A new paper from scientists at the Vaccine Research Center reports that their Ad5 vaccine may induce less vector-specific immunity than other similar constructs. The original prototype of the Merck Ad5 vaccine had deletions in the E1 and E3 adenovirus genes, but this prototype turned out to be genetically unstable and the E3 gene was restored to the final vector that was used in the STEP trial. A part of the Merck vector called the 5’ packaging region was also modified “to make it more like wild-type adenovirus.”
In contrast, the VRC Ad5 vector has the E1, E3 and E4 genes deleted. In the paper, the researchers compare adenoviral protein synthesis after in vitro infection with a vector containing deletions in E1/E3 versus deletions in E1, E3 and E4. The results show that synthesis of the early adenoviral protein ssDNA binding protein (DBP) and the capsid proteins (hexon, penton base and fiber) is significantly lower with the triple-deleted vector; the capsid proteins in particular appear barely detectable.
An additional analysis of CD4 and CD8 T cell responses to vector proteins in 31 human recipients of the VRC vaccine is consistent with the protein synthesis data. At four weeks after immunization, statistically significant increases in CD4 and CD8 T cell responses to the HIV Env antigen encoded by the vector were detectable At the same time point, only CD8 T cell responses to the Ad5 hexon protein showed a significant increase in magnitude. CD4 T cell responses to the hexon protein increased slightly overall, but the change did not reach statistical significance. There were no significant changes in either CD4 or CD8 T cell responses to the adenovirus E2A protein. Echoing several other recent studies, no correlation was found between baseline adenovirus-specific CD4 T cell responses and anti-Ad5 neutralizing antibody titers.
In sum, if the enhancement of susceptibility to HIV infection documented in a subset of STEP participants was somehow related to Ad5 protein expression by the Merck vector, these data might suggest that the VRC Ad5 vaccine would not be similarly affected. However, unless some clear correlate of the enhanced susceptibility in STEP emerges – which at this point seems unlikely – then it is hard to imagine a scenario in which the FDA would approve another test of an Ad5 vaccine among the population that was most at risk for enhancement in STEP (uncircumcised men, particularly those with pre-existing neutralizing antibodies to Ad5).
J. Virol. doi:10.1128/JVI.00384-09
Richard A. Koup, Laurie Lamoreaux, David Zarkowsky, Robert T. Bailer, C. Richter King, Jason G. D. Gall, Douglas E. Brough, Barney S. Graham, and Mario Roederer
Immunology Laboratory, Immunology Core Section, Clinical Trials Core, and ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; GenVec Inc. Gaithersburg, MD, USA
The magnitude and character of adenovirus type 5 (Ad5) -specific T cells was determined in volunteers with and without pre-existing neutralizing antibodies (NA) to Ad5 who received rAd5-based HIV vaccines. There was no correlation between T cell responses and NA to Ad5. There was no increase in magnitude or activation state of Ad5-specific CD4+ T cells at time points where antibodies to Ad5 and T cell responses to the recombinant gene products could be measured. These data indicate that rAd5-based vaccines containing deletions in the E1, E3 and E4 region do not induce appreciable expansion of vector-specific CD4+ T cells.
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