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publicado em 28/12/2011 às 11h11:00
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Immunity to adenovirus reduces effectiveness of HIV vaccine, study shows

Discovery represents another obstacle to the development of a vaccine against AIDS and other diseases caused by viruses

 
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Vaccines offer the most effective and durable interventions for the prevention of infectious diseases. Classic approaches to developing highly efficacious vaccines for major global health threats, including HIV, malaria, and tuberculosis, have been unsuccessful. Recombinant vectors that encode pathogen proteins hold promise, and adenovirus and pox vectors have been commonly employed for this purpose. For example, adenovirus serotype 5 (Ad5) vectors containing HIV-1 gene inserts are notable for their ability to induce strong HIV-1 specific cellular immune responses (1, 2) and have advanced to efficacy trials. One obstacle in the use of vectors based on human viruses is that naturally acquired immunity to these viruses has the potential to modulate ensuing insert-specific immune responses. The dampening effect of preexisting Ad5-specific humoral immunity, defined by type-specific neutralizing antibodies (nAbs), on the induction of HIV-specific cellular immune responses has previously been recognized (1, 2). This has led to the development of alternative human adenovirus vectors based on Ad35 and Ad26, which are under evaluation for HIV-1, tuberculosis, and malaria vaccines and may offer advantages over Ad5-based vectors because of their lower seroprevalence (3).

Concerns about reduced immunogenicity due to preexisting Ad5 immunity have focused largely on vector-specific antibodies, but little is known about Ad5-specific cellular immune responses after natural Ad5 exposure or vaccination using an Ad5 vector. The unexpected results from the Step study, showing an increased number of HIV infections in vaccinees and an early association of this risk with higher baseline Ad5 nAb titers, highlighted the need for improved understanding of vector-specific T cells, to assess their role in serving as susceptible targets for HIV infection and their interaction with their humoral counterparts (1). Identifying the epitope specificities of these responses is critical, particularly since multiple adenovirus serotypes are under evaluation as vaccine vectors, and the extent of T cell cross-reactivity between serotypes has not been defined at the epitope level. Previous studies suggested that any adenovirus could induce T cells that partially protect against many circulating serotypes (4 6) and that primarily target the hexon capsid protein (7 9). The recognition of MHC class I and II restricted Ad epitopes within other proteins has rarely been shown (9, 10), although most published studies are based on small cohorts and more comprehensive analyses of T cell memory responses among Ad5 proteins have not been reported.

To further our understanding of cellular immune responses against Ad5 and their impact on HIV-specific T cell responses, we conducted a comprehensive analysis in samples from more than 400 vaccine and placebo recipients enrolled in the Step study evaluating the MRKAd5/HIV-1 vaccine, as well as 35 recipients of the same vaccine from another trial (HVTN 071) conducted in parallel. We observed that a higher magnitude of baseline Ad-specific CD4 T cell responses was inversely associated with the magnitude of HIV-specific CD4 T cell responses and the breadth of HIV-specific CD8 T cell responses, independent of Ad5 nAb titers. Using polychromatic flow cytometry, we determined preferred T cell targets in participants with or without preexisting Ad5 nAbs and mapped the adenovirus responses to distinct epitopic regions. We found preferential T cell targeting of epitopes within regions conserved across many serotypes, including Ad26 and Ad35. Our results emphasize that preexisting serotype-specific nAb titers do not predict cellular immunity to adenoviruses and that Ad-specific T cell responses play a major role in determining the outcome of vaccination using Ad vectors. This is an important consideration in the choice of alternate Ad vectors to circumvent preexisting adenovirus immunity in regions with high Ad5 seroprevalence.

A clinical trial testing a candidate HIV vaccine known as the STEP study was halted in September 2007 after interim analysis indicated that the vaccine did not work. Moreover, subsequent analyses indicated that the vaccine made some individuals more susceptible to HIV, in particular individuals who had pre-existing immune effectors (antibodies) that recognized a component of the vaccine (adenovirus serotype 5 [Ad5]). A team of researchers led by Juliana McElrath, at the Fred Hutchinson Cancer Research Center, Seattle, has now determined that individuals from the STEP study in whom they could detect large numbers of immune cells (T cells) responsive to Ad5 generated a less robust immune response to HIV than those who had few Ad5-responsive T cells prior to vaccination. More worryingly, the Ad5-responsive T cells were found to also respond to other adenoviruses that are being considered as vaccine components in place of Ad5. This finding implies that vaccines based on adenoviruses other than Ad5 might not be effective in individuals with large numbers of Ad5-responsive T cells. As noted by McElrath and colleagues, this is something that will have to be carefully evaluated in any future clinical trial of any adenovirus-based vaccine, not just Ad5-based vaccines and not just adenovirus-based vaccines for HIV.

Full study ://www.jci.org/articles/view/60202

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HIV    AIDS    HIV vaccine    adenovirus    Juliana McElrath    Fred Hutchinson Cancer Research Center    Journal of Clinical Investigation   
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