Determinants of poor responsiveness to the booster dose of the RTS,S malaria vaccine in African children - PROJECT SUMMARY Implementation of the RTS,S malaria vaccine in sub Saharan Africa has been recommended by the WHO and UNICEF has pledged $170 million for production of the first vaccine supply. Because the efficacy of RTS,S wanes within one year from the primary doses, the regimen includes a 4th booster dose. However, based on findings from the phase 3 trial, the magnitude of Ab responses induced by the booster dose is significantly lower than those induced by the primary regimen. The booster dose increased duration of efficacy marginally. The regimen of another leading vaccine candidate, R21, also requires a booster dose. Understanding the immune mechanisms underlying poor booster dose responses will be important to support the design of future implementation studies and optimize actual implementation of RTS,S and other malaria vaccines. The limited effect of the booster dose might be explained by repeated exposure to malaria compounded to exposure to other infections after the first months of life. Extensive epidemiological evidence supports this hypothesis including a recent trial that showed that efficacy of administration of RTS,S in combination with repeated chemoprophylaxis was higher than RTS,S or chemoprophylaxis alone. Repeated malaria exposure may negatively affect Ab magnitude and functional activity via effects on innate, memory cells, and T cells. Additionally, our data, and data from others suggest that deficiency of micronutrients, particularly iron and zinc, acquired after cessation of breast feeding may impact responses to the booster dose. A third determinant of reduced responses to the booster dose could be the suboptimal spacing between the primary and booster doses, whereby memory B cells induced by the primary doses have waned before the booster dose. Following a cohort of 600 Malawian children from the primary vaccination until eight months after the booster dose, we will undertake comprehensive immunologic analyses to investigate the mechanisms underpinning the poor responses to the booster. We will identify the specific Ab responses and functions that are suboptimal after the booster dose. Additionally, we will i) quantify innate cell responses with and without the stimulation with AS01, and assess epigenetic changes leading to tolerogenic responses in monocytes; ii) quantify subpopulations of vaccine specific CD4+ T follicular helper cells and regulatory cells and their effect on Ab and B cell responses; iii) quantify induction and duration of memory cells, that may be impairing Ab responses to the booster dose; iv) assess whether exposure to malaria parasites, and micronutrient deficiency may be affecting all these immune responses; v) evaluate whether children with dysfunctional immunity to RTS,S also have impaired immunity to other childhood vaccines associated with the same determinants. Data generated by this study will help elucidate the basis of the limited effect of the booster dose and, thus, will be crucial to inform strategies to optimize boosting of the RTS,S-induced response.
