Immunology and data science come together to reveal that the RTS,S malaria vaccine may offer broader protection than thought

October 2021 will go down in malaria history: the WHO recommended the use of RTS,S, the first-ever malaria vaccine. Despite its moderate efficacy (it reduces hospital admissions from severe malaria by about 30%), its widespread use is expected to save the lives of an additional 40,000 to 80,000 African children each year.

As of April 2022, 1 million children in Ghana, Kenya and Malawi had received one or more doses of the world’s first malaria vaccine

An unexpected bonus

The RTS,S vaccine contains a fragment of the CSP protein, one of more than 5,000 proteins expressed by the P. falciparum parasite at some stage in its lifecycle. When Carlota Dobaño, Head of the Malaria Immunology Group, and her team analysed antibodies in vaccinated children, they detected antibodies to parasite antigens other than CSP. But the reasons for this were not clear.

So Dobaño teamed up with the Data Science group led by Paula Petrone to see if RTS,S could induce antibody responses to parasite antigens not contained in the vaccine. They measured IgG antibodies against 1,000 P. falciparum antigens (representing 762 genes, or 14% of the parasite genome) in blood samples from 2,138 infants and children from six African sites of the phase 3 vaccine trial, taken before and after vaccination.

The results show that some children in the vaccinated group had antibodies that were highly reactive to a small subset of malaria antigens not contained in the vaccine. The levels of these ‘off-target’ antibodies correlated strongly with anti-CSP levels, declined similarly over time and increased again with a booster dose. “This strongly suggests that, in some children, the vaccine is inducing antibodies that can also recognise other malaria antigens,” says Dídac Macià, first author of the study.

Children who developed higher off-target antibodies were less likely to develop clinical disease. In other words, “strong responses to other malaria antigens were a predictor of increased vaccine protection, beyond what anti-CSP levels alone could predict,” says Dobaño. The researchers now need to confirm whether this off-target response confers greater protection against malaria, or whether it is only a marker of efficient vaccine responses.

Although imperfect, RTS,S may offer more than we bargained for.

Macià D, Campo JJ, Moncunill G et al. Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with increased protection. JCI Insight. doi: 10.1172/jci.insight.158030

Photo: ©WHO, Fanjan Combrink