Another abstract from the recent Keystone meeting (see below). The data suggests that, as some researchers had hypothesized, Ad5-specific memory CD4 T cells may be rendered particularly susceptible to HIV after Ad5 stimulation. Further research will be needed to try and ascertain if these observations are relevant to the evidence of enhanced susceptibility to HIV acquisition that emerged from the STEP trial. Notably, there was no indication that Ad5-specific immunity enhanced post-infection HIV viral load among STEP participants (people with pre-existing immunity to Ad5 actually had slightly lower viral load setpoints than Ad5 seronegative participants).
In light of the concerns about adenovirus vectors raised by the STEP data, it seems a little odd that a week after the NIAID HIV Vaccine Summit, GenVec announced receipt of a $600,000 NIAID grant to develop their Ad5-based malaria vaccine candidate and Crucell – another company that has invested heavily in the adenovirus vector vaccine platform – announced the initiation of a phase I trial of an Ad26-based HIV vaccine candidate. Ad26 is far less prevalent in nature than Ad5, so few people have antibody responses to the Ad26 hexon protein (the major target for antibody responses to adenoviruses). However, studies have clearly shown that Ad-specific memory CD4 T cell responses are highly cross-reactive against different serotypes, which may call into serious question the safety of any adenovirus-based vaccine candidate in individuals at risk for HIV infection (this may even hold true for vectors based on chimpanzee adenoviruses, see second abstract below). As the data stands currently, if GenVec successfully developed an Ad5-based malaria vaccine, it would be contraindicated in anyone at risk for HIV infection with pre-existing immunity to the vector; this would represent a substantial portion of the population that stands to benefit from immunization against malaria. And for the Crucell construct, it is also difficult to imagine a scenario where the vaccine could be ethically studied in individuals at risk for HIV infection, unless it can be proven that the risk of enhancement seen in STEP related entirely to immune responses specific to Ad5 and not immune responses cross-reactive with other adenovirus serotypes (or some other immune-modulating effect of adenoviruses generally). The comments of Crucell’s Jaap Goudsmit in the company’s press release seem not only premature, but bordering on delusional: “We are excited about the first in man study of this newly developed vector, that could provide a solution to the issues that raised from previous HIV vaccine trials.”
Keystone Symposia: HIV Vaccines: Progress and Prospects
Banff, Alberta, Canada, March 27-April 1, 2008
Abstract# 328
HIV-1 replication in CD4 T cells from Adenovirus experienced and Naïve Donors
A. Gregory Spies, Jason Stucky, John McNevin and Juliana McElrath.
Vaccine and Infectious Disease Research Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98105.
Preliminary analysis of the Merck STEP Study suggests that there is a higher rate of HIV infection in vacinees who had positive human adenovirus serotype-5 titers on enrollment compared to those with undetectable Ad5 titers. Therefore, we have utilized a human in vitro T cell priming assay to determine whether prior infection by Ad5 affects replication of HIV-1 in human CD4 T cells following exposure to a replication-defective Ad5 vector. Immature dendritic cells were generated using GM-CSF/IL-4 treatment of CD14 positive cells. Immature DC were exposed to an empty Ad5 vector resulting in increased levels of HLA-Class I, HLA-DR, CCR7, CD40, CD80 and CD83. CD4 T cells were primed with mock or Ad5-stimulated DCs and subsequently infected with the CCR5-tropic HIV-1 strain, YU2. HIV-1 replication was monitored by p24 ELISA of supernatants from DC-primed CD4 T cell cultures. Exposure of DC to Ad5 resulted in increased HIV growth in CD4 T cells from both Ad5-naive and Ad-experienced donors. At day 6, following addition of T cells, the Ad5-experienced CD4 T cells were found to produce twice the p24 as the Ad5-naive CD4 T cells. However FACS analysis of these cells using CD38, Ki67, Bcl-2, CCR5, CCR7 and CD-27 showed no phenotypic difference.
Abstract #223
T-cell responses in healthy adults to replication deficient AdHu5 vector
Natalie Hutnick, Hildegund Ertl, Michael R. Betts.
Microbiology Dept, University of Pennsylvania, Philadelphia PA, USA, 19104
A current strategy for an HIV vaccine employs the use of a replication deficient AdHu5 vector. However, it has been shown that pre-existing antibodies against AdHu5 reduce vaccine efficacy. To avoid the problems associated with pre-existing AdHu5 humoral immunity, vectors based on 2 serologically distinct chimpanzee adenoviruses (AdC6 and AdC7) have been developed.. While this strategy may avoid issues with pre-existing humoral immunity, it remains possible that cross-reactive Ad-specific CD8+ T cells could similarly limit vaccine efficacy. Here, we examined the response to replication defective AdHu5, AdC6 and AdC7 vectors in 10 healthy subjects from North America not expected to have been exposed previously to chimp-derived Ad strains. Eight of the ten subjects exhibited a polyfunctional CD8 T cell response to AdHu5 as measured by IL-2, TNF-a, IFN-g and perforin expression. The responding cells were a mixed population composed of CD27- CD45RO+ effector memory and CD27+CD45RO+ central memory phenotype. The 8 subjects who responded to AdHu5 also exhibited a cross reactive response to AdC6, and three responded to AdC7, though at a lower frequency. We further examined Ad-specific T cell responses in one subject who participated in a phase I AdHu5 HIV vaccine safety trial. A substantial expansion of polyfunctional AdHu5-specific CD8+ (1.06%) and CD4+ (0.57%) T cells were noted approximately 4 months after the final inoculation. These cells also exhibited cross-reactivity with both AdC6 and AdC7. These data indicate that Adenovirus-specific T cell responses are common in humans, and that shared elements between disparate Ad strains can be serve as targets for Ad-specific T cells. Vaccination with replication defective AdHu5 vectors also appears to enhance the frequency of Ad specific T-cells.
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