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The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic types.

A blood-stage vaccine based on Plasmodium falciparum merozoite surface protein 3 (MSP3) was tested for efficacy in a primate model. Aotus nancymai monkeys were vaccinated with yeast-expressed MSP3 before a lethal challenge with Plasmodium falciparum parasites. Five of 7 control monkeys had acute infections and required treatment to control parasitemia. Only 1 of 7 monkeys vaccinated with MSP3 required this treatment. The efficacy of the MSP3 vaccination appeared to be comparable to that of MSP1(42), a leading asexual vaccine candidate, in response to which 2 monkeys experienced acute infections. In the MSP3-vaccinated group, protection correlated with prechallenge titers of antibody to MSP3. In the MSP1 and control groups, protection correlated with antibody to MSP3 raised by challenge infection.

Malaria causes much physical and economic hardship in tropical regions, particularly in communities where medical care is rudimentary. Should a vaccine be developed, it is the residents of these areas that stand to benefit the most. But the vaccine, which has been promised to be 'just round the corner' for many years, remains elusive. It is important to ask why this is so, when effective vaccines exist for many other infectious diseases. What are the reasons for the slow rate of progress, and what has been learned from the first clinical trials of candidate malaria vaccines? What are the remaining challenges, and what strategies can be pursued to address them?

Two strains of transgenic mice have been generated that secrete into their milk a malaria vaccine candidate, the 42-kDa C-terminal portion of Plasmodium falciparum merozoite surface protein 1 (MSP1(42)). One strain secretes an MSP1(42) with an amino acid sequence homologous to that of the FVO parasite line, the other an MSP1(42) where two putative N-linked glycosylation sites in the FVO sequence have been removed. Both forms of MSP1(42) were purified from whole milk to greater than 91% homogeneity at high yields. Both proteins are recognized by a panel of monoclonal antibodies and have identical N termini, but are clearly distinguishable by some biochemical properties. These two antigens were each emulsified with Freund's adjuvant and used to vaccinate Aotus nancymai monkeys, before challenge with the homologous P. falciparum FVO parasite line. Vaccination with a positive control molecule, a glycosylated form of MSP1(42) produced in the baculovirus expression system, successfully protected five of six monkeys. By contrast, vaccination with the glycosylated version of milk-derived MSP1(42) conferred no protection compared with an adjuvant control. Vaccination with the nonglycosylated, milk-derived MSP1(42) successfully protected the monkeys, with 4/5 animals able to control an otherwise lethal infection with P. falciparum compared with 1/7 control animals. Analysis of the different vaccines used suggested that the differing nature of the glycosylation patterns may have played a critical role in determining efficacy. This study demonstrates the potential for producing efficacious malarial vaccines in transgenic animals.