[Show abstract][Hide abstract] ABSTRACT: Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow-up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.
We included participant-level data from all three efficacy trials, and three Phase 1-2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.
Results are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99-1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11-1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61-1.26, P = 0.48). Results were similar when including the Phase 1-2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58-1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61-1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89-1.14, P = 0.18).
The data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations.
PLoS ONE 09/2015; 10(9):e0136626. DOI:10.1371/journal.pone.0136626 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: To define features of the B cell response to HIV that may be translated to vaccine development, we have isolated a panel of monoclonal antibodies (MAbs) from HIV-infected patients. These MAbs are all highly reactive to HIV envelope (Env) from multiple clades, and include gp120 and gp41 specificities. Three of the MAbs exhibit substantial homology to previously described VH1-69, VH3-30, and VH4-59 HIV broadly neutralizing antibody lineages. An inherently autoreactive VH4-34 encoded MAb was reactive to diverse Env despite its minimal mutation from germline. Its isolation is consistent with our previous observation of increased VH4-34+antibodies in HIV-infected patients. These results suggest that conserved developmental processes contribute to immunoglobulin repertoire usage and maturation in response to HIV Env and that intrinsically autoreactive VH genes, despite the absence of mutation, could serve as effective templates for maturation and development of protective antibodies. These results also bear significant implications for the development of immunogens.
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 04/2015; 34(2):65-72. DOI:10.1089/mab.2014.0064
[Show abstract][Hide abstract] ABSTRACT: In light of the increasing rates of HIV infection in African Americans, it is essential that black faith leaders become more proactive in the fight against the epidemic. The study aim was to engage faith leaders in a sustainable partnership to increase community participation in preventive HIV vaccine clinical research while improving their access to and utilization of HIV/AIDS prevention services.
Leadership Development Seminars were adapted for faith leaders in Rochester, NY, with topics ranging from the importance of preventive HIV vaccine research to social issues surrounding HIV/AIDs within a theological framework. Seminars were taught by field-specific experts from the black community and included the development of action plans to institute HIV preventive ministries. To assess the outcome of the Seminars, baseline and post-training surveys were administered and analyzed through paired sample t Tests and informal interviews.
19 faith leaders completed the intervention. In general, the majority of clergy felt that their understanding of HIV vaccine research and its goals had increased postintervention. A critical outcome was the subsequent formation of the Rochester Faith Collaborative by participating clergy seeking to sustain the collaborative and address the implementation of community action plans.
Providing scientific HIV/AIDS knowledge within the context of clergy members' belief structure was an effective method for engaging black Church leaders in Rochester, NY. Collaborative efforts with various local institutions and community-based organizations were essential in building trust with the faith leaders, thereby building bridges for better understanding of HIV/AIDS prevention efforts, including HIV vaccine research.
Progress in Community Health Partnerships Research Education and Action 12/2014; 8(3):305-16. DOI:10.1353/cpr.2014.0050
[Show abstract][Hide abstract] ABSTRACT: Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 mu g), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 mu g). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P <= 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452) + LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452) + LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited.
[Show abstract][Hide abstract] ABSTRACT: Men who sleep with men (MSM) and transgender individuals of color, the largest demographic in the House Ball community (HBC) are amongst the group at highest risk for HIV infection in the United States. The HBC have limited access to culturally appropriate HIV education. This study aimed to develop a partnership with HBC leaders to uncover strategies for increasing HIV prevention knowledge, including participation in HIV vaccine trials. To this end a research institution-community-HBC partnership was established. In-depth qualitative and quantitative data were collected from the 14 HBC leaders in western New York, revealing that knowledge of HIV and related vaccine trials was limited. Barriers to increasing HIV knowledge included fear of peer judgment, having inaccurate information about HIV, and lack of education. Among the HBC, community partnerships will further aid in the development of future HIV prevention programs and increase individuals' willingness to participate in future HIV vaccine trials.
Journal of Gay & Lesbian Social Services 07/2014; 26(3):336-354. DOI:10.1080/10538720.2014.924892
[Show abstract][Hide abstract] ABSTRACT: The informed consent process (ICP) for HIV vaccine trials poses unique challenges and would benefit from improvements to its historically based structure and format. Here, we propose a theoretical framework that provides a basis for systematically evaluating and addressing these challenges. The proposed framework follows a linear pathway, starting with the precondition of voluntariness, three main variables of valid decision-making (competency, provision of information and understanding) and then the consequential outcome of either refusal or consent to participate. The existing literature reveals that culturally appropriate provision of information and resultant understanding by the vaccine trial participant are among the most significant factors influencing the authenticity of valid decision-making, though they may be overridden by other considerations, such as individual altruism, mistrust, and HIV-related stigma. Community collaborations to foster bidirectional transmission of information and more culturally tailored consenting materials, therefore, represent a key opportunity to enhance the ICP. By providing a visual synopsis of the issues most critical to IC effectiveness in a categorical and relational manner, the framework provided here presents HIV vaccine researchers a tool by which the ICP can be more systematically evaluated and consequently improved.
