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Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 ( pages 268–270 and 324–328 ). The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development 1 , 2 . 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 3 . 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.

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 4×1010vp 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.

The phase 2b trial of Merck's recombinant adenovirus type 5–based HIV-1 vaccine was halted as the vaccine seemed to have increased HIV-1 acquisition in vaccine recipients who had preexisting immunity to the adenovirus vector. One theory to explain these results is that the preexisting antibody response to the vector may have been a surrogate for increased vector-specific CD4 + T cells, which would have been amplified after vaccination and may have served as increased target cells during subsequent HIV-1 exposure. Daniel Barouch and his colleagues and Michael Betts and his colleagues now challenge this view. 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.

Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 ((https://www.nature.com/articles/nm0310-268) and (https://www.nature.com/articles/nm.2108)).

The immunologic basis for the potential enhanced HIV-1 acquisition in Ad5 seropositive individuals who received the Merck rAd5 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 following 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.