The malaria sporozoite injected into a host by the bite of the mosquito vector initiates the parasite cycle that culminates in clinical disease. This sporozoite stage is highly antigenic, and immunization with irradiated sporozoites has prevented the development of malaria in rodent and simian hosts as well as in several human volunteers (1). Antisporozoite antibodies detectable in the sera of the immunized primate hosts appear to be associated with immune resistance.Recently, hybridoma-derived monoclonal antibodies directed against sporozoites of rodent and simian malaria were found to be protective, i.e., to abolish sporozoite infectivity both in vivo (2) and in vitro (3). 1 These antibodies react with circumsporozoite (CS) 2 proteins; that is, stage-and species-specific polypeptides that are uniformly distributed over the entire surface of the parasite and that are shed when cross-linked by antibodies (2, 4). 1The hybridoma technique was therefore used to develop monoclonal antibodies against sporozoites of P falciparum and P. vivax in an attempt to identify the protective antigens of the human pathogens for their application in a vaccine.
Materials and MethodsMice. BALB/c mice were immunized using viable and frozen sporozoites of P.falciparum or P. vivax. The P. falciparum spomzoites were of West African origin and were obtained by membrane feeding Anopheles gambiae mosquitoes on blood obtained from patients carrying P. falciparum gametoeytes. P. vivax sporozoites for immunization were obtained from Anopheles
Saimiri monkeys immunized with a recombinant protein containing 20 copies of the nine amino acid repeat of the Plasmodium vivax circumsporozoite (CS) protein developed high concentrations of antibodies to the repeat sequence and to sporozoites, but were not protected against challenge. After intravenous injection of an immunoglobulin G3 monoclonal antibody (NVS3) against irradiated P. vivax sporozoites, four of six monkeys were protected against sporozoite-induced malaria, and the remaining two animals took significantly longer to become parasitemic. Epitope mapping demonstrated that NVS3 recognizes only four (AGDR) of the nine amino acids within the repeat region of the P. vivax CS protein. The monkeys immunized with (DRAADGQPAG)20 did not produce antibodies to the protective epitope AGDR. Thus, determination of the fine specificity of protective immune responses may be critical to the construction of successful subunit vaccines.
Gametocytes of two strains of the human malaria parasite Plasmodium falciparum have been produced in high density by means of a continuous-flow cultivation system. The gametocytes of these two strains infected a mean of 36 percent and 71 percent, respectively, of Anopheles freeborni mosquitoes that fed on a suspension of red blood cells containing the culture gametocytes. Sporozoites harvested from the infected mosquito salivary glands were infective to the chimpanzee (Pan troglodytes) and the owl monkey (Aotus trivirgatus).
Sixty-seven splenectomized Aotus azarae boliviensis were infected with strains of Plasmodium vivax from Southeast Asia (2), New Guinea (2), North Korea (1), and Central America (3). Maximum parasitemias varied among the different strains, with the mean maximum parasitemia for the primary infection period being 16,200 per mm3. Animals previously infected with Plasmodium falciparum and Plasmodium malariae produced maximum parasitemias of 30,200 and 11,900 per mm3, respectively. Gametocytes infective to Anopheles freeborni mosquitoes were produced with 7 of the 8 strains examined.
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