that epitope masking rather than parasite clearance of Fc mediated immune regulator mechanisms account for antibody feedback not only in the mouse model but also in vaccinated individuals.…”

A Chemokine-Fusion Vaccine Targeting Immature Dendritic Cells Elicits Elevated Antibody Responses to Malaria Sporozoites in Infant Macaques

“…found that only concentrations of IgG3 specific for blood stage antigens were associated with reduced risk of infection in Senegal 43 . Studies with the RTS,S/AS01E vaccine in Mozambique and Ghana found protection against sporozoite mediated infection positively associated with concentrations of IgG1 and IgG3 antibodies specific for vaccine antigens 44 . These human antibody isotypes are important in mediating antibody-dependent cellular cytotoxicity and complement dependent killing, as are the mouse IgG2b and 2c isotypes elicited by AddaVax, but not alum, in the current study.…”