AIDS Care 05/2014; 26(11):1-9. DOI:10.1080/09540121.2014.920074 · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 03/2014; 9(3):e90378. DOI:10.1371/journal.pone.0090378 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Clade B DNA and recombinant modified vaccinia Ankara (MVA) vaccines producing virus-like particles displaying trimeric membrane-bound envelope glycoprotein (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.
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 MMM regimen); or placebo injections.
At peak response, 93.2% of the DDMM group and 98.4% of the MMM 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 (gp120) of Env. For both regimens, response rates were higher for CD4(+) T cells (66.4% in the DDMM group and 43.1% in the MMM group) than for CD8(+) T cells (21.8% in the DDMM group and 14.9% in the MMM 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.
DDMM and MMM vaccinations with virus-like particle-expressing immunogens elicited durable antibody and T-cell responses.
The Journal of Infectious Diseases 02/2014; 210(1). DOI:10.1093/infdis/jiu003 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Potent HIV-1 specific broadly neutralizing antibodies (BNA) are uncommon in HIV infected individuals, and have proven hard to elicit by vaccination. Several, isolated monoclonal BNA are polyreactive and also recognize self-antigens, suggesting a breach of immune tolerance in persons living with HIV (PLWH). Persons with systemic lupus erythematosus (SLE) often have elevated levels of autoreactive antibodies encoded by the VH4-34 heavy chain immunoglobulin gene whose protein product can be detected by the 9G4 rat monoclonal antibody. We have recently found that levels of these "9G4+" antibodies are also elevated in PLWH. However, the putative autoreactive nature of these antibodies and the relationship of such reactivities with HIV neutralization have not been investigated. We therefore examined the autoreactivity and HIV neutralization potential of 9G4+ antibodies from PLWH. Results show that 9G4+ antibodies from PLWH bound to recombinant HIV-1 envelope (Env) and neutralized viral infectivity in vitro, whereas 9G4+ antibodies from persons with SLE did not bind to Env and failed to neutralize viral infectivity. In addition, while 9G4+ antibodies from PLWH retained the canonical anti-i reactivity that mediates B cell binding, they did not display other autoreactivities common to SLE 9G4+ antibodies, such as binding to cardiolipin and DNA and had much lower reactivity with apoptotic cells. Taken together, these data indicate that the autoreactivity of 9G4+ antibodies from PLWH is distinct from that of SLE patients, and therefore, their expansion is not due to a general breakdown of B cell tolerance but is instead determined in a more disease-specific manner by self-antigens that become immunogenic in the context of, and possibly due to HIV infection. Further studies of 9G4+ B cells may shed light on the regulation of B cell tolerance and interface between the generation of specific autoreactivities and the induction of antiviral immunity in persons living with HIV.
PLoS ONE 12/2013; 8(12):e85098. DOI:10.1371/journal.pone.0085098 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BackgroundA safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime-recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States. Methods
At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24. ResultsIn April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, -25.0%; 95% confidence interval, -121.2 to 29.3; P=0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log(10) copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P=0.28). The vaccine regimen had an acceptable side-effect profile. Conclusions
The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.)
New England Journal of Medicine 10/2013; 369(22). DOI:10.1056/NEJMoa1310566 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed.
HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools.
Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4(+) or CD8(+) T-cell response after the second vaccination, and 88.9% developed a CD4(+) or CD8(+) T-cell response after the third vaccination.
Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.
The Journal of Infectious Diseases 07/2013; 208(5). DOI:10.1093/infdis/jit236 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Federal meaningful use standards are promoting adoption of online portals to personal health records (PHRs). However, relatively little is known regarding barriers and facilitators for vulnerable groups such as persons living with human immunodeficiency virus (PLWH).
The objective of this study was to assess barriers and facilitators to use of online PHRs among PLWH.
We conducted formative research using a written waiting room survey among 120 PLWH regarding barriers and facilitators of portal PHR use. We supplemented findings with data collected from a PLWH focus group, where some members had personal experience with use of a portal.
The survey had 90 respondents. Eight PLWH participated in the focus group. Most patients (77/90, 86%) reported having at least some experience using the Internet and most expressed interest in features offered by the portal. Notably, 70% (63/90) expressed some interest in being taught how to use it to communicate with their provider. Focus group themes reinforced these findings, but also voiced concern regarding access to private computers.
Many PLWH in our sample have experience using computers and most are interested in PHR features. However, computer or broadband access and privacy are important barriers.