Poster Presentation Lorne Infection and Immunity 2019

Functional antibody mechanisms induced by the RTS,S malaria vaccine (#149)

Liriye Kurtovic 1 2 , Paul A. Agius 2 , Gaoqian Feng 2 , Damien R. Drew 2 , Itziar Ubillos 3 , Jahit Sacarla 4 , John J. Aponte 4 , Freya J. I. Fowkes 2 , Carlota Dobaño 3 , James G. Beeson 1 2
  1. Department of Immunology and Pathology, Monash University , Melbourne, Australia
  2. Burnet Institute, Melbourne , Australia
  3. Barcelona Centre for International Health Research, IS Global , Barcelona, Spain
  4. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique

Plasmodium falciparum malaria is a substantial cause of global morbidity and mortality, and the development of a highly efficacious vaccine would significantly contribute to eliminating malaria. RTS,S is the leading malaria vaccine, which is based on the major sporozoite surface antigen, circumsporozoite protein (CSP). In young children, RTS,S confers moderate protective efficacy against clinical malaria that wanes over time. Vaccine-induced protection is loosely associated with anti-CSP antibodies but it is unclear how they function, and we therefore lack strong immunological correlates of protection. This makes it challenging to develop strategies to improve vaccine immunogenicity, efficacy and longevity. 

We previously identified that antibodies to CSP and whole sporozoites could fix and activate the complement cascade, which hindered sporozoite function and also led to sporozoite death in vitro. Here we measured the induction of functional anti-CSP antibodies that fix complement in children aged 1-4 years enrolled in the RTS,S/AS02 phase IIb trial conducted in Mozambique.

RTS,S strongly induced complement-fixing antibodies, although responses were variable. This was likely due to differences in IgG subclass responses and epitope-specificity, both of which are known to impact complement-fixation. Interestingly participant age and malaria exposure were negatively associated the induction of complement-fixing antibodies. Furthermore complement-fixing antibodies were short-lived after vaccination, which was largely attributed to the loss of anti-CSP IgG1 and IgG3, and may also reflect the waning of vaccine efficacy over time.

We identified that RTS,S vaccination can induce functional antibodies that fix complement, although responses were variable and short-lived. Our findings suggests that improving the magnitude and durability of complement-fixing antibodies may be a strategy to enhance the RTS,S malaria vaccine, and could be achieved by altering the IgG subclass profile and specificity of vaccine-induced antibodies.