Title : Designing a conserved, immunogenic, and highly neutralizing vaccine targeting the AMA1-RON2 interaction in P. falciparum
Abstract:
In 2022, there were an estimated 249 million clinical cases and 608,000 deaths from malaria. A vaccine against Plasmodium falciparum would provide a critical tool for malaria control and eventual eradication. RTS,S, the first WHO approved vaccine for malaria, targets the antigen circumsporozoite protein (CSP) and demonstrates limited efficacy, reducing clinical malaria by a modest 30% and providing almost no protection once the parasite reaches the blood stages. Invasion of RBCs by P. falciparum relies on the interaction between two parasite proteins, apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2), making it an attractive antigenic target to combine with current CSP targeting vaccines. However, previous AMA1 vaccines have failed to generate high levels of neutralizing antibodies against parasite strains heterologous to the vaccine. Here, we designed a novel AMA1 vaccine to overcome this challenge. We demonstrate that immune focusing on AMA1 domains involved in antigen binding increases the proportion of neutralizing antibodies. Next, we developed a fusion protein that faithfully mimics the structure of AMA1 bound to a 49 amino acid peptide from its receptor RON2. Immunization with the fusion chimera enhanced antibodies targeting conserved epitopes on AMA1 resulting in greater neutralization of 3 different non-vaccine type parasites. Finally, a mRNA platform producing this chimera further enhances antibody titers. We show that transmembrane anchoring of the antigen may increase immunogenicity further. Advances from this study may aid the development of a blood stage malaria vaccine capable of synergizing with previous pre-erythrocytic vaccines targeting CSP.
Audience Takeaway:
- The importance of transmembrane anchoring in RNA vaccines
- Applications of structure guided vaccine design
- Comparisons of mRNA and protein vaccines against AMA1
- Applications of glycoengineering to vaccine design.
