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Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans.

ABSTRACT: 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.

SUBMITTER: O'Brien KL

PROVIDER: S-EPMC2756115 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans.

O'Brien Kara L KL Liu Jinyan J King Sharon L SL Sun Ying-Hua YH Schmitz Joern E JE Lifton Michelle A MA Hutnick Natalie A NA Betts Michael R MR Dubey Sheri A SA Goudsmit Jaap J Shiver John W JW Robertson Michael N MN Casimiro Danilo R DR Barouch Dan H DH

Nature medicine 20090720 8

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. Thes ...[more]

PMID: 19620961

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Project description:The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732). Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ?18; n?=?36) or Ad5-seropositive (titer >200; n?=?34). Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-?, IL-2, TNF-?, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes). At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p?=?0.008), and significantly more IP-10 (p?=?0.0009), IL-2 (p?=?0.006) and IL-10 (p?=?0.05) in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-?, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these results suggest that vector-specific humoral responses may reduce vaccine-induced T-cell responses by previously undetected mechanisms.

Dataset Information

Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans.

Publications

Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans.

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