Sheila A. Peel

A Recombinant Vesicular Stomatitis Virus Ebola Vaccine - Preliminary Report.

Background The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication‐competent, recombinant vesicular stomatitis virus (rVSV)–based vaccine candidate designed to prevent EVD. Methods We conducted two phase 1, placebo‐controlled, double‐blind, dose‐escalation trials of an rVSV‐based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV‐ZEBOV vaccine (3 million plaque‐forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. Results The most common adverse events were injection‐site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme‐linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV‐Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. Conclusions This Ebola vaccine candidate elicited anti‐Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV&Dgr;G‐ZEBOV‐GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408.)

Hepatitis B Virus Coinfection Negatively Impacts HIV Outcomes in HIV Seroconverters

BACKGROUND Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters. METHODS Participants with HIV diagnosis seroconversion window of ≤ 3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status. RESULTS Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15-2.71); 3.27 (2.71-3.84); 3.75 (2.25-5.25); and 5.41 (3.41-7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20-2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94-1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75-1.75). CONCLUSIONS HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.

Hepatitis B vaccine responses in a large U.S. military cohort of HIV-infected individuals: Another benefit of HAART in those with preserved CD4 count

The influence of highly active antiretroviral therapy (HAART) upon hepatitis B virus (HBV) vaccine responses in HIV-infected individuals is unclear. After classification of vaccinees as non-responders (HBsAb <10IU/L) or responders (HBsAb >or=10IU/L) in our HIV cohort, multivariate logistic regression was used to assess factors associated with subsequent vaccine response. Of 626 participants vaccinated from 1988 to 2005, 217 (35%) were vaccine responders. Receipt of >or=3 doses of vaccine (OR 1.83, 95% CI 1.24-2.70), higher CD4 count at vaccination (OR 1.09, 95% CI 1.05-1.13 per 50 cells/microl increase), and use of HAART (OR 2.37, 95% CI 1.56-3.62) were all associated with increased likelihood of developing a response. However, only 49% of those on HAART at last vaccination responded, and 62% of those on HAART, with CD4 count >or=350, and HIV RNA <400 copies/mL responded. Compared to those on HAART with CD4 count >or=350, those not on HAART with CD4 count >or=350 had significantly reduced odds of developing a vaccine response (OR 0.47, 95% CI 0.30-0.70). While HAART use concurrent with HBV immunization was associated with increased probability of responding to the vaccine, the response rate was low for those on HAART. These data provide additional evidence of HAART benefits, even in those with higher CD4 counts, but also highlight the need for improving HBV vaccine immunogenicity.

Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand

BACKGROUND Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment strategies to eradicate HIV-1 or achieve a functional cure. METHODS We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly. RESULTS Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits. CONCLUSIONS The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.).

DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial

Background DNA vaccine immunogenicity has been limited by inefficient delivery. Needle-free delivery of DNA using a CO2-powered Biojector® device was compared to delivery by needle and syringe and evaluated for safety and immunogenicity. Methods Forty adults, 18–50 years, were randomly assigned to intramuscular (IM) vaccinations with DNA vaccine, VRC-HIVDNA016-00-VP, (weeks 0, 4, 8) by Biojector® 2000™ or needle and syringe (N/S) and boosted IM at week 24 with VRC-HIVADV014-00-VP (rAd5) with N/S at 1010 or 1011 particle units (PU). Equal numbers per assigned schedule had low (≤500) or high (>500) reciprocal titers of preexisting Ad5 neutralizing antibody. Results 120 DNA and 39 rAd5 injections were given; 36 subjects completed follow-up research sample collections. IFN-γ ELISpot response rates were 17/19 (89%) for Biojector® and 13/17 (76%) for N/S delivery at Week 28 (4 weeks post rAd5 boost). The magnitude of ELISpot response was about 3-fold higher in Biojector® compared to N/S groups. Similar effects on response rates and magnitude were observed for CD8+, but not CD4+ T-cell responses by ICS. Env-specific antibody responses were about 10-fold higher in Biojector-primed subjects. Conclusions DNA vaccination by Biojector® was well-tolerated and compared to needle injection, primed for greater IFN-γ ELISpot, CD8+ T-cell, and antibody responses after rAd5 boosting. Trial Registration ClinicalTrials.gov NCT00109629

Comprehensive analysis of unique cases with extraordinary control over HIV replication.

