RESUMEN
Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×10(10)vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.
Asunto(s)
Infecciones por Adenoviridae/epidemiología , Infecciones por Adenoviridae/inmunología , Adenoviridae/inmunología , Anticuerpos Antivirales/inmunología , Vacunas Virales/inmunología , Vacunas contra el SIDA/inmunología , Adenoviridae/aislamiento & purificación , Infecciones por Adenoviridae/sangre , Infecciones por Adenoviridae/virología , Adolescente , Adulto , Animales , Anticuerpos Antivirales/sangre , Niño , VIH-1/inmunología , Humanos , Lactante , Macaca mulatta/inmunología , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.
Asunto(s)
Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/farmacología , VIH-1/inmunología , Inmunidad Celular , Animales , Formación de Anticuerpos/inmunología , Formación de Anticuerpos/fisiología , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/fisiología , Antígenos VIH/inmunología , Proteasa del VIH/inmunología , Inmunidad Celular/inmunología , Inmunidad Celular/fisiología , Activación de Linfocitos/inmunología , Activación de Linfocitos/fisiología , Macaca mulatta/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T/inmunología , Linfocitos T/fisiología , Vacunas Sintéticas , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study.