Vincent C. McCarthy

Immunization of man against sporozite-induced falciparum malaria

Based on successful work with nonhuman malarias, an attempt was made to immunize man against mosquito-borne stages of Plasmodium falciparum. Strict ethical guidelines were followed. Mosquitoes carrying sporozoites of P. falciparum were X-irradiated and then fed on volunteers who had not previously been exposed to malaria. The sporozoites were inactivated at a minimum dosage of 15,000 rads, and did not produce adverse reactions in the volunteers. Three volunteers were each exposed during 84 days to 379 infected irradiated mosquitoes, and on day 98 were fed on by nonirradiated mosquitoes heavily infected with homologous strain P. falciparum. One of these men did not develop malaria, and continued to be immunized during the ensuing 217 days with 819 infected mosquitoes. On day 327, when antisporozoite antibody was first demonstrated in his serum by the circumsporozoite precipitation test, he was fed on by nonirradiated mosquitoes carrying homologous strain P. falciparum, and did not develop malaria. Possible causes of his failure to become infected were investigated, and it was concluded that he had become immunized to falciparum sporozoites of that strain. His continued susceptibility to strain-specific falciparum malaria induced by direct blood transfer was demonstrated.

Immunization of Man against Falciparum and Vivax Malaria by Use of Attenuated Sporozoites

With strict adherence to ethical guidelines, a volunteer was immunized against sporozoites of Plasmodium falciparum and P. vivax, the antigen consisting of attenuated sporozoites of each species inoculated through bites of mosquitoes X-irradiated at a minimum dosage of 15,000 rads. On one occasion this dosage did not render all P. vivax sporozoites noninfective. Species specificity of antigen and antibody was demonstrated, but within each species a wide geographical diversity of strains proved interchangeably antigenic and susceptible to the antibody. Once immunized, the volunteer was protected for not more than 3 months and 6 months, respectively, from infective P. falciparum and P. vivax sporozoites, the duration of protection being reflected by a positive species-specific circumsporozoite reaction. Studies in this volunteer, and in two others immunized with P. falciparum sporozoites, did not reveal any increase in serum levels of immunoglobulins G and M.

Specificity of protection of man immunized against sporozoite-induced falciparum malaria.

During a period of 421 days a total of 1,441 X-irradiated mosquitoes inoculated attenuated sporozoites of Burma (Thau.) strain Plasmodium falciparum into a volunteer. Strict ethical guidelines were followed. The volunteer was also exposed at various times to nonirradiated mosquitoes carrying infective sporozoites of the same strain and of strains from Malaya, Panama and the Philippines, and did not develop falciparum malaria. Following exposure to nonirradiated mosquitoes carrying Chesson strain P. vivax, he developed vivax malaria. Antisporozoite antibody, demonstrated by the circumsporozoite precipitation test, appeared in his serum and reacted equally against the Burma strain of P. falciparum and strains from Malaya, Panama and the Solomon Islands, but did not react with Chesson vivax sporozoites.

Radical cure of Chesson strain vivax malaria in man by 7, not 14, days of treatment with primaquine.

Glucose-6-phosphate dehydrogenase-normal adult volunteers infected with mosquito-bone Chesson strain vivax malaria were treated with chloroquine and primaquine during the initial attack. Administration of 60 mg (base) of primaquine daily for 7 days was as effective in preventing relapse as is the regimen customarily used for the radical cure of infections produced by this strain, namely, 30 mg daily for 14 days. However, it is stressed that because of the risk of primaquine-induced hemolysis in individuals having genetically-transmitted erythrocyte abnormalities this high dosage should not be used routinely.

Plasmodium vivax: correlation of circumsporozoite precipitation (CSP) reaction with sporozoite-induced protective immunity in man.

Abstract A volunteer was immunized with X-irradiated sporozoites of Plasmodium vivax against a nonirradiated, infective sporozoite challenge of the same species and strain. Shortly before his first successful challenge, his serum was found to contain anti-sporozoite antibodies. Subsequent immunizations and challenges with another strain demonstrated that his protective immunity lasted 3–5 months and could be restored or boosted by challenge with a small number of nonirradiated, infective sporozoites. His CSP serum reaction paralleled his level of protective immunity.

