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Adenovirus Vector-Induced Immune Responses in Nonhuman Primates: Responses to Prime Boost Regimens¹

Nia Tatsis^2,*, Marcio O. Lasaro^2,*, Shih-Wen Lin^2,*,, Zhi Q. Xiang^*, Dongming Zhou^*, Lauren DiMenna^*, Hua Li^*, Ang Bian^*, Sarah Abdulla^*, Yan Li^*, Wynetta Giles-Davis^*, Jessica Engram, Sarah J. Ratcliffe, Guido Silvestri, Hildegund C. Ertl^3,* and Michael R. Betts^¶

^* The Wistar Institute, Philadelphia, PA 19104; University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Department of Pathology and Laboratory Medicine, Department of Biostatistics and Epidemiology, and ^¶ Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104

In the phase IIb STEP trial an HIV-1 vaccine based on adenovirus (Ad) vectors of the human serotype 5 (AdHu5) not only failed to induce protection but also increased susceptibility to HIV-1 infection in individuals with preexisting neutralizing Abs against AdHu5. The mechanisms underlying the increased HIV-1 acquisition rates have not yet been elucidated. Furthermore, it remains unclear if the lack of the vaccine’s efficacy reflects a failure of the concept of T cell-mediated protection against HIV-1 or a product failure of the vaccine. Here, we compared two vaccine regimens based on sequential use of AdHu5 vectors or two different chimpanzee-derived Ad vectors in rhesus macaques that were AdHu5 seropositive or seronegative at the onset of vaccination. Our results show that heterologous booster immunizations with the chimpanzee-derived Ad vectors induced higher T and B cell responses than did repeated immunizations with the AdHu5 vector, especially in AdHu5-preexposed macaques.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was sponsored by National Institutes of Health Grants P01AI052271 (to H.C.E.), U19AI074078 (to M.R.B.), and U19 AI074078 (to G.S.); by institutional grants to the Wistar Institute, including a U.S. National Cancer Institute Cancer Core Grant (CA10815); and by the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

² N.T., M.O.L., and S.-W.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Hildegund C. J. Ertl, The Wistar Institute, 3601 Spruce Streeet, Philadelphia, PA 19104. E-mail address: ertl{at}wistar.upenn.edu

⁴ Abbreviations used in this paper: Ad, adenovirus; AdC, Ad vector from chimpanzee serotype; AdHu5, adenovirus vector of the human serotype 5; ICS, intracellular cytokine staining; NA, neutralizing Ab; NHP, nonhuman primate; vps, virus particles.