Mapping functional humoral correlates of protection against malaria challenge following RTS,S/AS01 vaccination

Abstract

Vaccine development has the potential to be accelerated by coupling tools such as systems immunology analyses and controlled human infection models to define the protective efficacy of prospective immunogens without expensive and slow phase 2b/3 vaccine studies. Among human challenge models, controlled human malaria infection trials have long been used to evaluate candidate vaccines, and RTS,S/AS01 is the most advanced malaria vaccine candidate, reproducibly demonstrating 40 to 80% protection in human challenge studies in malaria-naïve individuals. Although antibodies are critical for protection after RTS,S/AS01 vaccination, antibody concentrations are inconsistently associated with protection across studies, and the precise mechanism(s) by which vaccine-induced antibodies provide protection remains enigmatic. Using a comprehensive systems serological profiling platform, the humoral correlates of protection against malaria were identified and validated across multiple challenge studies. Rather than antibody concentration, qualitative functional humoral features robustly predicted protection from infection across vaccine regimens. Despite the functional diversity of vaccine-induced immune responses across additional RTS,S/AS01 vaccine studies, the same antibody features, antibody-mediated phagocytosis and engagement of Fc gamma receptor 3A (FCGR3A), were able to predict protection across two additional human challenge studies. Functional validation using monoclonal antibodies confirmed the protective role of Fc-mediated antibody functions in restricting parasite infection both in vitro and in vivo, suggesting that these correlates may mechanistically contribute to parasite restriction and can be used to guide the rational design of an improved vaccine against malaria.

Discrete SARS-CoV-2 antibody titers track with functional humoral stability

“…However, emerging data point to the functional quality, rather than the quantity of the humoral immune response, as a correlate of immunity 22,23 . For example, vaccine-induced antibodies lacking the ability to recruit NK cells or monocytes fail to protect against malaria challenge 24 . While previous studies have noted a robust correlation between RBD-specific antibodies and neutralization 17 , not all antibodies against the RBD are neutralizing 25 .…”

Immune responses to malaria pre‐erythrocytic stages: Implications for vaccine development

“…It is also conceivable that NK and NKT cells participate in IFN‐γ‐independent killing of infected hepatocytes. Recently, serological profiling studies suggested that NK cells may inhibit sporozoite invasion through antibody‐mediated interactions 94 . On the other hand, NKT cells may be dispensable in the development of sterile immunity 95 …”

“…Antibodies may remove the surface coat protein of sporozoites in the skin and expose the parasites to their own pore‐forming proteins 110 . Beyond inhibiting sporozoite mobility, antibodies also aid in sporozoite destruction through activation of the complement system, phagocytosis and Fc‐mediated innate cell functions 94,111‐113 …”

“…It remains poorly understood if protection against sporozoites is dependent on immunoglobulin sub‐class, but high levels of antigen‐specific IgG3 and IgG1 in participants receiving RTS,S have been observed 111,119 . Although individuals with higher antibodies against sporozoite antigens have better protection against infection, 105‐107 antibody titres have generally performed poorly as correlates of protection in malaria vaccine studies 94,120 . The modest efficacy of RTS,S in endemic regions suggests that the functionality and avidity of the antibodies, rather than the antibody titres, is a better correlate of immune protection to malaria 94,113 .…”

Breadth of humoral immune responses to the C-terminus of the circumsporozoite protein is associated with protective efficacy induced by the RTS,S malaria vaccine

“…Antibodies targeting the C-terminus have been associated with phagocytic activity, but the phagocytic opsonization index was found to be negatively correlated with protection in a phase 2 RTS,S trial [8]. A recent systems serology study extended protective correlates to NK cell activity and other Fc-mediated activities [9]. A recent study of B-cell responses in malaria-naïve adults who were vaccinated with live sporozoites identified only 2 out of 215 antibodies that were specific to the C-terminus from subjects who were protected from subsequent challenge infections, and these antibodies did not exhibit neutralizing characteristics in vitro or confer protection in mice challenged with PfCSP transgenic Plasmodium berghei parasites [10].…”