Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Abstract

The utility of recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 and other pathogens will likely be limited by the high prevalence of pre-existing Ad5-specific neutralizing Abs (NAbs) in human populations. However, the immunodominant targets of Ad5-specific NAbs in humans remain poorly characterized. In this study, we assess the titers and primary determinants of Ad5-specific NAbs in individuals from both the United States and the developing world. Importantly, median Ad5-specific NAb titers were >10-fold higher in sub-Saharan Africa compared with the United States. Moreover, hexon-specific NAb titers were 4- to 10-fold higher than fiber-specific NAb titers in these cohorts by virus neutralization assays using capsid chimeric viruses. We next performed adoptive transfer studies in mice to evaluate the functional capacity of hexon- and fiber-specific NAbs to suppress the immunogenicity of a prototype rAd5-Env vaccine. Hexon-specific NAbs were remarkably efficient at suppressing Env-specific immune responses elicited by the rAd5 vaccine. In contrast, fiber-specific NAbs exerted only minimal suppressive effects on rAd5 vaccine immunogenicity. These data demonstrate that functionally significant Ad5-specific NAbs are directed primarily against the Ad5 hexon protein in both humans and mice. These studies suggest a potential strategy for engineering novel Ad5 vectors to evade dominant Ad5-specific NAbs.

Efficient antitumor effects of carrier cells loaded with a fiber-substituted conditionally replicating adenovirus on CAR-negative tumor cells

“…More than 50% of adults have been reported to possess anti-Ad5 antibodies. 35 Sumida et al 36 demonstrated that neutralizing anti-Ad5 antibodies mainly recognize the hexon protein among Ad5 capsid proteins. The tumor cell lysis activity of both CRAd-F5 and CRAd-F35 was largely reduced by pre-incubation with anti-Ad5 serum, probably because of neutralizing anti-Ad5 antibodies recognizing hexon bound to the hexon of CRAd-F5 and CRAd-F35, leading to inhibition of infection with CRAd-F5 and CRAd-F35.…”

Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

“…However, this effect will be limited because the immune response is also directed toward the adenovirus hexon protein, which is part of the Ad capsid. 49 Therefore additional modifications such as replacing the hexon protein of Ad5 by that of a group B serotype seems to be needed to effectively reduce preexisting immunity against the chimeric vectors.…”

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

“…21,50 Ad35 vectors possess several advantages, including low seroprevalence in adults and the capacity to evade immunity for Ad5, although AdF35 vectors are inactivated by anti-Ad5-neutralizing antibodies. [51][52][53] This study indicates that fiber-mutant Ad35 vectors displaying foreign peptides in the fiber knob could be constructed. Hamilton et al 54 developed fiber-mutant Ad35 vectors containing an RGD peptide in the HI loop.…”