Protective antibody threshold of RTS,S/AS01 malaria vaccine correlates antigen and adjuvant dose in mouse model

Abstract

Mouse models are useful for the early down-selection of malaria vaccine candidates. The Walter Reed Army Institute of Research has optimized a transgenic Plasmodium berghei sporozoite challenge model to compare the efficacy of Plasmodium falciparum circumsporozoite protein (CSP) vaccines. GSK’s RTS,S vaccine formulated in the adjuvant AS01 can protect malaria-naïve individuals against malaria. We report that the RTS,S/AS01 vaccine induces high level sterile protection in our mouse model. Down titration of the antigen at a constant AS01 dose revealed a potent antigen dose-sparing effect and the superiority of RTS,S/AS01 over a soluble CSP antigen. RTS,S-mediated protective immunity was associated with a threshold of major repeat antibody titer. Combined titration of the antigen and adjuvant showed that reducing the adjuvant could improve antibody boosting post-3rd vaccination and reduce the threshold antibody concentration required for protection. Mouse models can provide a pathway for preclinical assessment of strategies to improve CSP vaccines against malaria.

Establishing RTS,S/AS01 as a benchmark for comparison to next-generation malaria vaccines in a mouse model

“…Two recent studies report immunization using RTS,S/AS01 in a mouse model 31 , 49 . In the first study, RTS,S/AS01 was compared with the similar vaccine R21/Matrix-M.…”

“…We hope that a side-by-side comparison of RTS,S/AS01 with other vaccines, including R21/Matrix-M, may be possible in the near future. In the second and more recent study 31 , RTS,S/AS01 was used to compare various ratios of immunogen to the same adjuvant dose as reported in the present study. Results are similar between the two reports in that a plateau of antibody levels at similar concentration of immunogen is observed when three administrations were given.…”

“…Other investigators have used similar but not identical mouse models to draw conclusions on relative potency from intra-study comparisons of vaccines 27 , 28 and mAbs 29 , 30 . In addition, recently RTS,S/AS01 has been used in a similar mouse model to explore antigen and vaccine titration using sterile protection as an endpoint 31 . In the present study, we focus on a clinically relevant benchmark for comparison studies by studying responses elicited by RTS,S/AS01 immunization.…”

A new landscape for malaria vaccine development

“…Now, with data from multiple clinical trials of RTS,S, recent advances in our understanding of vaccine-induced immunity to P . falciparum malaria, and refinement of preclinical models, it is possible to use mouse models to improve existing CSP-based vaccines [ 19 ]. Adjuvants can now be carefully selected based on the desired effector function, [ 20 ] obviating the need for large CHMI and/or efficacy studies to optimize adjuvant selection.…”