Breakthrough in the development of anti-malarial vaccines
Malaria is still one of the most devastating diseases worldwide.Over the past three decades,significant efforts have been made to develop highly efficient vaccines against malaria.Recently,two subunit malaria vaccines,RTS,S/AS01(called Mosquirix)and R21/Matrix-M,were sequentially recommended by the World Health Organization(WHO)for vaccination of children in moderate to high malaria-endemic regions.This was a significant breakthrough in the development of antimalarial vaccines.RTS,S/AS01,also called Mosquirix,was designed by Walter Army Institute and GSK corporation in 1987.RTS,S/AS01 is a Plasmodium falciparum CSP-based recombinant protein vaccine and contains the NANP major repeats and C-terminal domain of CSP,which is coexpressed with fused and free hepatitis B surface antigen(HBsAg)at a ratio of 1∶3 and formulated with the AS01 adjuvant.In 2011 and 2012,phase Ⅲ studies showed that RTS,S/AS01 is safe and tolerant,and had a moderate protection efficacy in reducing both mortality and morbidity of infants and children in malaria-endemic regions.In Oct 2021,RTS,S/AS01 was approved by WHO,which allowed the vaccination of children in malaria-endemic regions.Therefore,RTS,S/AS01 became the first licensed malaria vaccine to be used in Africa.In a major analysis in Africa,RTS,S/AS01 exhibited considerable effect in reducing deaths and severe malaria.However,RTS,S/AS01 is relatively expensive,and could not be manufactured in enough doses for vaccination.To improve the immunogenicity of the CSP-based malaria vaccine,R21,a next-generation RTS,S-like vaccine,was developed by Professor Adrian V.S.Hill at the University of Oxford.In contrast to RTS,S,R21 particles are formed from a single CSP-HBsAg fusion protein,which leads to a vaccine composed of a much higher proportion of CSP than RTS,S.Therefore,R21 was designed to elicit a stronger anti-CSP antibody response while minimizing the anti-HBsAg antibody response,making it a promising RTS,S-like vaccine.In a phase Ⅱ trial,R21 in the adjuvant Matrix-M was also found to be safe and highly immunogenic in African children and showed promising high-level efficacy.Furthermore,R21/Matrix-M costs significantly less.It is also easier to manufacture than Mosquirix and has been approved as the second malaria vaccine by the WHO to prevent malaria.Vaccination with RTS,S/AS01 and R21/Matrix-M can induce antibodies against CSP,which immobilize sporozoites and prevent hepatocyte infection.However,anti-CSP antibodies could not exert their neutralization effect on sporozoites that had already invaded hepatocytes,and the elimination of parasites in hepatocytes is largely dependent on parasite-specific CD8+T cells.Recent studies confirmed that tissue-resident memory CD8+T cells(CD8+Trms)form a frontline defense mechanism against liver-stage malarial infections.Therefore,elucidation of the regulatory mechanism of liver CD8+Trms,identification of the protective antigens recognized by CD8+Trms,and subsequent design of an effective malaria prophylactic vaccine capable of simultaneously inducing high titers of anti-CSP antibodies and malaria-specific CD8+Trms responses should be one of the primary research directions in the future.The licensed RTS,S/AS01 and R21/Matrix-M provided powerful tools for fighting malaria.However,these two vaccines only reduce the morbidity and mortality of children in malaria-endemic regions,and their roles in the prevention of malaria infection remain to be defined.Furthermore,a much higher efficacy of malaria-preventive and transmission-blocking vaccines is required to control and eliminate malaria worldwide.
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