Abstract
ABSTRACTEfforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced.
Highlights
Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens
We previously demonstrated that PfUIS3, administered in a chimpanzee adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) prime-boost regimen with an 8-week interval, could induce protective immune responses in BALB/c mice as determined by a significant delay in the time to 1% parasitemia after challenge with chimeric P. berghei-P. falciparum parasites expressing PfUIS3 [9]
We demonstrate that protective immune responses can be induced in two strains of inbred mice, as shown by a consistent delay of more than 1 day in the time to 1% parasitemia after challenge with chimeric P. berghei-P. falciparum parasites expressing PfUIS3
Summary
Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. When mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. A prime-boost regimen using the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) has so far proved to be the most adept at inducing high-magnitude cellular immunity [7] Use of this regimen with vectors encoding the thrombospondin-related adhesion protein (TRAP) along with a multiepitope (ME) string resulted in moderate efficacy against P. falciparum sporozoites in malaria-naive adults [5] and in a field trial in a region where malaria is endemic [8]. Using a vaccination regimen of DNA followed by a replication-competent vaccinia virus vector, these antigens together resulted in 43% sterile protection in outbred mice [13]
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