Failure of recombinant vaccinia viruses expressing Plasmodium falciparum antigens to protect Saimiri monkeys against malaria

Abstract

Saimiri sciurus monkeys were immunized at multiple sites with recombinant vaccinia viruses expressing Plasmodium falciparum antigen genes and boosted 4 weeks later. Control monkeys were immunized with a thymidine kinase-negative vaccinia virus mutant. Two weeks later, all of the monkeys were challenged by intravenous inoculation of P. falciparum (Indochina strain) parasites. A group of unimmunized monkeys was challenged in parallel. All of the monkeys that received vaccinia virus recombinants or the control virus produced good anti-vaccinia virus antibody responses. However, those that received a single construct containing ring-infected erythrocyte surface antigen (RESA) given at eight sites did not produce significant antibody to any of the three major RESA repeat epitopes after immunization but were primed for an enhanced antibody response after challenge infection with P. falciparum. Most of the monkeys produced detectable antibodies to the RESA epitopes after challenge infection. One group of monkeys was immunized with four constructs (expressing RESA, two merozoite surface antigens [MSA-1 and MSA-2], and a rhoptry protein [AMA-1]), each given at two sites. While these monkeys failed to produce significant antibody against MSA-2 or AMA-1 after immunization, they produced enhanced responses against these antigens after challenge infection. Immunization involved an allelic form of MSA-2 different from that present in the parasite challenge strain, so that the enhanced responses seen after challenge infection indicated the presence of T-cell epitopes common to both allelic forms. No groups of monkeys showed any evidence of protection against challenge, as determined by examination of the resulting parasitemias.

Recombinant chimeric proteins generated from conserved regions of Plasmodium falciparum merozoite surface protein 2 generate antiparasite humoral responses in mice

“…The merozoite surface protein 2 (MSP2) of Plasmodium falciparum is an attractive candidate for a sexual stage vaccine against malaria due to its surface location, and its suitability is supported by numerous studies that describe MSP2-speci®c inhibitory monoclonal antibodies (Stanley et al 1985, Ramasamy 1987, Epping et al 1988, Miettinen et al 1988, Smythe et al 1988, Clark et al 1989, Lyon et al 1989, Saul et al 1989, Thomas et al 1990). However, the two MSP2 vaccine trials reported to date in monkeys and human volunteers were of limited success (Pye et al 1991, Stuerchler et al 1995 and the evaluation of MSP2 in model systems has been retarded due to the failure to identify homologous proteins in Plasmodium species other than P. falciparum. It is possible that one such homologue may exist for P. berghei, since mice immunized with P. falciparum MSP2 peptides were protected against challenge with P. berghei (Saul et al 1992).…”

Synthetic peptides based on conserved Plasmodium falciparum antigens are immunogenic and protective against Plasmodium yoelii malaria

“…The major merozoite surface antigen MSA-I (Holder & Freeman 1982) and the RESA (Wahlin et al 1984) are two prominent vaccine target antigens of the asexual blood stage of P. falciparum. Nevertheless, recombinant proteins representing the complete or portions of these antigens have not provided the expected protection against P. falciparum infection in animal model systems (Herrara et al 1990, Pye et al 1991. There is some evidence suggesting that identification of protective epitopes and their presentation as synthetic peptides may provide a viable alternative to the use of whole antigens as vaccine candidates (Patarroyo et a/.…”

NYVAC-Pf7: a poxvirus-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria

“…Vaccinia virus recombinants expressing antigens from pathogenic agents can stimulate both humoral (8,13,15,34,55,56,75,79,85) and cellular (12,13,79,88,91) immunity and confer protection against both experimental and natural challenge (4,13,26,49,79). Notably, however, vaccinia virus recombinants derived from laboratory or vaccine strains that express single malarial antigens have failed to confer protection in rodents (46,68,71) and monkeys (64). The failure of these recombinants may relate to the choice of poxvirus vector or the suboptimal quality of foreign-gene expression (64,82).…”

“…Notably, however, vaccinia virus recombinants derived from laboratory or vaccine strains that express single malarial antigens have failed to confer protection in rodents (46,68,71) and monkeys (64). The failure of these recombinants may relate to the choice of poxvirus vector or the suboptimal quality of foreign-gene expression (64,82).…”

“…not diminish its immunizing potential as a vector in experimental or target species (5,14,43,78,80). In contrast to the failure of other vaccinia virus-malaria recombinants (46,64,68,71), the potential of NYVAC-based recombinants to confer pro-tection from experimental challenge with malaria parasites has been demonstrated (45). NYVAC thus provides a suitable foundation for the development of a multiantigen, multistage vaccine for human malaria.…”