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.
