A Phase I Double Blind, Placebo-Controlled, Randomized Study of a Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults

<div><h3>Background</h3><p>We conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.</p> <h3>Methods</h3><p>Ad35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×10⁹ (A), 2×10¹⁰ (B), 2×10¹¹ (C), or Ad35-GRIN 1×10¹⁰ (D) viral particles.</p> <h3>Results</h3><p>No vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A–D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 10⁶ PBMC to any antigen was 78–139 across Groups A–C and 158–174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A–C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.</p> <h3>Conclusion/Significance</h3><p>Ad35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT00851383">NCT00851383</a></p> </div

Safety and Immunogenicity of DNA and MVA HIV-1 Subtype C Vaccine Prime-Boost Regimens: A Phase I Randomised Trial in HIV-Uninfected Indian Volunteers

STUDY DESIGN: A randomized, double-blind, placebo controlled phase I trial. METHODS: The trial was conducted in 32 HIV-uninfected healthy volunteers to assess the safety and immunogenicity of prime-boost vaccination regimens with either 2 doses of ADVAX, a DNA vaccine containing Chinese HIV-1 subtype C env gp160, gag, pol and nef/tat genes, as a prime and 2 doses of TBC-M4, a recombinant MVA encoding Indian HIV-1 subtype C env gp160, gag, RT, rev, tat, and nef genes, as a boost in Group A or 3 doses of TBC-M4 alone in Group B participants. Out of 16 participants in each group, 12 received vaccine candidates and 4 received placebos. RESULTS: Both vaccine regimens were found to be generally safe and well tolerated. The breadth of anti-HIV binding antibodies and the titres of anti-HIV neutralizing antibodies were significantly higher (p<0.05) in Group B volunteers at 14 days post last vaccination. Neutralizing antibodies were detected mainly against Tier-1 subtype B and C viruses. HIV-specific IFN-γ ELISPOT responses were directed mostly to Env and Gag proteins. Although the IFN-γ ELISPOT responses were infrequent after ADVAX vaccinations, the response rate was significantly higher in group A after 1(st) and 2(nd) MVA doses as compared to the responses in group B volunteers. However, the priming effect was short lasting leading to no difference in the frequency, breadth and magnitude of IFN-γELISPOT responses between the groups at 3, 6 and 9 months post-last vaccination. CONCLUSIONS: Although DNA priming resulted in enhancement of immune responses after 1(st) MVA boosting, the overall DNA prime MVA boost was not found to be immunologically superior to homologous MVA boosting. TRIAL REGISTRATION: Clinical Trial Registry CTRI/2009/091/00005

Prevalence of peripheral artery disease and risk factors in the elderly: A community based cross-sectional study from northern Kerala, India

Background and objective: There are no data on the prevalence of peripheral artery disease (PAD) and risk factors in Indians. This study was aimed at studying the prevalence of PAD and risk factors in elderly population of northern parts of Kerala, South India. Methods: In a prospective observational survey we evaluated men and women of age between 60 and 79 years from Kerala. Anthropometric measurements, biochemical investigations and electrocardiogram were done. The diagnosis of PAD was made by ABI < 0.9. Assessment of coronary artery disease CAD was performed using historical, angina questionnaire and electrocardiographic criteria. Results: Of the total sample of 1330, we could evaluate 1148 respondents (86.3%). Overall mean (SD) ABI was 0.97 (0.19). Age-adjusted prevalence of PAD was 26.7% (95% CI (24.3, 29.4)) with no difference between urban and rural population. Prevalence of symptomatic PAD was low. Diabetes, hypertension, high cholesterol, low high-density lipoprotein cholesterol, sedentary life style and smoking was observed in 25.5%, 62.9%, 61.6%, 35.9% 38.1% and 30.7%, respectively. On multivariate analysis age, smoking and physical inactivity were strong predictors of PAD. There was independent association of PAD with definite CAD. Conclusions: There was high prevalence of PAD in Kerala, driven by high prevalence of risk factors. The prevalence was equal in rural and urban population. Intermittent claudication was uncommon. Age, female gender, smoking, physical inactivity, diabetes were independent predictors for presence of PAD. Keywords: Prevalence, Peripheral artery disease, Risk factor

Frequency of grade 1, 2 and 3 unsolicited adverse events recorded within 28 days post-vaccinations.

<p>Bars represent the maximum severity per volunteers within 28 days after either 2 vaccinations in Group A (separately for ADVAX and TBC-M4) or 3 vaccinations in Group B. Relative frequency of adverse events is plotted on the Y axis and Groups A, B vaccine or placebo recipients are plotted on the X-axis.</p

HIV binding ELISA antibody response rates.

<p>HIV binding ELISA antibody response rates.</p

Frequency of IFN- γ ELISPOT T-cell response.

<p>na: Not Applicable, nd: not done.</p

Spectrum of HIV-specific antibodies as determined by Western blot among Groups A and B vaccine recipients.

<p>Antigens recognized by HIV-specific antibodies as determined by HIV Western blot assay by group and visit after the last vaccination. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055831#pone-0055831-g002" target="_blank">Figure 2a</a> shows the frequency of volunteers recognizing each HIV antigen (Env: gp160, gp120 and gp41, Pol: p65, Gag: p55, p24 and p40) by the presence of bands in Western blot. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055831#pone-0055831-g002" target="_blank">Figure 2b</a> shows the distribution of the spectrum of HIV-specific antibodies (number of HIV antigens identified) by Western blot. median, inter-quartile and minimum-maximum ranges are presented in the Box-Whiskers plots.</p

HIV neutralizing antibody titres (expressed as ID₅₀ values) of Group A and Group B volunteers after last vaccination.

<p>ID₅₀ values were determined by TZM-bl assay from serum samples of Group A (red in colour) and Group B (blue in colour) volunteers at 14 days (indicated as circles) and 3 months (indicated as squares) after last vaccination against a panel of pseudoviruses (X-axis). The pseudoviruses shown in the graph are MW965.26 (Tier-1 subtype C), SF162.LS (Tier-1 subtype B), IVC 5–41 (recently transmitted Indian strain) and TV1.21 (Tier-2 subtype C). No neutralization response was seen against HIV 001428-2.42 (Tier-2 subtype C) (not shown). The neutralizing antibody titres from Group B volunteers were found to be higher than in Group A volunteers at 14 days and 3 months following last vaccination. P-values were calculated by the Mann Whitney test. The vertical bars represent median and inter-quartile range.</p