How can we increase efficacy of malaria vaccines? – New insights from analysis of the RTS,S vaccine

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. A burning question in the field, and one that has been the focus of intense research, is how to achieve higher vaccine efficacy?

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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)


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

James Beeson

Deputy Director and Research Fellow, Burnet Institute

James is a public health physician and PhD graduate who has worked on the pathogenesis and immunology of malaria for many years through clinical and population studies and clinical trials. The major focus of his research is aimed at understanding the targets and mechanisms of protective immunity to malaria in humans, how protective immunity is acquired and maintained, and using this knowledge to advance malaria vaccine development and evaluation.