By Liriye Kurtovic and James Beeson
While RTS,S is the world’s most advanced malaria vaccine to date, efficacy is only 30-50% against clinical malaria in infants and young children. No other vaccines are yet to achieve higher efficacy in malaria-endemic populations. A burning question in the field, and one that has been the focus of research for many years, is how to achieve higher malaria vaccine efficacy?
RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, but it is unclear how these protective antibodies function.
Our previous research has shown that antibodies can kill and inhibit malaria sporozoites by the recruitment of complement proteins in the blood (Kurtovic L, et al 2018 and 2019; Behet M, et al 2018). Our recent studies have also suggested the importance of phagocytes in clearing antibody-opsonised sporozoites.
To understand whether these effector mechanisms of antibodies to sporozoites could be important in mediating immunity with the RTS,S malaria vaccine, we quantified the induction of functional anti-CSP antibody responses in healthy malaria-naïve adults vaccinated with RTS,S. We found that RTS,S-induced antibodies could fix and activate complement. We also found that antibodies to CSP could bind to Fc-receptors (FcγRIIa and FcγRIII) that are expressed on the surface of immune cells and promote cell-mediated immune mechansms, including phagocytosis and cell killing (ADCC).
Importantly, we found that vaccinated participants who had higher levels of functional antibodies had a reduced risk of developing malaria parasitemia following experimental infection challenge. These findings suggest that achieving better induction of antibody Fc-dependent effector functions (interactions with complement and Fc-receptors on immune cells) could be a promising and feasible strategy to achieve higher vaccine efficacy.
An intriguing finding was that functional antibodies were higher after the second vaccine dose rather than the third dose. This suggests that the current three dose vaccine schedule may not be optimal. Interestingly, non-protected subjects had higher levels of anti-CSP IgM and a higher IgM to IgG ratio.
These data give important insights into the mechanisms of RTS,S-induced immunity to inform future malaria vaccine development and bring us closer to identifying functional immune correlates of protection and vaccines with higher efficacy.
Figure: Rate of infection with P. falciparum after vaccination with RTS,S was substantially lower for individuals who had high levels of multi-functional antibodies (Adapted from Kurtovic L, et al, Journal of Infectious Diseases, PMID: 32236404)
Figure: Targets of malaria vaccine strategies. The RTS,S vaccine targets sporozoites (from Beeson JG et al, Science Translational Medicine, 2019. Vol. 11, Issue 474, eaau1458)
UPDATE: September 2022
In subsequent studies, we have evaluated the ability of the RTS,S vaccine to induce protective functional antibodies among young children in Mozambique, since young children in areas of moderate to high malaria transmission are the primary target group for the vaccine. We show that the vaccine generated antibodies that promote clearance of malaria sporozoites by neutrophils and monocytes, and can activate Natural Killer cells (NK cells). Unfortunately, immune responses are not long-lived and wane rapidly after vaccination. Importantly, our findings suggest that vaccine responses are lower in children who have had more malaria exposure. We need to understand the mechanisms underlying this effect so we can develop strategies to improve vaccine efficacy. Findings are published here
Kurtovic L, Atre T, Feng G, Wines BD, Chan JA, Boyle MJ, Drew DR, Hogarth PM, Fowkes FJI, Bergmann-Leitner ES, Beeson JG. Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial J Infect Dis. 2020 Mar 31:jiaa144. doi: 10.1093/infdis/jiaa144
Kurtovic L, Agius PA, Feng G, Drew DR, Ubillos I, Sacarlal J, Aponte JJ, Fowkes FJI, Dobaño C, Beeson JG. Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure. BMC Med. 2019 Feb 25;17(1):45
Kurtovic L, Behet MC, Feng G, Reiling L, Chelimo K, Dent AE, Mueller I, Kazura JW, Sauerwein RW, Fowkes FJI, Beeson JG. Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children. BMC Med. 2018 Apr 30;16(1):61
Behet MC, Kurtovic L, van Gemert GJ, Haukes CM, Siebelink-Stoter R, Graumans W, van de Vegte-Bolmer MG, Scholzen A, Langereis JD, Diavatopoulos DA, Beeson JG, Sauerwein RW. The Complement System Contributes to Functional Antibody-Mediated Responses Induced by Immunization with Plasmodium falciparum Malaria Sporozoites. Infect Immun. 2018 Jun 21;86(7):e00920-17