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1.  Impact of Herpes Simplex Virus Type 2 on HIV-1 acquisition and progression in an HIV vaccine trial (the Step Study) 
Introduction
Extensive observational data suggest that HSV-2 infection may facilitate HIV acquisition, increase HIV viral load, and accelerate HIV progression and onward transmission. To explore these relationships, we examined the impact of pre-existing HSV-2 infection in an international HIV vaccine trial.
Methods
We analyzed the associations between prevalent HSV-2 infection and HIV-1 acquisition and progression among 1836 men who have sex with men (MSM). We used Cox proportional hazards regression models to estimate the association between HSV-2 infection and both HIV acquisition and ART initiation, and linear regression to explore the effect of HSV-2 on pre-ART viral load.
Results
HSV-2 infection increased risk of HIV-1 acquisition among all volunteers (adjusted hazard ratio 2.2; 95% CI, 1.4 to 3.5). Adjusting for demographic variables, circumcision, Ad5 titer and significant risk behaviors, the risk of HIV acquisition among HSV-2 infected placebo recipients was three fold higher than HSV-2 seronegatives (hazard ratio 3.3; 95% CI, 1.6 to 6.9). Past HSV-2 infection was associated with a 0.2 log10 copies/ml higher adjusted mean set point viral load (95% CI, 0.3 lower to 0.6 higher). HSV-2 infection was not associated with time to ART initiation.
Conclusions
Among MSM in an HIV-1 vaccine trial, pre-existing HSV-2 infection was a major risk factor for HIV acquisition. Past HSV-2 did not significantly increase HIV viral load or early disease progression. HSV-2 seropositive persons will likely prove more difficult than HSV-2 seronegative persons to protect against HIV infection using vaccines or other prevention strategies.
doi:10.1097/QAI.0b013e31821acb5
PMCID: PMC3446850  PMID: 21860356
Herpes Simplex Virus Type II; HIV incidence
2.  Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults 
Abstract
The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 × 109 or 1 × 1010 viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-γ ELISPOT gag 15-mer assay with positive responses defined as ≥55 SFC/106 PBMCs and ≥4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/106 PBMCs in the placebo, 1 × 109 vp/dose, and 1 × 1010 vp/dose groups, respectively. Overall, responses to 1 × 1010 vp were 85% and 68% in subjects with low (≤200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 × 1010 vp/dose groups than in the 1 × 109 vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity.
doi:10.1089/aid.2010.0151
PMCID: PMC3422055  PMID: 20854108
4.  Safety and Immunogenicity of the Merck Adenovirus Serotype 5 (MRKAd5) and MRKAd6 Human Immunodeficiency Virus Type 1 Trigene Vaccines Alone and in Combination in Healthy Adults▿  
Preexisting immunity to adenovirus serotype 5 (Ad5) diminishes immune responses to vaccines using Ad5 as a vector. Alternate Ad serotypes as vaccine vectors might overcome Ad5-specific neutralizing antibodies and enhance immune responses in populations with a high prevalence of Ad5 immunity. To test this hypothesis, healthy human immunodeficiency virus (HIV)-seronegative adults were enrolled in a blinded, randomized, dose-escalating, placebo-controlled study. In part A, subjects with baseline Ad6 titers of ≤18 received the Merck Ad6 (MRKAd6) HIV type 1 (HIV-1) trigene vaccine at weeks 0, 4, and 26. In part B, subjects stratified by Ad5 titers (≤200 or >200) and Ad6 titers (≤18 or >18) received the MRKAd5-plus-MRKAd6 (MRKAd5+6) HIV-1 trigene vaccine at weeks 0, 4, and 26. Immunogenicity was assessed by an enzyme-linked immunospot (ELISPOT) assay at week 30. No serious adverse events occurred. MRKAd6 trigene vaccine recipients responded more often to Nef than to Gag or Pol. In part A, ELISPOT response rates to ≥2 vaccine antigens were 14%, 63%, and 71% at 109, 1010, and 1011 viral genomes (vg)/dose, respectively. All responders had positive Nef-specific ELISPOT results. In part B, Nef-ELISPOT response rates at 1010 vg/dose of the MRKAd5+6 trigene vaccine were 50% in the low-Ad5/low-Ad6 stratum (n = 8), 78% in the low-Ad5/high-Ad6 stratum (n = 9), 75% in the high-Ad5/low-Ad6 stratum (n = 8), and 44% in the high-Ad5/high-Ad6 stratum (n = 9). The MRKAd6 and MRKAd5+6 trigene vaccines elicited dose-dependent responses predominantly to Nef and were generally well tolerated, indicating that Ad6 should be considered a candidate vector for future vaccines. Although small sample sizes limit the conclusions that can be drawn from this exploratory study, combining two Ad vectors may be a useful vaccine strategy for circumventing isolated immunity to a single Ad serotype.
doi:10.1128/CVI.00144-09
PMCID: PMC2745015  PMID: 19605598
5.  Efficient and robust method for comparing the immunogenicity of candidate vaccines in randomized clinical trials 
Vaccine  2008;27(3):396-401.
