Roger M. Miller

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.

Lack of enhanced oxygen consumption by polymorphonuclear leukocytes on phagocytosis of virulent Salmonella typhi.

Human polymorphonuclear leukocytes exhibit an enhanced rate of oxygen consumption during phagocytosis of relatively avirulent strains of Salmonella typhi or Staphylococcus aureus. However, phagocytosis of a virulent strain of Salmonella typhi is not associated with augmented oxygen consumption. The ability of a bacterial strain to alter the postphagocytic rate of oxygen consumption of polymorphonuclear leukocytes may be related to its in vivo virulence.

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.

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.