Development of HIV-1 vaccines based on replication competent Tiantan vaccinia vector in China

Abstract

BackgroundA vaccine is the best solution to stop the AIDS pandemic, but how to develop a vaccine is an unprecedented challenge to the global scientific community. The HIV vaccine programme of the China Center for Disease Control and Prevention (CDC) is being developed through careful selection of the representative circulating HIV-1 strain CRF07 in China, through a nationwide molecular epidemiology survey involving all provinces. The replication competent Tiantan vaccinia (VTT, smallpox vaccine in China) was used as an AIDS vaccine vector. A DNA/rTV HIV-1 vaccine containing gag, pol, and env genes has been developed. In preclinical tests in monkeys, this vaccine gives high protection (more than 80%) against homologous SHIV (SHIV97001) challenge and partial protection (50%) against heterologous SHIV (SHIV SF162 P3) challenge when boosted with HIV-1 envelop protein. The aim of this study was to test the safety and immunological effect of the HIV-1 vaccine in healthy human volunteers. MethodsA double-blind, placebo-controlled phase 1 trial was done at the Peking Union Medical College Hospital, Beijing, China. We enrolled HIV-1 uninfected healthy adults with or without history of smallpox vaccination. The subjects were randomly assigned to receive DNA alone (DNA 4 mg, DNA-H/rTV (DNA 4 mg), DNA-L/rTV (DNA 2 mg), or placebo. Randomisation was done by the Division of Health Statistics, China CDC, using SAS version 9.1.2. Participants, site staff, laboratory personnel responsible for endpoint assays, and investigators were blinded as to treatment assignments during the trial. Participants were primed with DNA vaccine (4 mg, intramuscular) three times at 1 month intervals and boosted once with rTV (5×104 plaque-forming units, skin scratches). The participants were monitored for safety and immunological outcomes. Vaccine-induced immunogenicity were measured by the enzyme-linked immunospot assay, intracellular cytokine staining, and antibody assays. All available data were used, according to randomization assignment. The analyses for the primary objectives of safety and tolerability were descriptive. For the secondary analyses of immunogenicity, we used assay-specific predefined positivity criteria to categorise each individual as a responder or a non-responder at each time point. Between-group comparisons were based on Fisher's Exact Test for binary data and Wilcoxon rank sum tests for the magnitude of the response. The protocol was approved by the ethics committees of PUMCH and National Center for AIDS/STD Control and Prevention, China CDC. All participants provided written informed consent. This trial was registered at chictr.org, number ChiCTR-PRC-10001287. Findings36 HIV-1 uninfected healthy adults with or without history of smallpox vaccination were enrolled; ten participants were women, and the mean age of the participants was 28·28 years (6·46). Among the participants, 23 were vaccinia-naive, and 13 were vaccinia-vaccinated. Six participants received DNA alone, 12 participants received DNA-H/rTV, 12 participants received DNA-L/rTV, and six participants received placebo. 34 (94%) participants completed all study visits. Results of the completed phase 1 trial showed that DNA/rTV vaccines were well tolerated in participants. We detected HIV-1-specific binding antibody against gp140 protein and V1V2 in all volunteers. T-cell responses induced by the vaccines were found in two-thirds of participants and were multi-functional (IL2/IFN-g/TNF-α). Typical skin reaction in all rTV vaccinated 22 participants, enlargement of the lymph nodes under the same arm receiving rTV (13 cases), and slight fever (37·6°C for 1 day, 1 case) were observed. No severe adverse events related to the vaccines were found. InterpretationThe DNA/rTV vaccines are safe and stimulate an immunogenic response. In order to protect primate against heterologous SHIV challenges, HIV envelop proteins needed as a boosting immunogen. Study is required to further test the safety and immunogenicity of DNA/rTV vaccine in high-risk groups to HIV infection. It is worthwhile to compare the non-replicating pox vector of the Pox Protein public Private Partnership (p5 project) with the replicating Tiantan vector. The China CDC and US National Institutes of Health (NIH) have planned a joint phase 2b vaccine trial of the DNA/rTV of China CDC and gp145 of US NIH. FundingNational Science and Technology Major Projects for Infectious Diseases Control and Prevention (2008ZX10104 and 2012ZX10001008).