Better late than never: defining the ideal vaccine that targets pre-erythrocytic malaria infection

Progress towards a much-needed malaria vaccine has accelerated in recent years. The most significant recent event was the independent licensure of the first two subunit vaccines against malaria, RTS,S/AS01 (MosquirixTM) from GSK and R21/Matrix-M from the Serum Institute of India, which received full World Health Organisation (WHO) prequalification in 2022 and 2023, respectively. Both vaccines require a primary series of four doses to confer maximum protection to children against the most virulent species of malaria caused by Plasmodium falciparum. This immunisation series, given over a 12 to 18-month period, elicits an immune response that targets the free parasite form—called a sporozoite—during its journey from mosquito bite, through the dermis and on to the liver, where it infects hepatocytes. It elicits a predominantly B-cell response (with a modest CD4+ T-cell response) specifically aimed at the circumsporozoite protein (CSP), the main sporozoite surface protein, aiming to block parasite colonisation of the liver. Whilst the licensure of these two vaccines heralds a landmark in global health, the level and durability of protection each confers is still uncertain, especially in infants and in areas of perennial, high-intensity transmission. Rather than quell enthusiasm for further vaccine development, however, this benchmark has bolstered efforts to find alternative strategies that complement or improve on overall vaccine efficacy and longevity. This enthusiasm is still urgent, with over half a million children under 5 still dying each year from malaria (Venkatesan P, 2025).