Poster Presentation Lorne Infection and Immunity 2023

Defining the fine specificity of antibody responses to polymorphic and conserved epitopes of the lead malaria vaccine antigen: Plasmodium falciparum circumsporozoite protein (#143)

Alessia Hysa 1 2 , Liriye (Lydia) Kurtovic 1 3 , Herbert D Opi 1 2 3 , Myo Naung 1 4 5 , Alyssa E Barry 1 4 5 , David Wetzel 6 7 , Michael Piontek 6 , Jahit Scaralal 8 9 , Carlota Dobaño 9 10 , James Beeson 1 3 11
  1. Burnet Institute, Melbourne, Victoria, Australia
  2. Department of Infectious Diseases , The University of Melbourne , Melbourne , Victoria, Australia
  3. Department of Immunology and Pathology, Monash University , Melbourne , Victoria, Australia
  4. School of Medicine, Deakin University , Waurn Ponds, Victoria , Australia
  5. Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  6. ARTES Biotechnology GmbH, Langenfeld, North Rhine-Westphalia, Germany
  7. Laboratory of Plant and Process Design, Technical University of Dortmund, Dortmund, Germany
  8. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique
  9. Faculdade de Medicina , Universidade Eduardo Mondlane (UEM), Maputo, Mozambique
  10. ISGlobal, Hospital Clínic Universitat de Barcelona, Barcelona, Catalonia, Spain
  11. Department of Medicine , The University of Melbourne , Melbourne , Victoria , Australia

Malaria caused over 240 million infections resulting in over 600,000 deaths in 2020. In 2021, RTS,S became the first malaria vaccine recommended for susceptible young children; however, it confers modest efficacy (~30–50%). Developing highly effective vaccines requires understanding the specific epitopes within the vaccine antigen that mediate highly protective responses and how polymorphisms in the vaccine antigen impact efficacy.

RTS,S is based on the P. falciparum parasite circumsporozoite protein (PfCSP) of one strain, 3D7. CSP includes an N-terminal, a central repeat composed of ~ 40 NANP and ~ 4 NVDP sequences, and highly polymorphic C-terminal regions. RTS,S comprises 19 NANP repeats and the entire C-terminal region. The central repeat region is intrinsically disordered forming epitopes that vary by the number of NANP and NVDP repeats. The C-terminal region is incredibly diverse between parasites and the 3D7 RTS,S strain represents less than 10% of African parasites. Furthermore, recent studies identified a highly conserved CSP epitope that is a target of potent neutralising antibodies but is excluded from the RTS,S construct.

We defined the fine specificity of RTS,S-induced antibodies to variable central repeat, polymorphic C-terminal and conserved epitopes of CSP. Our primary study population were children recruited in an RTS,S phase IIb clinical trial. We demonstrate that vaccine-induced antibody binding increases with the number of NANP repeats in a sequence; however, short NANP sequences may better represent the epitopes within CSP that mediate protection. Additionally, a proportion of children had promiscuous antibodies that cross-reacted with the highly conserved CSP epitope excluded from the vaccine construct. Lastly, RTS,S-induced antibodies appear to have reduced binding to diverse CSP alleles prevalent in African populations, which appears to contribute to low vaccine efficacy. Our findings reveal how targeting cross-reactive and conserved epitopes could achieve highly-effective next-generation malaria vaccines.