HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, ...later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four
single-nucleotide polymorphism SNP sites) (hazard ratio HR = 9.79,
= 0.035) but not among participants without the haplotype (HR = 0.86,
= 0.67); the interaction of vaccine and haplotype effect was significant (
= 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3
SNPs) (HR = 2.78,
= 0.058) but not among participants without the haplotype (HR = 0.73,
= 0.44); again, the interaction of vaccine and haplotype was significant (
= 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8
T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an
SNP and two
SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.
By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.
A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an ...emulsion in incomplete Freund's adjuvant (IFA).
Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1, and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, (51)Cr release assays were performed on fresh PBMCs following 14-day stimulation with individual vaccine peptide antigens.
24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses. Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higher antibody responses than those with mild or no reactions.
The severity of local responses related to the formulation of these four peptides in IFA is clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events.
ClinicalTrials.gov NCT00000886.
Abstract Plasmid DNA vaccines have been licensed for use in domesticated animals because of their excellent immunogenicity, but none have yet been licensed for use in humans. Here we report a ...retrospective analysis of 1218 healthy human volunteers enrolled in 10 phase I clinical trials in which DNA plasmids encoding HIV antigens were administered. Elicited T-cell immune responses were quantified by validated intracellular cytokine staining (ICS) stimulated with HIV peptide pools. HIV-specific binding and neutralizing antibody activities were also analyzed using validated assays. Results showed that, in the absence of adjuvants and boosting with alternative vaccines, DNA vaccines elicited CD8+ and CD4+ T-cell responses in an average of 13.3% (95% CI: 9.8–17.8%) and 37.7% (95% CI: 31.9–43.8%) of vaccine recipients, respectively. Three vaccinations (vs. 2) improved the proportion of subjects with antigen-specific CD8+ responses ( p = 0.02), as did increased DNA dosage ( p = 0.007). Furthermore, female gender and participants having a lower body mass index were independently associated with higher CD4+ T-cell response rate ( p = 0.001 and p = 0.008, respectively). These vaccines elicited minimal neutralizing and binding antibody responses. These findings of the immunogenicity of HIV DNA vaccines in humans can provide guidance for future clinical trials.
A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in ...peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cell-focused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus.
Live attenuated herpes zoster vaccine administered to HIV-infected adults suppressed on antiretroviral therapy with CD4+ counts ≥200 cells/µL was generally safe and immunogenic. Antibody responses ...were similar to those observed in older adults without HIV infection who received the same vaccine.
Abstract
Background
Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)-infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited.
Methods
We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4+ count (200-349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus VZV-specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination.
Results
Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% 95% confidence interval {CI}, 2.9%-8.2% vs 2.1% 95% CI, .3%-7.3%; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%-47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%-20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 Q1, Q3, 5.64, 6.96) vs placebo (5.48 Q1, Q3, 4.63, 6.44; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction-confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related.
Conclusions
Two doses of ZV in HIV-infected adults suppressed on ART with CD4+ counts ≥200 cells/µL were safe and immunogenic.
Clinical Trials Registration
NCT00851786.
Vaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been ...evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines.
Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. 'Routine cardiac investigations' (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and 'Symptom-driven cardiac investigations' are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine.
Four hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine.
Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.
ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337.
Efficacious HIV-1 vaccination requires elicitation of long-lived antibody responses. However, our understanding of how different vaccine types elicit durable antibody responses is lacking. To assess ...the impact of vaccine type on antibody responses, we measured IgG isotypes against four consensus HIV antigens from 2 weeks to 10 years post HIV-1 vaccination and used mixed effects models to estimate half-life of responses in four human clinical trials. Compared to protein-boosted regimens, half-lives of gp120-specific antibodies were longer but peak magnitudes were lower in Modified Vaccinia Ankara (MVA)-boosted regimens. Furthermore, gp120-specific B cell transcriptomics from MVA-boosted and protein-boosted vaccines revealed a distinct signature at a peak (2 weeks after last vaccination) including CD19, CD40, and FCRL2-5 activation along with increased B cell receptor signaling. Additional analysis revealed contributions of RIG-I-like receptor pathway and genes such as SMAD5 and IL-32 to antibody durability. Thus, this study provides novel insights into vaccine induced antibody durability and B-cell receptor signaling.
In an efficacy trial, 2504 persons at high risk for HIV-1 acquisition received either a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine or placebo. The vaccine regimen did not reduce ...either HIV-1 acquisition or viral load.
The epidemic infection caused by the human immunodeficiency virus type 1 (HIV-1) is now in its fourth decade, with an estimated 2.5 million new infections occurring annually worldwide.
1
The number of newly infected persons, although diminishing, outpaces the number of patients who initiate antiretroviral therapy. Despite a number of successful prevention interventions that have been reported, including preexposure prophylaxis and treatment as prevention,
2
–
9
ultimate control of the HIV epidemic will most likely come only with the development of a safe and effective preventive vaccine.
This goal has proved to be elusive. Of the efficacy trials of HIV vaccines that . . .
Abstract
AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further ...assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation.
In a large cohort of human immunodeficiency virus (HIV) controllers (AIDS Clinical Trials A5308), HIV-specific T-cell responses were higher in nonviremic than in viremic controllers. Despite decreasing T-cell responses on antiretroviral therapy, controller status was preserved after therapy was stopped.
Background. Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope giycoprotein (Env) were tested in a phase 2a ...trial in human immunodeficiency virus (HIV)-uninfected adults for safety, immunogenicity, and 6-month durability of immune responses. Methods. A total of 299 individuals received 2 doses of JS7 DNA vaccine and 2 doses of MVA/HIV62B at 0, 2, 4, and 6 months, respectively (the DDMM regimen); 3 doses of MVA/HIV62B at 0, 2, and 6 months (the regimen); or placebo injections. Results. At peak response, 93.2% of the DDMM group and 98.4% of the group had binding antibodies for Env. These binding antibodies were more frequent and of higher magnitude for the transmembrane subunit (gp41) than the receptor-binding subunit (gpl20) of Env. For both regimens, response rates were higher for CD4⁺ T cells (66.4% in the DDMM group and 43.1% in the group) than for CD8⁺ T cells (21.8% in the DDMM group and 14.9% in the group). Responding CD4⁺ and CD8⁺ T cells were biased toward Gag, and > 70% produced 2 or 3 of the 4 cytokines evaluated (ie, interferon γ, interleukin 2, tumor necrosis factor α, and granzyme B). Six months after vaccination, the magnitudes of antibodies and T-cell responses had decreased by <3-fold. Conclusions. DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
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