Following 30 years of research, 2021 marked an important year in the battle against malaria as the world’s first malaria vaccine was approved and endorsed by the WHO. RTS,S/AS01, a first not only for malaria but any human parasitic disease, is a recombinant protein vaccine that targets the circumsporozoite protein (CSP) of P. falciparum. Since 1992 when the first trial of RTS,S was conducted, it has progressed through multiple trials with mixed results. Early testing of RTS,S/AS01 showed high efficacy in a small sample size however when deployed in a real world setting – in phase III clinical trials- observed efficacy dropped to 40% in children aged 5 to 17 month, and even lower in younger infants. Now, a next-generation vaccine called R21 has been developed by scientists at the University of Oxford. R21 uses the same antigen as RTS,S- CSP, with slight modifications.
CSP is the most abundant protein on the sporozoite’s surface and consists of a highly polymorphic central repeat region flanked by less polymorphic N-terminal and highly polymorphic C-terminal non-repeat regions. The central region constitutes immunodominant B cell epitopes made up predominantly of tandem repeats of NANP (Asparagine, Valine, Aspartic acid and Proline) and small number of NVDP (Asparagine, Valine, Aspartic acid, Proline) repeats. The C-terminal region makes both B cell and T cell epitopes. In RTS,S, 19 NANP repeats and the entire C-terminal sequence are fused to the hepatitis B surface antigen (HBsAg) to generate the RTS fusion proteins, which are then co-expressed in Saccharomyces cerevisiae yeast with unmodified recombinant HBsAG (S). Following yeast cell lysis, lipid protein particles form spontaneously. This results in the hybrid formation of proteins, the full RTS and S proteins, at a ratio of 1:4. As a consequence, CSP fusion proteins comprise only 20% of the molecule in the particle and a large proportion of the antibody response is towards the HBsAg, hindering CSP-specific immunity.
By contrast, R21 lacks the excess HBsAG comprising only fusion protein moieties. This was achieved by using a different expression platform, the Pichia pastoris yeast strain. This methylotrophic yeast has emerged as an attractive alternate expression platform due to a much higher cell density growth and higher secreted protein yield. The R21 fusion protein form particles when expressed alone in this yeast, without the requirement of additional HBsAg. As a result, the majority of R21 surface is coated in CSP antigen and predicted to yield a greater humoral response through enhanced surface recognition by B cell receptors. Phase II trials indicate 70-77% protective efficacy against a first episode of malaria in the first year following vaccination. Unpublished early phase III data, which began in April 2021, shows similar performance and has been extended to 2024. Ghana’s drug regulators have already assessed the trial data and are the first country to approve this new vaccine’s use in children aged between five months to three years old. Time will tell if real-world testing holds up for R21, especially in regions where transmission is all year round and not just seasonal.
In any case, vaccine development, and refinement, is sure to continue at a rapid pace and advances in CRISPR and Artificial Intelligence are sure to increase novel ways to design vaccines.
References:
https://www.nature.com/articles/srep46621
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121760/
