Oral Presentation First Malaria World Congress 2018

Investigating functional antibody mechanisms against Plasmodium falciparum sporozoites in naturally-acquired and RTS,S vaccine-induced immunity    (#73)

Liriye Kurtovic 1 2 , Marije Behet 3 , Gaoqian Feng 1 , Linda Reiling 1 , Paul Agius 1 , Damien Drew 1 , Kiprotich Chelimo 4 , Arlene Dent 5 , Joe Campo 6 , Itziar Ubillos 6 , Ivo Mueller 7 , James Kazura 5 , Robert Sauerwein 3 , Freya Fowkes 1 , Carlota Dobaño 6 , James Beeson 1
  1. Burnet Institute, Melbourne , Australia
  2. Monash University , Melbourne, Australia
  3. Radboud University Medical Centre , Nijmegen , Netherlands
  4. Kenya Medical Research Institute , Kisian, Kenya
  5. Case Western University , Cleveland , US
  6. Barcelona Centre for International Health Research, IS Global , Barcelona, Spain
  7. Walter and Eliza Hall Institute , Melbourne, Australia

Developing and licensing highly efficacious vaccines against Plasmodium falciparum malaria would substantially reduce disease-associated morbidity and mortality, and aid malaria elimination efforts worldwide. Sporozoites are attractive vaccine targets because blocking this initial stage of infection prevents onset of blood-stage parasitemia, clinical disease and subsequent transmission. Leading vaccine candidate, RTS,S, is based on major sporozoite surface antigen, circumsporozoite protein (CSP). RTS,S was moderately efficacious in clinical trials and protection had some association with anti-CSP antibodies; however, it is unclear how antibodies confer protection. This hinders our ability to evaluate RTS,S and develop strategies to enhance vaccine-induced immunity and efficacy, or to develop more efficacious next generation vaccines. Here we demonstrate that  antibodies to CSP and sporozoites function by activating complement, and this activity can be naturally-acquired or induced by RTS,S-immunisation.

Firstly, we demonstrated that naturally-acquired human antibodies and vaccine-induced anti-CSP antibodies in rabbits fix complement initiation protein, C1q, and subsequently activate the antibody-dependent complement cascade. P. falciparum sporozoites were susceptible to antibody-complement attack in vitro, which inhibited sporozoite motility and could lead to sporozoite death.  Furthermore, in a longitudinal cohort study of children (5-14yrs) in Papua New Guinea, those who had naturally-acquired high levels of complement-fixing antibodies had a significantly reduced risk of clinical malaria.

Subsequently, we evaluated complement-fixing antibodies in a sub-study of children (1-4yrs) enrolled in a RTS,S/AS02 phase II clinical trial conducted in Mozambique. Complement-fixing antibodies to CSP were strongly induced following RTS,S-immunisation, although responses were variable. This appeared to be explained by differences in IgG subclass profiles and epitope-specificities among vaccinees. Additionally, complement-fixing antibodies substantially declined in the follow-up months post-vaccination, which may reflect the waning of vaccine efficacy.

In summary, these novel findings point to complement activation as an important mechanism of anti-sporozoite human immunity, and provide important insights for developing highly efficacious malaria vaccines.