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

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.

Role of Different Subpopulations of CD8+ T Cells during HIV Exposure and Infection

“…In addition, the ability to maintain this response during the chronic phase is critical, as the depletion of CD8 + T cells in the SIV model showed a loss of viral control ( 69 ). Supporting the crucial role of CD8 + T cells in HIV, vaccine strategies in the SIV model promote the response of this population reducing viral replication once the challenge is established ( 70 ); in this respect, the use of some prospective vaccines tested in humans designed to trigger a strong response of this cell population showed promising results ( 71 – 73 ).…”

A Zigzag but Upward Way to Develop an HIV-1 Vaccine

“…To date, SeV-based HIV-1 vaccine has been launched in phase I trials. A clinical trial, priming intranasally with replication-competent SeV vector expressing HIV-1 Gag and then boosting with Ad35-vectored HIV-1 vaccines, elicited a robust and long-lasting HIV-specific T cell responses and antibody responses [ 81 ].…”

Novel viral vectors in infectious diseases

“…Ad26 was also used as a priming vector in Ebola clinical trials, where together with a Modified Vaccinia virus Ankara (MVA) boost, vaccination was able to elicit a strong and durable antibody response to the Ebola virus antigen . Ad35 has additionally been evaluated in several other HIV vaccine trials, where it was demonstrated to be safe and immunogenic. Furthermore, in a tuberculosis vaccine trial it was found to be safe in both infants and HIV +/− adults.…”