Sporozoite-Induced Immunity in Mammalian Malaria

Nussenzweig, Ruth S.; Vanderberg, Jerome P.; Spitalny, George L.; Rivera, C. I. O.; Orton, Colin G.; Most, Harry

doi:10.4269/ajtmh.1972.21.722

Cited by 53 publications

(26 citation statements)

References 2 publications

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“…These observations, initially made for RAS in mice more than 40 years ago (19) and more recently for Spz plus CQ (2, 3) and GAS (16,31), gained in importance and relevance to vaccine development when they were repeated in humans in the 1970s for RAS (4,12,22) and last year for Spz plus CQ (23). Clinical trials to test the efficacy of immunization with recently produced P. falciparum GAS (30) are imminent.…”

Section: Discussionmentioning

confidence: 99%

“…Three vaccination protocols have been shown to confer sterile immunity (absence of blood stage parasites after challenge with sporozoites) against PE stages. First, immunization with radiation-attenuated sporozoites (RAS) has long been the gold standard for the induction of sterile immunity in rodents, monkeys, and humans (12,19). Second, immunization with a smaller number of live sporozoites under chloroquine prophylaxis (Spz plus CQ) equally conferred sterile protection against sporozoite challenge in mice (2,3).…”

Section: Immunization With Livementioning

confidence: 99%

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Minimal Role for the Circumsporozoite Protein in the Induction of Sterile Immunity by Vaccination with Live Rodent Malaria Sporozoites

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Section: Immunization With Livementioning

confidence: 99%

Minimal Role for the Circumsporozoite Protein in the Induction of Sterile Immunity by Vaccination with Live Rodent Malaria Sporozoites

et al. 2010

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“…Inactivated sporozoites that are not able to infect hepatocytes have consistently failed to induce protective immune responses (1,23,31), although they can efficiently prime the immune system (15). Conversely, malaria-infected hepatocytes and their extracts induce significant protection when they are injected into rats or mice (37,41).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, some RAS and GAS seem to induce long-lasting, cross-species protection (11,31,32). Attenuation of irradiated sporozoites presumably occurs due to double-strand breaks in the DNA that lead to a block in liver stage development.…”

Section: Discussionmentioning

confidence: 99%

Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice

et al. 2008

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Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.The development of an effective vaccine is critical to curb the significant health, social, and economic impacts caused annually by malaria in countries where the disease is endemic (39). Malaria infection involves injection of Plasmodium sporozoites from a mosquito into humans. The sporozoites migrate to the liver, invade hepatocytes, and transform into exoerythrocytic forms (EEFs) that replicate to produce schizonts containing thousands of merozoites (35). These merozoites are released into the host bloodstream and invade erythrocytes. The blood stages of malaria are responsible for producing the symptoms of the disease. Many attempts have been made in recent years to develop effective subunit vaccines composed of recombinant Plasmodium antigens. Due to the complexity of Plasmodium, these vaccines have been only partially effective (2,12,14,38).Recently, there has been renewed interest in the attenuated whole-organism vaccine strategy (16,22,38,53). The wholeorganism approach has historically used radiation-attenuated sporozoites (RAS) to obtain sterile immunity experimentally in both mice and humans (16,30). The RAS invade hepatocytes in a susceptible host and begin to develop into EEFs, but the majority of parasites fail to undergo nuclear division and do not progress to the merozoite form (44, 45). Using mice, RAS dosing regimens that generate protective immunity have varied, although most regimens require a prime-boost schedule (4,11,32,50). A meta-analysis of 10 years of immunization of human volunteers using irradiated Plasmodium falciparum sporozoites showed a dose response in terms of the immunization dose required for protection (16,22). One key issue with RAS has been the delivery of the correct irradiation dose to ensure adequate attenuation of the parasite (16,23,38,41,51). A strategy to overcome this issue has been to generate genetically attenuated ...

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“…This work followed studies where immunization of animals with radiation-attenuated sporozoites was similarly highly protective [10,11]. Recently, immunization of rodents with genetically attenuated sporozoites (GAS) also afforded high-grade (>90%) protection [12].…”

Section: The Sporozoitementioning

confidence: 99%