We searched PubMed using the phrase “malaria and vaccine” with a limit for clinical trials. We also searched for papers that detailed antigen characterisation or vaccine platform evaluation by use of in-vitro assays and animal models. The phrase for the second search was “malaria vaccines[MeSH]”. We reviewed all abstracts and selected relevant articles. We also identified relevant articles from the reference lists in articles from these two searches. Searches were done in November, 2002, and
SeriesMalaria vaccine developments
Section snippets
Some history
Which statement speaks to your instinct: Plutarch's “history repeats itself” or Robert Walpole's “anything but history, for history must be false”? Your answer could determine your level of optimism in malaria vaccine development. 1973 saw the first report of human protection from malaria by vaccination.15 However, the vaccination consisted of the bites of about a thousand mosquitoes infected with malaria parasites that had been X irradiated.16 This demonstration was obviously unlikely to be a
The life cycle of P falciparum
A female anopheline mosquito requires a blood meal for egg production (figure 1). During such a meal, a mosquito infected with P falciparum will inject five to 20 sporozoites,25, 26 which invade hepatocytes within minutes. Sporozoites migrate through several hepatocytes before entering one; this is the start of the liver stage.27, 28 The sporozoite and liver stages are the pre-erythrocytic parts of the life cycle. Over an average of 6·5 days, parasites develop within the liver into schizonts.
Subunit vaccination
The production of live, attenuated, or killed inactivated vaccines is not practical for many diseases. In subunit vaccination, part or complete antigens are identified from a pathogen's proteomic complement, which can induce protective immunity to the whole pathogen on vaccination. The hepatitis B vaccine is an effective recombinant protein subunit vaccine.29 This vaccine was designed to induce the maximum antibody (humoral) immune response.
Unfortunately, proteins vary greatly in their
Natural and vaccine induced immunity
Natural exposure to P falciparum gradually elicits, in human hosts, short-lived strain-specific malaria immunity: first to severe disease and death, and then to mild disease.40 Repeated infections are required to maintain immunity, which is both antibody and T-cell based, although evidence is most clear for antibody-mediated immunity to blood-stage malaria.41, 42, 43 Exactly which of the 5300 antigens encoded by the P falciparum parasite produces the key protective immune responses is not
Pre-erythrocytic vaccines
The ideal vaccine for this stage would induce high titres of functional antibodies against sporozoites to prevent all parasites entering the liver stage, and induce potent cytotoxic T-lymphocyte immunogenicity against the liver stage to kill infected hepatocytes, while not harming the human host. The lead candidate vaccine of this type is RTS,S—a recombinant protein vaccine.46 Hepatitis B surface antigen DNA was fused to DNA encoding a large part of the best characterised pre-erythrocytic
Blood-stage vaccines: invasion and complication
There are two possible classes of blood-stage vaccine: anti-invasion and anticomplication. A vaccine that could prevent invasion of red blood cells by merozoites would prevent malaria disease. Development of such vaccines has been hampered by the lack of an established human challenge model, by the limitations of available animal models, and by unclear immunological correlates of protection. Merozoite surface protein-1 (MSP-1) is the most well characterised antigen involved in invasion, and is
Sexual-stage vaccines: the altruistic vaccine
Induction of antibodies to gametocyte antigens can prevent fertilisation in the mosquito; as well as its blood meal, the mosquito ingests antibodies that block fertilisation. As a result, assessment of the efficacy of gametocyte vaccines is possible with a simple ex-vivo assay. Mosquitoes are fed on gametocytes with or without the addition of human serum samples from vaccinated volunteers. The US National Institute for Allergy and Infectious Disease Malaria Vaccine Development Unit plans
Vaccine development in the post-genomic era
Results of whole-genome sequencing indicate that there are probably 5300 P falciparum antigens. Genome databases can be used for identifying hundreds of candidates for vaccination. However, the number of possible antigens is not rate-limiting for malaria vaccine development. Identification of antigens does not help solve some key problems in malaria vaccine development: how to induce strong, durable immune responses; and how to combine multiple antigens without interference or competition.
Discussion
Development of an effective and deployable malaria vaccine seems technically feasible in the view of most malaria researchers. New vaccine delivery methods and adjuvants could continue to increase the antibody and cellular immunogenicity of subunit vaccination. The rate of clinical assessment of candidate malaria vaccines is increasing; in the past 5 years, the number of groups doing such research has increased from three to 11. Careful clinical expansion is needed to translate immunogenicity
Search strategy
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