Phase I safety and immunogenicity evaluations of an alphavirus replicon HIV-1 subtype C gag vaccine in healthy HIV-1-uninfected adults

Abstract

On the basis of positive preclinical data, we evaluated the safety and immunogenicity of an alphavirus replicon HIV-1 subtype C gag vaccine (AVX101), expressing a nonmyristoylated form of Gag, in two double-blind, randomized, placebo-controlled clinical trials in healthy HIV-1-uninfected adults. Escalating doses of AVX101 or placebo were administered subcutaneously to participants in the United States and Southern Africa. Because of vaccine stability issues, the first trial was halted prior to completion of all dose levels and a second trial was implemented. The second trial was also stopped prematurely due to documentation issues with the contract manufacturer. Safety and immunogenicity were evaluated through assessments of reactogenicity, reports of adverse events, and assessment of replication-competent and Venezuelan equine encephalitis (VEE) viremia. Immunogenicity was measured using the following assays: enzyme-linked immunosorbent assay (ELISA), chromium 51 ((51)Cr)-release cytotoxic T lymphocyte (CTL), gamma interferon (IFN-γ) ELISpot, intracellular cytokine staining (ICS), and lymphoproliferation assay (LPA). Anti-vector antibodies were also measured. AVX101 was well tolerated and exhibited only modest local reactogenicity. There were 5 serious adverse events reported during the trials; none were considered related to the study vaccine. In contrast to the preclinical data, immune responses in humans were limited. Only low levels of binding antibodies and T-cell responses were seen at the highest doses. This trial also highlighted the difficulties in developing a novel vector for HIV.

Trial registration: ClinicalTrials.gov NCT00063778 NCT00097838.

Fig 1

Virus-like replicon particle vaccine and packaging system.

Fig 2

Maximum local (A) and systemic (B) reactogenicity following each dose (1, 2, or 3) at each dose level.

Fig 3

ELISA responses 2 weeks after 3rd vaccination (day 98). A solid dot represents a positive response, and an open dot is for a negative response. Numbers at the top show the number of responders/number of assay results and the percentage with a positive result. For each box plot, 25% of the data points lie below the box and 25% lie above the box, and the horizontal line inside the box is the median. The vertical lines (whiskers) above and below the box extend to the most extreme data point, which is no more than 1.5 times the height of the box.

Fig 4

⁵¹Cr release. The left panel shows CD4 responses 2 weeks after 3rd vaccination (day 98), presented as the percentage of specific lysis after CD8 depletion. The right panel shows the CD8 responses at the same time point, presented as the percentage of specific lysis after CD4 depletion. A solid dot represents a positive response, and an open dot represents a negative response. Numbers at the top show the number of responders/number of assay results. For each box plot, 25% of the data points lie below the box and 25% lie above the box, and the and the horizontal line inside the box is the median. The vertical lines (whiskers) above and below the box extend to the most extreme data point, which is no more than 1.5 times the height of the box.

Fig 5

ELISpot 2 weeks after 3rd vaccination (day 98). Data were obtained only for U.S. participants in study HVTN 059. A solid dot represents a positive response, and an open dot represents a negative response. Numbers at the top show the number of responders/number of assay results and the percentage with a positive result. For each box plot, 25% of the data points lie below the box and 25% lie above the box, and the horizontal line inside the box is the median. The vertical lines (whiskers) above and below the box extend to the most extreme data point, which is no more than 1.5 times the height of the box.

Fig 6

ICS 2 weeks after 3rd vaccination (day 98). Data were obtained only for U.S. participants in study HVTN 059. A solid dot represents a positive response, and an open dot represents a negative response. Numbers at the top show the number of responders/number of assay results and the percentage with a positive result. For each box plot, 25% of the data points lie below the box and 25% lie above the box, and the horizontal line inside the box is the median. The vertical lines (whiskers) above and below the box extend to the most extreme data point, which is no more than 1.5 times the height of the box.