RTS,S/AS01E Malaria Vaccine Induces Memory and Polyfunctional T Cell Responses in a Pediatric African Phase III Trial

Abstract

Comprehensive assessment of cellular responses to the RTS,S/AS01E vaccine is needed to understand potential correlates and ultimately mechanisms of protection against malaria disease. Cellular responses recognizing the RTS,S/AS01E-containing circumsporozoite protein (CSP) and Hepatitis B surface antigen (HBsAg) were assessed before and 1 month after primary vaccination by intracellular cytokine staining and 16-color flow cytometry in 105 RTS,S/AS01-vaccinated and 74 rabies-vaccinated participants (controls) in a pediatric phase III trial in Africa. RTS,S/AS01E-vaccinated children had significantly higher frequencies of CSP- and HBsAg-specific CD4+ T cells producing IL-2, TNF-α, and CD40L and HBsAg-specific CD4+ T producing IFN-γ and IL-17 than baseline and the control group. Vaccine-induced responses were identified in both central and effector memory (EM) compartments. EM CD4+ T cells expressing IL-4 and IL-21 were detected recognizing both vaccine antigens. Consistently higher response rates to both antigens in RTS,S/AS01E-vaccinated than comparator-vaccinated children were observed. RTS,S/AS01E induced polyfunctional CSP- and HBsAg-specific CD4+ T cells, with a greater degree of polyfunctionality in HBsAg responses. In conclusion, RTS,S/AS01E vaccine induces T cells of higher functional heterogeneity and polyfunctionality than previously characterized. Responses detected in memory CD4+ T cell compartments may provide correlates of RTS,S/AS01-induced immunity and duration of protection in future correlates of immunity studies.

Emerging role of γδ T cells in vaccine‐mediated protection from infectious diseases

“…67 However, as the authors examined total cd T cells rather than Vd2 + or other cd T-cell subsets, it will be important for future studies to determine whether specific subsets correlate with protection and if so, whether future RTS,S formulations can target these subsets. The malaria vaccine that has advanced farthest to date is the RTS,S vaccine, which is based on the Pf circumsporozoite (CSP) protein and targets the sporozoite and liver stages of infection.…”

“…Interestingly, RTS,S phase 3 trials in African children detected no significant change in cd T-cell frequencies following vaccination and minimal cytokine production by these cells in response to in vitro CSP stimulation. 67 However, as the authors examined total cd T cells rather than Vd2 + or other cd T-cell subsets, it will be important for future studies to determine whether specific subsets correlate with protection and if so, whether future RTS,S formulations can target these subsets. RTS,S trials in malaria-na€ ıve populations have generally focused on anti-CSP antibody studies and CD4 + / CD8 + T-cell responses without examining innate populations like cd T cells.…”

Vaccinating for natural killer cell effector functions

“…Protective titres of neutralising antibodies and expanded populations of effector and memory B and T lymphocytes are viewed as measures of protection for many vaccines. Currently, the generation of durable antigen‐specific memory forms the basis of vaccine development and evaluation of vaccine efficacy . Developing vaccines to overcome pathogen polymorphism and complexity demands new approaches to vaccine design and evaluation; this in turn requires the identification of novel correlates of protection and determination of optimal dosing schedules.…”

“…Currently, the generation of durable antigen-specific memory forms the basis of vaccine development and evaluation of vaccine efficacy. 1,2 Developing vaccines to overcome pathogen polymorphism and complexity demands new approaches to vaccine design and evaluation; this in turn requires the identification of novel correlates of protection and determination of optimal dosing schedules. The activation of Natural Killer (NK) cells represents a potential route for further optimisation of vaccination strategies by harnessing their role as antipathogen effector cells which integrate innate and acquired immune responses.…”

Characterisation of anti-parasitic CD4+ T cell responses during malaria

“…A number of studies have identified attributes of CD4 + T cell subsets which contribute to protection and pathology, some of which are exploited by vaccinations to improve protection 69,[210][211][212] . Unfortunately, robust and long term protection against malaria remains elusive, with the most established vaccine candidate, RTS,S, only having an average efficacy of ~35%, and protection which wanes in a relatively short time 213 .…”