In randomized clinical trials designed to compare the magnitude of vaccine-induced immune responses between vaccination regimens, the statistical method used for the analysis typically does not account for baseline participant characteristics. This article shows that incorporating baseline variables predictive of the immunogenicity study endpoint can provide large gains in precision and power for estimation and testing of the group mean difference (requiring fewer subjects for the same scientific output) compared to conventional methods, and recommends the “semiparametric efficient” method described in Tsiatis et al. [Tsiatis AA, Davidian M, Zhang M, Lu X. Covariate adjustment for two-sample treatment comparisons in randomized clinical trials: a principled yet flexible approach. Stat Med 2007. doi:10.1002/sim.3113] for practical use. As such, vaccine clinical trial programs can be improved (1) by investigating baseline predictors (e.g., readouts from laboratory assays) of vaccine-induced immune responses, and (2) by implementing the proposed semiparametric efficient method in trials where baseline predictors are available.
doi:10.1016/j.vaccine.2008.10.083
PMCID: PMC2653280  PMID: 19022314
Immune responses; Statistical analysis; Vaccine trial
6.  Safety and Immunogenicity of Adenovirus-Vectored Near-Consensus HIV Type 1 Clade B gag Vaccines in Healthy Adults 
Abstract
Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-γ ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers <200 versus ≥200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers <200 versus ≥200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers <200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.
doi:10.1089/aid.2008.0212
PMCID: PMC3256563  PMID: 19108693
7.  HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis 
Lancet  2008;372(9653):1894-1905.
Background
In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not lower post-infection plasma viremia, and HIV-1 incidence was higher in vaccine-treated than placebo-treated males with pre-existing adenovirus serotype 5 (Ad5) immunity. We evaluated vaccine-induced immunity and its potential contributions to infection risk.
Methods
To assess immunogenicity, HIV-specific T-cells were characterized ex vivo using validated IFN-γ ELISpot and intracellular cytokine staining (ICS) assays, employing a case-cohort design. To determine effects of vaccine and pre-existing Ad5 immunity on infection risk, flow cytometric studies measured Ad5-specific T-cells and circulating activated (Ki67+/Bcl- 2lo) CD4+ T-cells expressing CCR5.
Findings
IFN-γ-secreting HIV-specific T-cells (range, 163–686/106 PBMC) were detected ex vivo by ELISpot in 77% (258/354) of vaccinees; the majority recognized 2–3 HIV proteins. HIV- specific CD4+ T-cells were identified by ICS in 41%; ~85% expressed IL-2, and two-thirds of these co-expressed IFN-γ and/or TNF-α. HIV-specific CD8+ T-cells (range, 0.4–1.0%) were observed in 73%, expressing predominantly either IFN-γ alone or with TNF-α. No major differences were found in vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile comparing vaccinated male cases (pre-infection) with non-cases. Interestingly, Ad5-specific T-cells were lower in cases than non-cases in several subgroup analyses. The percent circulating Ki67+Bcl-2lo/CCR5+ CD4+ T-cells did not differ between cases and non-cases.
Interpretation
Consistent with previous trials, the MrkAd5/HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T-cells. Comparative analyses did not reveal differences in HIV-specific immunologic responses between cases and non-cases that explain the lack of vaccine efficacy and potential infection enhancement. If T-cell immunity is critical in vaccine-induced HIV protection, our findings suggest that future candidate vaccines must elicit responses that either exceed in magnitude or differ in breadth and/or function from those observed in this trial.
Funding
National Institute of Allergy and Infectious Diseases, U.S. National Institute of Health; Merck Research Laboratories
doi:10.1016/S0140-6736(08)61592-5
PMCID: PMC2774110  PMID: 19012957
8.  Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial 
Lancet  2008;372(9653):1881-1893.
Background
Observational data and non-human primate challenge studies suggest that cell-mediated immune (CMI) responses may provide control of HIV replication. The Step Study is the first direct assessment of the efficacy of a CMI vaccine to protect against HIV infection or alter early plasma HIV levels in humans.
Method
HIV-seronegative participants (3000) were randomized (1:1) to receive 3 injections of MRKAd5 HIV-1 gag/pol/nef vaccine or placebo. Randomization was pre-stratified by gender, baseline adenovirus type 5 (Ad5) titer, and study site. Participants were tested ~every 6 months for HIV acquisition; early plasma HIV RNA was measured ~3 months post-HIV diagnosis.
Findings
The vaccine elicited IFN-γ ELISPOT responses in 75% of vaccinees. In a pre-specified interim analysis among participants with baseline Ad5 ≤200, 24 of 741 vaccinees became HIV infected, versus 21 of 762 placebo recipients. All but one infection occurred in men. The early geometric mean plasma HIV RNA was comparable in infected vaccine and placebo recipients. In exploratory multivariate analyses, HIV incidence was higher in vaccinees versus placebo recipients among Ad5 seropositive men (5.1% versus 2.2% per year, respectively) and uncircumcised men (5.2% versus 1.4% per year, respectively). HIV incidence was similar in vaccinees versus placebo recipients among Ad5 seronegative men and circumcised men.
Interpretation
This CMI vaccine did not prevent HIV infection or lower early viral level. Mechanisms for failure of the vaccine to protect and for the increased HIV infection rates in subgroups of vaccinees are being explored. Additional follow-up will determine if elevated HIV incidence in vaccinee subgroups persists.
doi:10.1016/S0140-6736(08)61591-3
PMCID: PMC2721012  PMID: 19012954
HIV vaccine; efficacy; adenovirus; HIV acquisition; viral load; male circumcision; test of concept

Results 1-8 (8)