Strategies for maximizing malaria vaccine efficacy - Antibodies and cells combine against malaria

Understanding mechanisms of antibody-mediated immunity is crucial for developing malaria vaccines with high efficacy. New findings reveal key roles in humoral immunity for Fcγ-receptor interactions promoting phagocytosis of sporozoites, especially by neutrophils.

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By James Beeson and Gaoqian Feng

Despite international control efforts, the malaria burden has remained constant in recent years. There is a strong need for a highly efficacious vaccine for malaria control and elimination, which is further emphasised by increasing reports of antimalarial drug resistance and insecticide resistance, and the impacts of COVID-19. The World Health Organisation and funding partners set a goal to develop a vaccine with ≥75% efficacy by 2030, but this has proven challenging to achieve. A greater understanding of the mechanisms that mediate immunity is needed to develop strategies that generate more potent protective immune responses. Our recent findings shed light on potential strategies to achieve high vaccine efficacy.

Blocking malaria before it takes hold

The sporozoite is the form of the malaria parasites that is inoculated by a mosquito and subsequently establishes infection in the liver. Therefore, sporozoites represent a priority target of malaria vaccines because clearing sporozoites will halt infection prior to the onset of clinical malaria. Ideally immune responses would act immediately after inoculation to clear sporozoites – but it has been unclear whether, and how, immune responses can achieve this.

 

Antibodies call on neutrophils, monocytes, and NK cells for the killer punch

Our studies found that antibodies to the major antigen on the surface of the sporozoite can effectively engage Fcγ-receptors (FcγRs) expressed on neutrophils, monocytes and natural killer (NK) cells to promote phagocytosis and cellular killing. Interestingly, neutrophils were much more active and effective in phagocytosis than monocytes. Since neutrophils are highly abundant in blood and can act quickly, they are likely to play an important early role in attacking sporozoites immediate after they enter the bloodstream. Our findings suggest that harnessing this immune response in vaccine development could enable vaccines with rapid killing power and, ultimately, with high efficacy to prevent infection in the liver.

Interestingly, antibody interactions with FcγRIIa and IIIa and IIIb appeared to be the most important. Antibodies target all 3 domains of the circumsporozoite protein (CSP) expressed by sporozoites. We identified a novel sequence in the N-terminal domain which is not currently included in leading malaria vaccines – its inclusion may help boost vaccine efficacy.

 

Antibodies to circumsporozoite protein promote phagocytosis
Figure shows level of phagocytosis induced by human antibodies to CSP
Neutrophils (dark blue) are much more active in opsonic phagocytosis than monocytes (light blue)

Mapping epitopes targeted by  antibodies that harness neutrophil killing

It takes time to develop good immunity naturally - can be induced by vaccination

Evaluating immune responses in Kenyan children and adults, we found that the natural development of this antibody mechanism takes a long time to develop and is seen in adults only after many many infections over years. The hope is that vaccines could aim to achieve quickly what the immune system takes a long time to achieve naturally. Our early findings suggest that vaccines such as RTS,S (the leading malaria vaccine currently) can induce these immune responses - those with high antibodies for FcγR interactions and neutrophil phagocytosis had higher levels of vaccine protection.

 

Antibodies that promote killing by neutrophils
Only seen among adults for sporozoite killing (CSP), and rarely in young children (aged 1-5y)
In contrast, antibody-neutrophil killing develops much earlier for malaria blood stages (merozoites)

Looking to the future

Future studies should investigate how effectively current vaccines in clinical trials generate antibodies with these functional activities. Harnessing this knowledge in vaccine development may be an effective strategy for generating a potent immune response that provides higher levels of protection against malaria. This will require detailed knowledge of antibody targets and properties, and greater depth of knowledge of the functions and phenotypes of neutrophils, monocytes, and NK cells in malaria

Related papers

Feng, G., Wines, B.D., Kurtovic, L., Chan, J.A., Boeuf, P., Mollard, V., Cozijnsen, A., Drew, D.R., Center, R.J., Marshall, D.L., et al. (2021). Mechanisms and targets of Fcgamma-receptor mediated immunity to malaria sporozoites. Nat Commun 12, 1742.

https://www.nature.com/articles/s41467-021-21998-4#Sec9

Kurtovic, L., Atre, T., Feng, G., Wines, B.D., Chan, J.A., Boyle, M.J., Drew, D.R., Hogarth, P.M., Fowkes, F.J.I., Bergmann-Leitner, E.S., et al. (2020). Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial. J Infect Dis.

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa144/5814271

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.