1. 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.
- Author
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Nyombayire J, Anzala O, Gazzard B, Karita E, Bergin P, Hayes P, Kopycinski J, Omosa-Manyonyi G, Jackson A, Bizimana J, Farah B, Sayeed E, Parks CL, Inoue M, Hironaka T, Hara H, Shu T, Matano T, Dally L, Barin B, Park H, Gilmour J, Lombardo A, Excler JL, Fast P, Laufer DS, and Cox JH
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines genetics, Administration, Intranasal, Adult, Female, Genes, Viral immunology, Genetic Vectors, HIV Antibodies blood, HIV Antibodies immunology, HIV Infections immunology, HIV-1 genetics, Humans, Immunity, Cellular, Immunity, Humoral, Immunization, Secondary, Immunogenicity, Vaccine, Kenya, Male, Middle Aged, Rwanda, Sendai virus immunology, Sendai virus physiology, United Kingdom, Vaccines, DNA administration & dosage, Virus Replication, AIDS Vaccines adverse effects, AIDS Vaccines immunology, CD8-Positive T-Lymphocytes immunology, HIV Infections prevention & control, HIV-1 immunology, Sendai virus genetics, Vaccines, DNA adverse effects, Vaccines, DNA immunology
- Abstract
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 (S
L A); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SH A); 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 (SH SH )., 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 (SL A and SH A) 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 SL A and SH A 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., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)- Published
- 2017
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