First-in-Human Evaluation of a Hexon Chimeric Adenovirus Vector Expressing HIV-1 Env (IPCAVD 002)

Background. We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. Methods. Forty-eight...

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Veröffentlicht in:The Journal of infectious diseases 2014-10, Vol.210 (7), p.1052-1061
Hauptverfasser: Baden, Lindsey R., Walsh, Stephen R., Seaman, Michael S., Johnson, Jennifer A., Tucker, Robert P., Kleinjan, Jane A., Gothing, Jon A., Engelson, Brian A., Carey, Brittany R., Oza, Avinash, Bajimaya, Shringkhala, Peter, Lauren, Bleckwehl, Chelsea, Abbink, Peter, Pau, Maria G., Weijtens, Mo, Kunchai, Meghan, Swann, Edith M., Wolff, Mark, Dolin, Raphael, Barouch, Dan H.
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Sprache:eng
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Zusammenfassung:Background. We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. Methods. Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10⁹ to 10¹¹ viral particles (vp) of the Ad5HVR48. EnvA. 01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. Results. Self-limited reactogenicity was observed after the initial immunization in the highest (10¹¹ vp) dose group. Responses in vaccinées included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10⁹, 10¹⁰, and 10¹¹ vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. Conclusions. Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.
ISSN:0022-1899
1537-6613
1537-6613
DOI:10.1093/infdis/jiu217