Journal Article

First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

Hara, Hiroto, Nyombayire, Julien, Dally, Len, Anzala, Omu, Jackson, Akil, Laufer, Dagna S., Karita, Etienne, Sayeed, Eddy, Bizimana, Jean, Park, Harriet, Fast, Patricia, Parks, Christopher L., Omosa-Manyonyi, Gloria, Gazzard, Brian, Farah, Bashir, Shu, Tsugumine, Kopycinski, Jakub, Inoue, Makoto, Barin, Burc, Hayes, Peter, Matano, Tetsuro, Cox, Josephine H., Gilmour, Jill, Lombardo, Angela, Hironaka, Takashi, Bergin, Philip, Excler, Jean-Louis

2017

Overview

Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). Results. All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8⁺ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. Conclusions. SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated. Clinical Trials Registration. NCT01705990.

• Publisher: Oxford University Press
• Subject: Administration, Intranasal / Adult / AIDS Vaccines - administration & dosage / AIDS Vaccines - adverse effects / AIDS Vaccines - genetics / AIDS Vaccines - immunology / CD8-Positive T-Lymphocytes - immunology / Female / Genes, Viral - immunology / Genetic Vectors / HIV Antibodies - blood / HIV Antibodies - immunology / HIV Infections - immunology / HIV Infections - prevention & control / HIV-1 - genetics / HIV-1 - immunology / HIV/AIDS / Humans / Immunity, Cellular / Immunity, Humoral / Immunization, Secondary / Immunogenicity, Vaccine / Kenya / Major and Brief Reports / Male / Middle Aged / Rwanda / Sendai virus - genetics / Sendai virus - immunology / Sendai virus - physiology / United Kingdom / Vaccines, DNA - administration & dosage / Vaccines, DNA - adverse effects / Vaccines, DNA - immunology / Virus Replication