Why do malaria vaccines protect some children and not others?
Burnet researchers have identified antibody responses that are linked to stronger protection from malaria in vaccinated children. The findings could help improve future malaria vaccines.
Several tools are available to control malaria. These include antimalarial drugs, insecticides and 2 vaccines for children: RTS,S and R21.
Despite such tools, malaria remains one of the world’s deadliest infectious diseases. Each year, malaria causes about 240 million infections and 600,000 deaths, mostly in children under the age of 5.
The RTS,S and R21 vaccines provide modest and short-lived protection against malaria in children (about 55 to 75% effectiveness over 1 year). This highlights the need to understand how these vaccines work and which immunological responses drive protection in children .
In our recent study, Antibody fine specificity correlates with protection from malaria for the RTS,S vaccine in young African children, we asked:
- What are the specific immunological responses present in young, vaccinated children who are protected against malaria?
- How does this compare to vaccinated children who remain unprotected?
Looking beyond antibody levels
RTS,S and R21 vaccines both target a protein on the malaria parasite called the circumsporozoite protein (CSP). CSP is the most abundant protein present on the surface of the parasite at the pre-erythrocytic stage (the stage that comes after the parasite enters the body via a mosquito bite and before the parasite enters the liver).
The protein has 3 main parts:
- the N-terminal region
- the central repeat region
- the C-terminal region.
The vaccines include only part of the central repeat region and the entire C-terminal region.
Most studies of RTS,S and R21 measure the level of antibodies that recognise the central repeat region. However, this measure doesn’t consistently differentiate between children who are protected and those who are not protected from malaria following vaccination.
In our study, we measured antibody responses to 2 specific CSP targets to evaluate if this could better identify protected children.
These targets were:
- NANP2 – a short sequence from the central repeat region
- the junction – a short sequence that overlaps the N-terminal and central repeat regions that is not included in the current vaccines.
We measured antibody responses to these targets in 735 children from Mozambique aged 1 to 4 years old who received RTS,S vaccine in a phase IIb clinical trial.
A surprising finding
RTS,S-vaccinated children developed antibodies that could bind the short NANP2 sequence and recognise the junction sequence which is excluded from the vaccine construct.
Children with low responses to both NANP2 and junction had malaria rates similar to children who did not receive the RTS,S vaccine at all.
Additional analysis demonstrated that children with high antibody responses to both NANP2 and the junction also had stronger antibody functions linked to protection against malaria parasites.
The specific antibody signatures we identified were able to effectively identify vaccinated children who were protected from malaria.
Not all children respond to the vaccine in the same way
All children in the study received the same vaccine schedule, but their immune responses varied considerably.
- 38% of children in the study developed high antibody levels to the NANP2 and junction sequences (the responses we identified as most protective against malaria).
- 41% of children demonstrated antibody specificity to a sequence that represents the central repeat region (a response not linked with protection in our study).
- 21% of children demonstrated low antibody responses overall.
The differences we observed in antibody responses may explain why the RTS,S vaccine protects some children better than others.
What this means for next-generation malaria vaccines
Our findings have 2 major implications:
First, we have identified valuable immunological correlates of protection which may be used in future vaccine trials to evaluate vaccine efficacy and monitor immune responses in vaccine recipients. Further studies are required to confirm these results with samples from additional vaccine trials.
Second, the current malaria vaccine constructs should be optimised to promote higher antibody responses, across more children, to CSP targets that are clinically important, such as the NANP2 and junction sequences we identified in this study.
