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

Julien Nyombayire, Omu Anzala, Brian Gazzard, Etienne Karita, Philip Bergin, Peter Hayes, Jakub Kopycinski, Gloria Omosa-Manyonyi, Akil Jackson, Jean Bizimana, Bashir Farah, Eddy Sayeed, Christopher L Parks, Makoto Inoue, Takashi Hironaka, Hiroto Hara, Tsugumine Shu, Tetsuro Matano, Len Dally, Burc Barin, Harriet Park, Jill Gilmour, Angela Lombardo, Jean-Louis Excler, Patricia Fast, Dagna S Laufer, Josephine H Cox, S001 Study Team, Rosine Ingabire, Gina Ouattara, Alan Steele, Anne Gumbe, Kundai Chinyenze, Sabrina Welsh, Carl Verlinde, Deborah King, Cynthia Bishop, Paramesh Chetty, Lorna Clark, Mumtaz Booley, Devika Zachariah, Kristen Syvertsen, Kamaal Anas, Marloes Naarding, Emmanuel Cormier, Jim Ackland, Mamoru Hasegawa, Julien Nyombayire, Omu Anzala, Brian Gazzard, Etienne Karita, Philip Bergin, Peter Hayes, Jakub Kopycinski, Gloria Omosa-Manyonyi, Akil Jackson, Jean Bizimana, Bashir Farah, Eddy Sayeed, Christopher L Parks, Makoto Inoue, Takashi Hironaka, Hiroto Hara, Tsugumine Shu, Tetsuro Matano, Len Dally, Burc Barin, Harriet Park, Jill Gilmour, Angela Lombardo, Jean-Louis Excler, Patricia Fast, Dagna S Laufer, Josephine H Cox, S001 Study Team, Rosine Ingabire, Gina Ouattara, Alan Steele, Anne Gumbe, Kundai Chinyenze, Sabrina Welsh, Carl Verlinde, Deborah King, Cynthia Bishop, Paramesh Chetty, Lorna Clark, Mumtaz Booley, Devika Zachariah, Kristen Syvertsen, Kamaal Anas, Marloes Naarding, Emmanuel Cormier, Jim Ackland, Mamoru Hasegawa

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 (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.

Keywords: HIV-1 vaccine; Sendai virus vector; adenovirus 35; immunogenicity; intranasal delivery; mucosal responses; prime-boost; replication competent.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Administration of a Sendai virus (SeV)–vectored vaccine encoding human immunodeficiency virus 1 (HIV-1) Gag (SeV-Gag) primes Gag-specific T-cell responses detected by interferon γ enzyme-linked immunospot analysis. The y-axis shows spot-forming units (SFU)/106 peripheral blood mononuclear cells (PBMCs) on a log scale. All responses reflect subtraction of background spots. Black circles denote response below the cutoff, defined in the Materials and Methods, to the Gag peptide pool; red circles denote response above the cutoff to the Gag peptide pool. The overlaid box plots summarize the responses (ie, median value, the 1st and 3rd quartiles, and the 5th and 95th percentiles). Red bars represent median values. The placebo responses are combined for all groups. The prime-boost regimens as follows: 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). Arrows show the timing of vaccinations in each group. In the x-axis, weeks represent the time after the most recent vaccination, to facilitate cross-regimen comparisons.
Figure 2.
Figure 2.
Characterization of human immunodeficiency virus (HIV-1) Gag–specific CD4+ and CD8+ T-cell responses. Gag-specific CD4+ and CD8+ T-cell responses as assessed by intracellular cytokine staining (ICS; A and B). Time points displayed are 2 weeks after the indicated vaccination. T-cell responses were evaluated by 7-color ICS to assess the expression of interleukin 2 (IL-2), interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) with peptides matched to the Gag peptide pool. The percentage of T cells expressing at least 1 cytokine (IL-2, IFN-γ, or TNF-α) is shown. Boxes represent interquartile ranges (IQRs), and whiskers extend to the 5th and 95th percentiles. Red bars represent median values. The placebo responses are combined for all groups. For the polyfunctional responses (bottom panels C and D), each dot represents a single volunteer. The prime-boost regimens as follows: 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; red dots); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA; green dots); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH; orange dots); and priming and boosting with a higher-dose SeV-Gag given intranasally. Ad35-GRIN prime alone is represented by blue dots, and placebo is represented by purple dots.
Figure 3.
Figure 3.
Sendai virus (SeV)–vectored vaccine encoding human immunodeficiency virus 1 (HIV-1) Gag (SeV-Gag) enhances the breadth of inhibition of a panel of diverse HIV-1 isolates. The breadth of inhibition among 8 viruses was assessed at baseline (bl) and specified time points 2 weeks after the indicated vaccination (vac). Lines represent median values, whiskers represent the 1st and 3rd quartiles, and gray dots represent individual responses. The placebo (Pbo) responses are combined for all groups. The prime-boost regimens as follows: 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).
Figure 4.
Figure 4.
Human immunodeficiency virus type 1 (HIV-1) Gag p24 immunoglobulin G (IgG) geometric mean titers (GMTs) after the following prime-boost combinations: 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). Titers below the level of detection (ie, <100) were given a value of 50. Arrows indicate vaccination time points for each group. Placebo responses are combined for all groups. Abbreviation: CI, confidence interval.

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