RT Journal Article
SR Electronic
T1 Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 7179
OP 7185
DO 10.4049/jimmunol.174.11.7179
VO 174
IS 11
A1 Sumida, Shawn M.
A1 Truitt, Diana M.
A1 Lemckert, Angelique A. C.
A1 Vogels, Ronald
A1 Custers, Jerome H. H. V.
A1 Addo, Marylyn M.
A1 Lockman, Shahin
A1 Peter, Trevor
A1 Peyerl, Fred W.
A1 Kishko, Michael G.
A1 Jackson, Shawn S.
A1 Gorgone, Darci A.
A1 Lifton, Michelle A.
A1 Essex, Myron
A1 Walker, Bruce D.
A1 Goudsmit, Jaap
A1 Havenga, Menzo J. E.
A1 Barouch, Dan H.
YR 2005
UL http://www.jimmunol.org/content/174/11/7179.abstract
AB 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.