Scientific Publications by FDA Staff

Infect Immun 2019 Sep 19;87(10):e00236-19

Antibody-dependent IFN-gamma-independent sterilizing immunity, induced by a subunit malaria vaccine.

Chawla B, Mahajan B, Oakley M, Majam VF, Belmonte A, Sedegah M, Shimp RL Jr, Kaslow DC, Kumar S

Development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of Plasmodium falciparum circumsporozoite protein (CSP)-based RTS,S/AS01E vaccine in the phase 3 studies highlighted the urgency to design and test more efficacious next generation malaria vaccines. In this study, we report that immunization with recombinant CSP from Plasmodium yoelli (rPyCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice. This immunity was antibody-dependent, as evidenced by the complete loss of immunity in B-cell knockout (KO) mice and by the ability of immune sera to neutralize sporozoite infectivity in mice. Th2-type antibody isotype IgG1 levels were associated with protective immunity. The fact that immunized IFN-gamma KO mice and WT mice have similar levels of protective immunity and the absence of IFN-gamma producing CD4(+) and CD8(+) T cells in protected mice in flow cytometry indicate that immunity is IFN-gamma independent. Protection against sporozoite challenge correlated with the higher frequency of CD4(+) T cells that express IL-2, IL-4 and TNF-alpha. In the RTS,S study, clinical immunity was associated with the higher IgG levels and frequency of IL-2 and TNF-alpha producing CD4(+) T cells. The other hallmarks of immunity in our study included an increased number of the follicular B-cells, but a loss in Th follicular T cells. These resu-lts provide an excellent model system to evaluate the efficacy of novel adjuvants, vaccine dosage and determine the correlates of immunity in search for superior candidate malaria vaccines.