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

• Published in: The Journal of infectious diseases 2017-01, Vol.215 (1), p.95-104
• Main Authors: Nyombayire, Julien, Anzala, Omu, Gazzard, Brian, Karita, Etienne, Bergin, Philip, Hayes, Peter, Kopycinski, Jakub, Omosa-Manyonyi, Gloria, Jackson, Akil, Bizimana, Jean, Farah, Bashir, Sayeed, Eddy, Parks, Christopher L., Inoue, Makoto, Hironaka, Takashi, Hara, Hiroto, Shu, Tsugumine, Matano, Tetsuro, Dally, Len, Barin, Burc, Park, Harriet, Gilmour, Jill, Lombardo, Angela, Excler, Jean-Louis, Fast, Patricia, Laufer, Dagna S., Cox, Josephine H.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiw500

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.