Harriet Park

In Vivo Electroporation Enhances the Immunogenicity of an HIV-1 DNA Vaccine Candidate in Healthy Volunteers

Background DNA-based vaccines have been safe but weakly immunogenic in humans to date. Methods and Findings We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. Conclusions This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. Trial Registration ClinicalTrials.gov NCT00545987

Incidence of tuberculosis and HIV and progression of silicosis and lung function impairment among former Basotho gold miners.

BACKGROUND Pulmonary tuberculosis and HIV incidence, mortality, and the progression of silicosis and lung function impairment are described over a 1-year period in migrant ex-gold miners from Lesotho. METHODS Seven hundred seventy-nine Basotho miners were followed for 1 year starting 18 months after lay-off from a South African gold mine in 1998. At baseline and follow-up, they underwent a respiratory symptom interview, physical examination, HIV test, chest radiograph, and spirometry. RESULTS Five hundred thirteen of 779 (65.9%) participants attended both baseline and follow-up visits. HIV incidence was 5.4/100 person-years (95% CI: 3.4-8.2). Prevalence of silicosis (ILO score > or =1/1) was 26.6% at baseline and 27.0% at follow-up. Active tuberculosis diagnosed at baseline was a strong predictor of radiological progression of silicosis. Lung function as measured by FEV(1) declined an average of 91 ml between visits (95% CI: 67-116 ml). Calculated minimum incidence of tuberculosis was 3,085/100,000/years (95% CI: 1,797-4,940) at follow-up. Of those seen at baseline, 18 died before their scheduled follow-up visit (mean age: 51 years). CONCLUSIONS High rates of mortality and of HIV infection and pulmonary tuberculosis were found in this cohort after leaving the South African goldmines. Continuing lung function loss was also apparent. A partnership between the South African mining industry and governments in labor-sending areas of Southern Africa is needed to provide continuity of care and access to HIV and tuberculosis treatment and prevention services. Active silicosis surveillance and an improved statutory compensation system are also needed. These findings can serve as a baseline against which the impact of such interventions can be assessed.

First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine. Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH). Results. All vaccine regimens were well tolerated. Gag-specific IFN-&ggr; enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic. Conclusions. SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated. Clinical Trials Registration. NCT01705990.

OA05-01. In vivo electroporation enhances the immunogenicity of ADVAX, a DNA-based HIV-1 vaccine candidate, in healthy volunteers

Open Access Oral presentation OA05-01. In vivo electroporation enhances the immunogenicity of ADVAX, a DNA-based HIV-1 vaccine candidate, in healthy volunteers S Vasan*1, A Hurley1, SJ Schlesinger1, D Hannaman2, DF Gardiner1, DP Dugin1, MM Boente-Carrera1, RM Vittorino1, M Caskey1, J Andersen1, Y Huang1, J Cox3, T Tarragona3, DK Gill3, H Cheeseman3, L Clark3, L Dally4, C Smith4, C Schmidt3, H Park3, E Sayeed3, J Gilmour3, P Fast3, R Bernard2 and DD Ho1

Acceptability and Feasibility of Repeated Mucosal Specimen Collection in Clinical Trial Participants in Kenya

Background Mucosal specimens are essential to evaluate compartmentalized immune responses to HIV vaccine candidates and other mucosally targeted investigational products. We studied the acceptability and feasibility of repeated mucosal sampling in East African clinical trial participants at low risk of HIV and other sexually transmitted infections. Methods and Findings The Kenya AIDS Vaccine Initiative (KAVI) enrolled participants into three Phase 1 trials of preventive HIV candidate vaccines in 2011–2012 at two clinical research centers in Nairobi. After informed consent to a mucosal sub-study, participants were asked to undergo collection of mucosal secretions (saliva, oral fluids, semen, cervico-vaginal and rectal), but could opt out of any collection at any visit. Specimens were collected at baseline and two additional time points. A tolerability questionnaire was administered at the final sub-study visit. Of 105 trial participants, 27 of 34 women (79%) and 62 of 71 men (87%) enrolled in the mucosal sub-study. Nearly all sub-study participants gave saliva and oral fluids at all visits. Semen was collected from about half the participating men (47–48%) at all visits. Cervico-vaginal secretions were collected by Softcup from about two thirds of women (63%) at baseline, increasing to 78% at the following visits, with similar numbers for cervical secretion collection by Merocel sponge; about half of women (52%) gave cervico-vaginal samples at all visits. Rectal secretions were collected with Merocel sponge from about a quarter of both men and women (24%) at all 3 visits, with 16% of men and 19% of women giving rectal samples at all visits. Conclusions Repeated mucosal sampling in clinical trial participants in Kenya is feasible, with a good proportion of participants consenting to most sampling methods with the exception of rectal samples. Experienced staff members of both sexes and trained counselors with standardized messaging may improve acceptance of rectal sampling.

Assessment of Anti-HIV-1 Antibodies in Oral and Nasal Compartments of Volunteers From 3 Different Populations.

Abstract:In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda), and London (United Kingdom) using different collection devices and media (synthetic absorptive matrices versus flocked swabs, and Salimetrics oral swabs versus whole oral fluid collection). We detected anti-Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIV-infected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV-uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable with samples collected deeper in the nasopharyngeal tract, and the yield of anti-p24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy. Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low- and high-resource settings. These methods may be used in support for future HIV vaccine clinical trials.

Developing standards of care for HIV prevention research in developing countries – a case study of ten research centers in Eastern and Southern Africa

Background Standards of care in general vary across countries and communities and thus may affect decisions about standards of care provided by research centers in HIV prevention research. To serve as a basis for clarifying and improving standards, a systematic survey of practices at 10 experienced research centers affiliated with the International AIDS Vaccine Initiative in Eastern and Southern Africa was conducted between 2008 and 2010.

Uptake and tolerability of repeated mucosal specimen collection in two Phase 1 AIDS preventive vaccine trials in Kenya

Methods The Kenya AIDS Vaccine Initiative (KAVI) initiated two AIDS preventive vaccine trials in Nairobi in 2011. After informed consent for a mucosal substudy, participants were asked to provide any of several types of mucosal secretions: saliva, oral fluids, semen, cervico-vaginal and rectal. Specimens were collected at baseline, one month after final vaccination, and at the next scheduled trial visit. A tolerability questionnaire was administered at the final visit.