Suppressive Activity of Mefloquine in Sporozoite-Induced Human Malaria

Mefloquine hydrochloride [WR 142,490; α-(2-piperidyl)-2,8-bis(trifluoromethyl)-4-quinolinemethanol hydrochloride] was tested for suppressive effect on sporozoite-induced malaria in nonimmune volunteers living in an area where malaria is not naturally transmitted. Single doses of 250 mg were given at weekly intervals, 500 mg at intervals of 2 weeks and 1,000 mg at intervals of 4 weeks, to men bitten by 10 to 15 mosquitoes heavily infected with a chloroquine- and pyrimethamine-resistant strain of Plasmodium falciparum. None of the individuals so treated developed infections during the period of drug delivery or during the follow-up period of 60 days. Doses of 250 or 500 mg produced no adverse reactions; mild epigastric discomfort occurred in all three men given 1,000 mg. Sporozoite-induced P. vivax infections were suppressed by single doses of 250 mg of mefloquine given at weekly intervals, but malaria developed after completion of the course. At treatment intervals longer than 1 week, vivax malaria was not suppressed.

Prophylactic Activity of a Phenanthrene Methanol (WR 33063) and a Quinoline Methanol (WR 30090) in Human Malaria

WR 33063 (3-bromo-10-[α-hydroxy-β-(n, n-diheptylamino)ethyl]-phenanthrene hydrochloride) and WR 30090 (6,8-dichloro-2,3,4-dichlorphenyl-di-n-butylaminoethyl-4- quinolinemethanol hydrochloride) were tested for suppressive prophylactic effect on induced malaria in nonimmune volunteers living in an area where malaria is not naturally transmitted. Doses of 800 mg of WR 33063 and 690 or 460 mg of WR 30090 were given at weekly intervals to men exposed on the day of the first dose to mosquitoes heavily infected with chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum. WR 33063 did not interfere with early development of infection, but WR 30090 given for 8 weeks provided suppressive cures in 20 of 26 men. P. vivax infections similarly induced broke through WR 30090 treatment in 4 of 15 men, and most of the remainder experienced malaria after completion of the prophylactic course. No side effects of treatment were observed.

Influence of sulfalene upon gametocytogenesis of Plasmodium falciparum and subsequent infection patterns in Anopheles stephensi

Abstract Quinine and/or sulfalene were administered to non-immune volunteers during various stages of infection with Plasmodium falciparum . Administration of each drug early in the asexual parasitemia reduced or prevented the subsequent formation of gametocytes. Later administration of sulfalene produced a subsequent sterilizing effect upon immature, non-circulating gametocytes, which were non-infective to Anopheles stephensi when they appeared in the circulating blood. Gametocytes present in the peripheral circulation at the time of administration of both drugs or appearing shortly thereafter were infective to A. stephensi .

Prophylactic and sporontocidal treatment of chloroquine resistant Plasmodium falciparum from Malaya

Abstract The prophylactic and sporontocidal efficacy of standard antimalarials was studied among non-immune adult male volunteers challenged by mosquitoes heavily infected with two strains of chloroquine resistant Plasmodium falciparum from Malaya. The Poo. strain from Trengganu broke through in 12 of 15 men receiving chloroquine 300 mg. (base) and primaquine 45 mg. (base) at weekly intervals, whereas 8 weeks of this treatment protected all 3 men challenged with the Tay. strain from Kota Tinggi, Johore State. The Poo. strain broke through in 5 men given amodiaquine base 300 mg. and DDS 300 mg. weekly. Proguanil 200 mg. (2·1–3·2 mg. per kg. body weight) given daily for 8 weeks after challenge provided complete suppression of the Poo. strain in 4 men (and probably a fifth), and also of the Tay. strain in 4 men, nor did parasitaemia develop after completion of the prophylactic course. Pyrimethamine 25 mg. given weekly failed to protect 2 of 3 men challenged with Poo., and the Tay. strain also broke through in both men receiving this regimen. A single dose of 45 mg. (base) of primaquine was gametocytocidal for both strains and, in one case of Poo. infection studied, rendered gametocytes non-infective to an efficient vector mosquito fed on the patient 24 hours later.