RESUMO
T cell immunity is critical in controlling human cytomegalovirus (HCMV) infection in transplant recipients, and T cells targeting viral immediate early proteins such as IE1, IE2 and pp65 have been speculated to be more effective against reactivation. Here we report efforts to construct replication incompetent adenovirus 6 vectors expressing these viral antigens as vaccine candidates. To reduce the potential liabilities of these viral proteins as vaccine antigens, we introduced mutations to inactivate their reported functions including their nuclear localization signals. The modifications greatly reduced their localization to the nuclei, thus limiting their interactions with cellular proteins important for cell cycle modulation and transactivation. The immunogenicity of modified pp65, IE1 and IE2 vaccines was comparable to their wild-type counterparts in mice and the immunogenicity of the modified antigens was demonstrated in non-human primates.
Assuntos
Antígenos Virais/imunologia , Vacinas contra Citomegalovirus/imunologia , Citomegalovirus/imunologia , Vírus Defeituosos/genética , Portadores de Fármacos , Vetores Genéticos , Mastadenovirus/genética , Animais , Antígenos Virais/genética , Citomegalovirus/genética , Vacinas contra Citomegalovirus/administração & dosagem , Vacinas contra Citomegalovirus/efeitos adversos , Vacinas contra Citomegalovirus/genética , Feminino , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Primatas , Transativadores/genética , Transativadores/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/imunologiaRESUMO
Following the disappointing outcome of the phase IIb test-of-concept step study in which Merck's adenovirus type 5 (Ad5) HIV-1 clade B gag/pol/nef vaccine failed to demonstrate efficacy in HIV high-risk individuals, an extensive review of the trial and preclinical studies which supported the trial is ongoing. One point of interest is how well preclinical nonhuman primate immunogenicity studies predicted what was observed in humans. Here we compare the HIV-1-specific cellular immune responses elicited in nonhuman primates and human clinical trial subjects to several HIV-1 vaccine candidates. We find that although rhesus macaques are immunologically more responsive to vaccination than humans, the hierarchy in potency of single-modality prime-boost regimens using several vector approaches (adenovirus, DNA, and pox vectors) was well predicted. Vaccine approaches using complex formulations such as novel adjuvants (DNA+CRL1005) or mixed-modality prime-boost (DNA/Ad5; Ad5/ALVAC) did not correlate as well between rhesus macaques and humans. Although the immunogenicity of the vaccines and vaccine regimens evaluated were not all accurately predicted, testing in rhesus macaques generally offers an indispensable tool for ranking the immunological potential of HIV-1 vaccine candidates.
