The quest for the holy grail: an effective malaria vaccine?

12 February 2002

by Richard Reithinger rreithinger@yahoo.co.uk

Bojang K. A et al. (2001). Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet, 358:1927-1934.

High profile initiatives and programmes under the WHO Roll Back Malaria initiative as well as the unravelling of the human and malaria parasite genome have insured that malaria vaccine research and development is enjoying an unprecedented boom. So far, the possibility of developing a vaccine against a parasite that is extremely complex, has different life stages and is known to have elaborate ways of evading the human immune response, has proved to be an elusive quest. Recently, there have also been some concerns that imperfect vaccines could encourage the selection of more virulent parasite strains. However, there is compelling evidence that if an effective malaria vaccine were developed it would prove to be protective, as several studies have shown that (1) immunity to malaria is developed after multiple Plasmodium infection, and (2) exposure to bites from irradiated Anopheles mosquitoes infected with P. falciparum sporozoites can confer protection against infection for up to ten months. Based on these findings, effector T-cell vaccines that target the pre-erythrocytic stages of the parasite in infected hepatocytes have been developed.

Bojang et al. have now tested one such vaccine, RTS,S/AS02 for its efficacy in protecting semi-immune men from P. falciparum infection. RTS,S is a fusion protein combining most of the P. falciparum circumsporozoite protein and a surface antigen from hepatitis B virus (HbsAg) with a complex adjuvant (AS02). The authors report the results a of randomized, controlled trial in The Gambia where adult men were given three doses of either RTS,S/AS02 or rabies vaccine (control); the primary endpoint and outcome variable being time to first P. falciparum infection. Overall RTS,S/AS02 vaccine efficacy was shown to be 34% (95% C.I. 8 to 53, P=0.014), but efficacy against infection decreased from 71% (C.I. 46 to 85) during the first 9 weeks of follow-up to 0% (C.I. -52 to 34) in the last 6 weeks. A single booster vaccination achieved protection of 47% (C.I. 4-37, P=0.037). No significant difference in symptomatic malaria episodes between vaccine groups was observed.

Despite the observation that vaccine efficacy appeared to wane, the results are encouraging because protection was shown to be associated with a vaccine peptide-specific CD4 T cell response and because protection was not exclusively limited to the parasite genotype from which the vaccine had been derived. The authors acknowledge that the immune mechanisms that lead to protection after vaccination with RTS,S/AS02 have yet to be understood, but hope that vaccine efficacy could be improved with better adjuvant formulations, prime-boost immunization strategies or the addition of blood-stage antigens (e.g. merozoite surface protein 1). Further trials to evaluate the impact of the vaccine on morbidity and mortality in children are planned and should give some clues whether this vaccine candidate will only be of use in areas of low endemicity or seasonal transmission or of potential use in areas of high endemicity.

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See also:
Pre-erythrocytic immunity to Plasmodium falciparum: the case for an LSA-1 vaccine
Jonathan D. Kurtis, Michael R. Hollingdale, Adrian J.F. Luty, David E. Lanar, Urszula Krzych and Patrick E. Duffy (2001) Trends in Parasitology 17:219-223.

Malaria vaccine trials in a wormy world
Mathieu Nacher (2001) Trends in Parasitology 17:563-565.

The WHO Vaccine Trial Registry
Susan E. Robertson, Marti Vall Mayans, Amro El-Husseiny, John D. Clemens and Bernard Ivanoff (2001) Vaccine 20:31-41.

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