Malaria transmission-blocking vaccines—how can their development be supported?

Carter, Richard; Mendis, Kamini; Miller, Louis H.; Molineaux, L.; Saul, Allan

doi:10.1038/73062

Cited by 132 publications

(97 citation statements)

References 6 publications

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“…This altruistic approach does not protect the vaccinated individual but contributes to protection in the community. 30 In the absence of complete coverage, such a vaccine would be expected to decrease the number of infections only in low-transmission areas. Despite its efficacy in models, this approach is limited by overall poor immunogenicity and lack of natural boosting.…”

Section: Personal Viewmentioning

confidence: 99%

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Guérin¹,

Olliaro

Nosten

et al. 2002

The Lancet Infectious Diseases

320

201

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Section: Personal Viewmentioning

confidence: 99%

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Guérin¹,

Olliaro

Nosten

et al. 2002

The Lancet Infectious Diseases

320

201

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“…Animal studies demonstrated that anti-Pfs25-and anti-Pvs25-specific antibodies have the ability to block parasite development in the mosquito in an ex vivo membrane-feeding assay (2). A Phase 1 human trial of Pvs25 adsorbed onto aluminum hydroxide (Alhydrogel) induced transmission-blocking activity (TBA) that correlated with the titer of the anti-Pvs25 antibodies, thus establishing the feasibility of inducing transmission-blocking immunity by using Pvs25-based vaccines (3).…”

mentioning

confidence: 99%

Sustained high-titer antibody responses induced by conjugating a malarial vaccine candidate to outer-membrane protein complex

Przysiecki²,

Flanagan³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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117

113

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The development of protein subunit vaccines to combat some of the world's deadliest pathogens such as a malaria parasite, Plasmodium falciparum, is stalled, due in part to the inability to induce and sustain high-titer antibody responses. Here, we show the induction of persistent, high-titer antibody responses to recombinant Pfs25H, a human malarial transmission-blocking protein vaccine candidate, after chemical conjugation to the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B and adsorption to aluminum hydroxyphosphate. In mice, the Pfs25H-OMPC conjugate vaccine was >1,000 times more potent in generating anti-Pfs25H ELISA reactivity than a similar 0.5-g dose of Pfs25H alone in Montanide ISA720, a water-in-oil adjuvant. The immune enhancement requires covalent conjugation between Pfs25H and the OMPC, given that physically mixed Pfs25H and OMPC on aluminum hydroxyphosphate failed to induce greater activity than the nonconjugated Pfs25H on aluminum hydroxyphosphate. The conjugate vaccine Pfs25H-OMPC also was highly immunogenic in rabbits and rhesus monkeys. In rhesus monkeys, the antibody responses were sustained over 18 months, at which time another vaccination with nonconjugated Pfs25H induced strong anamnestic responses. The vaccine-induced anti-Pfs25-specific antibodies in all animal species blocked the transmission of parasites to mosquitoes. Protein antigen conjugation to OMPC or other protein carrier may have general application to a spectrum of protein subunit vaccines to increase immunogenicity without the need for potentially reactogenic adjuvants. malaria ͉ Pfs25 ͉ transmission-blocking vaccine A s reported by the World Health Organization in 2004, the worldwide incidence of malaria is Ϸ300 million clinical cases and 1.3 million deaths annually (1). Of the four species of malaria parasites that infect humans, Plasmodium falciparum is responsible for the majority of these deaths, and Plasmodium vivax accounts for Ͼ50% of all malarial infections outside Africa and 10% of those in Africa. Mounting drug resistance by the malaria parasite makes chemotherapy increasingly difficult. Three types of malarial vaccines are under research and development: (i) vaccines targeting the liver-stage parasite development for sterile immunity; (ii) vaccines targeting the blood-stage parasite to reduce disease burden; and (iii) vaccines targeting the parasite development in the mosquito stage to block transmission, called transmission-blocking vaccines (TBVs). For all three types of vaccines, antibody is important. For TBVs, antibody is the only mechanism for providing immune protection. TBVelicited functional antibodies, ingested with the sexual stages of the parasite in a blood meal by a mosquito, will inhibit or block parasite development in the mosquito.Pxs25 proteins encoded by orthologous genes and expressed on the surface of zygotes and ookinetes during the development of the malaria parasite P. falciparum (Pfs25) and P. vivax (Pvs25) are leading candidates for mosquito-stage transmission...

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“…When ingested by a mosquito with the blood meal, antibodies against the sexual and the mosquito stage-specific surface antigens can block parasite development inside the vector (1). Four proteins have been identified as potential inducers of transmission-blocking antibodies (2)(3)(4)(5).…”

mentioning

confidence: 99%

Long-lasting and transmission-blocking activity of antibodies toPlasmodium falciparumelicited in mice by protein conjugates of Pfs25

Kübler-Kiełb

Majadly

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Malaria is a leading cause of morbidity and mortality, estimated to cause >1 million childhood deaths annually. Plasmodium falciparum causes the most severe form of the disease. There is as yet no licensed vaccine for this disease, despite over a half century of research. In this study, we investigated a transmission-blocking vaccine candidate, the ookinete surface protein Pfs25. Antibodies against Pfs25, drawn in during a bite, can block parasite development in the mosquito midgut, preventing transmission to other individuals. Pfs25 is a low-molecular-weight protein, by itself not immunogenic. To increase its immunogenicity, we investigated several methods of conjugating Pfs25 to itself and to other proteins: recombinant Pseudomonas aeruginosa exotoxin A, and ovalbumin, using amide, hydrazone, or thioether linkages. All conjugates were immunogenic and induced booster responses in mice. The scheme to form amide bonds between proteins by using adipic acid dihydrizide as a linker produced the most immunogenic conjugates. Adsorption of the conjugates onto aluminum hydroxide further increased the antibody response. Remarkably, the antibody levels 3 or 7 months after the last injection were significantly higher than those 1 wk after that injection. The observed transmission-blocking activity of immune sera correlated with antibody levels measured by ELISA. malaria ͉ vaccine O ne approach for a vaccine against malaria is to block transmission of the parasite from mosquitoes to humans. When ingested by a mosquito with the blood meal, antibodies against the sexual and the mosquito stage-specific surface antigens can block parasite development inside the vector (1). Four proteins have been identified as potential inducers of transmission-blocking antibodies (2-5). Two of these are expressed on the surface of gametes and in intracellular gameotocytes. The other two are the Plasmodium falciparum surface proteins with apparent molecular masses of 25 kDa (Pfs25) and 28 kDa (Pfs28), expressed exclusively on the zygote and ookinete surfaces during the mosquito stage of the infection. No antibody response to these two proteins has been shown in people infected with malaria and living in endemic countries (6). Pfs25 from different parts of the world has shown minimal variation in its amino acid sequence (7). This relative homogeneity, likely a result from not being subjected to immune pressure in the human host, makes Pfs25 an attractive candidate for a malaria transmission-blocking vaccine (8). Pfs25 is poorly immunogenic in mice and in humans, even if administered with adjuvant (9, 10). In this article, we show that Pfs25 bound onto itself or onto another protein induced high levels of transmission-blocking antibodies in mice.

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Malaria transmission-blocking vaccines—how can their development be supported?

Cited by 132 publications

References 6 publications

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

Sustained high-titer antibody responses induced by conjugating a malarial vaccine candidate to outer-membrane protein complex

Long-lasting and transmission-blocking activity of antibodies toPlasmodium falciparumelicited in mice by protein conjugates of Pfs25

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