PerspectiveImmunology

Another Shot at a Malaria Vaccine

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Science  28 Oct 2011:
Vol. 334, Issue 6055, pp. 460-461
DOI: 10.1126/science.1213934

Malaria, an infectious disease caused by Plasmodium parasites that are transmitted by mosquito bite, has a devastating global impact, causing 300 to 500 million clinical cases and up to 800,000 deaths each year. Vaccine development for malaria is marked by many failures, some encouraging successes, and much hope. Recently, a malaria vaccine candidate (RTS,S/AS01) based on the major surface protein of the transmissible sporozoite form of the parasite advanced into phase three clinical trials in Africa, and preliminary data show 55% efficacy against malaria episodes and 35% efficacy against severe malaria (1). Although it is not yet known how long protection lasts, this vaccine constitutes a milestone for developing a more efficacious vaccine. A highly protective vaccine that prevents malaria infection will also prevent disease and further transmission by the mosquito and, hence, constitutes the potential “magic bullet” in our future armamentarium against malaria. Yet developing such a vaccine has been frustratingly difficult. On page 475 of this issue, Epstein et al. (2) report the results of a clinical trial with an injectable preparation of Plasmodium sporozoites, attenuated by exposure to DNA-damaging irradiation and intended to prevent infection. Their trial results mark an inflection point in malaria vaccine development.

The study by Epstein et al. is the result of decade-long efforts by the biotech company Sanaria to manufacture the irradiated sporozoite vaccine in mosquitoes under specifications that produce a clean, cryopreserved formulation suitable for injection. The vaccine is based on several small clinical studies in human volunteers since the 1970s (3), which demonstrated that repeated immunizations with irradiated sporozoites delivered by mosquito bite conferred more than 90% protection against infectious sporozoite challenge when the cumulative dose exceeded 1000 immunizing bites (challenges with malaria-infected mosquitoes are conducted safely because the infection is treatable). Moreover, numerous studies of irradiated sporozoite vaccinations in mice demonstrated that immune cells (CD8+ T cells) are critical to protection because they eliminate infected hepatocytes (4).

In the trial reported by Epstein et al., volunteers in four groups each received the irradiated sporozoites by accepted routes of vaccination with a syringe, either intradermally or subcutaneously. One group received low doses (4 × 7500), one group received medium doses (4 × 30,000), and two groups received high doses (4 × 135,000 or 6 × 135,000) of irradiated sporozoites. All groups were challenged with malaria-infected mosquitoes 3 weeks after the last immunization. All 44 volunteers challenged, except 2, developed malaria infection in the blood stream. Thus, vaccine efficacy was ∼5%.

Vaccination against malaria.

Sporozoit-based vaccines induce immune protection to subsequent infection. A live-attenuated sporozoite vaccine can be administered by syringe or mosquito bite (not shown). Intravenously delivered sporozoites effectively target the liver, potentially increasing efficacy. IFN-γ, interferon-γ

CREDIT: Y. HAMMOND/SCIENCE

Some might perceive this result as a monumental failure and reason to abandon development of any type of whole sporozoite-based vaccine. But the Sanaria team argues for moving quickly to further clinical studies that administer the same irradiated sporozoite preparations intravenously. The rationale for this path is supported by their animal model studies, which show better T cell responses (monkeys) and better protection (mice) after intravenous administration of irradiated sporozoites when compared to subcutaneous administration. These findings imply that targeting the sporozoite vaccine to the liver might be critical for inducing protective immunity, a controversial hypothesis because the liver is currently not considered a key organ for priming of protective T cells (5).

Other aspects of the trial results, its analysis, and the accompanying animal data raise important concerns about further clinical development of the current irradiated sporozoite formulation. The animal studies of Epstein et al. show that three- to four-fold higher doses are needed to protect mice with cryopreserved irradiated sporozoites as compared to fresh irradiated sporozoites, demonstrating that the cryopreservation procedure of Epstein et al. might inactivate a substantial number of sporozoites in the vaccine. In addition, the immunization of humans with increasing doses of irradiated sporozoites did not consistently correlate with a greater magnitude of cellular immune responses in the volunteers. Furthermore, the extremely limited protection (2 out of 44) against challenge did not fall into the highest-dose vaccination group, and no delay in the onset of blood-stage infection was observed in any group. Had the highest vaccine dose reached the threshold necessary to confer protection, these outcomes would not have been expected.

What then does it take to develop a protective attenuated sporozoite vaccine that can be administered by a reasonable route? Recent data point to the potential of improving the immunogenicity of whole-parasite vaccines (see the figure). A clinical study found that only three doses of 12 to 15 malaria-infected mosquito bites each, along with chloroquine to eliminate the ensuing blood-stage infection, conferred complete protection against subsequent malaria challenge in all volunteers (6). And a recent study in mice demonstrated that immunization with genetically engineered parasites that undergo development to late stage in the liver and then arrest improves their immunogenicity. Such parasites induce much better T cell responses and protect with much lower doses and by clinically relevant subcutaneous and intradermal routes as compared to irradiated sporozoites (7). These studies exemplify a simple principle; allowing the attenuated parasite vaccine to develop to a maximal point before it causes disease increases antigen payload, provides the immune system with a diversity of targets (the parasite is made of more than 5000 proteins), and elicits broad recognition by the immune system of many proteins that in total constitute an effective immune response against the parasite.

Beyond optimizing sporozoite immunogenicity and ensuring its safety, it is important to improve vaccine pre servation methods that retain maximum sporozoite viability. Moreover, improving subcutaneous or intradermal administration is critical, because an intravenously injected malaria vaccine will not be practical for immunizing the most vulnerable target population—infants and children in Africa. The mosquito bite appears to be the most effective method for delivering sporozoites, and further studying the mechanics of sporozoite transmission will inform the optimization of syringe injection. Together, this multipronged approach might be the best path to developing an efficacious, live-attenuated anti-infection vaccine for malaria.

References and Notes

  1. Seattle Biomedical Research Institute holds patents on the genetically attenuated parasite vaccine design.
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