True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.

Transfusion‐transmissible viral infections among US military recipients of whole blood and platelets during Operation Enduring Freedom and Operation Iraqi Freedom

BACKGROUND: Current US military clinical practice guidelines permit emergency transfusions of non–Food and Drug Administration (FDA)‐compliant freshly collected blood products in theaters of war. This investigation aimed to characterize the risks of transfusion‐transmitted infections (TTIs) associated with battlefield transfusions of non–FDA‐compliant blood products.

Large-Scale Human Immunodeficiency Virus Rapid Test Evaluation in a Low-Prevalence Ugandan Blood Bank Population

ABSTRACT The use of rapid tests for human immunodeficiency virus (HIV) has become standard in HIV testing algorithms employed in resource-limited settings. We report an extensive HIV rapid test validation study conducted among Ugandan blood bank donors at low risk for HIV infection. The operational characteristics of four readily available commercial HIV rapid test kits were first determined with 940 donor samples and were used to select a serial testing algorithm. Uni-Gold Recombigen HIV was used as the screening test, followed by HIV-1/2 STAT-PAK for reactive samples. OraQuick HIV-1 testing was performed if the first two test results were discordant. This algorithm was then tested with 5,252 blood donor samples, and the results were compared to those of enzyme immunoassays (EIAs) and Western blotting. The unadjusted algorithm sensitivity and specificity were 98.6 and 99.9%, respectively. The adjusted sensitivity and specificity were 100 and 99.96%, respectively. This HIV testing algorithm is a suitable alternative to EIAs and Western blotting for Ugandan blood donors.

Laboratory evaluation of rapid test kits to detect hepatitis C antibody for use in predonation screening in emergency settings.

BACKGROUND: Emergency whole blood transfusion is a lifesaving procedure employed on modern battlefields. Rapid device tests (RDTs) are frequently used to mitigate transfusion‐transmitted infection risks.

Evaluating respondent-driven sampling as an implementation tool for universal coverage of antiretroviral studies among men who have sex with men living with HIV.

Introduction:The TRUST model based on experimental and observational data posits that integration of HIV prevention and universal coverage of antiretroviral treatment at a trusted community venue provides a framework for achieving effective reduction in HIV-related morbidity and mortality among men who have sex with men (MSM) living with HIV, as well as reducing HIV incidence. The analyses presented here evaluate the utility of respondent-driven sampling as an implementation tool for engaging MSM in the TRUST intervention. Methods:The TRUST integrated prevention and treatment model was established at a trusted community center serving MSM in Abuja, Nigeria. Five seeds have resulted in 3–26 waves of accrual between March 2013 and August 2014, with results presented here characterizing HIV burden and engagement in HIV care for 722 men across study recruitment waves. For analytic purposes, the waves were collapsed into 5 groups: 4 equally spaced (0–4, 5–9, 10–14, and 15–19) and 1 ranging from the 20th to the 26th wave with significance assessed using Pearson &khgr;2 test. Results:In earlier waves, MSM were more likely to have reported testing for HIV (82.9% in waves 0–4, 47.7% in waves 20–26; P < 0.01). In addition, biologically confirmed HIV prevalence decreased from an average of 59.1% to 42.9% (P < 0.05) in later waves. In earlier waves, about 80% of participants correctly reported their HIV status as compared with less than 25% in the later waves (P < 0.01). Finally, participants reporting being on ART decreased from 50% to 22.2% in later waves (P < 0.01). Conclusions:Implementation science studies focused on demonstrating impact of universal HIV treatment programs among people living with HIV necessitate different accrual methods than those focused on preventing HIV acquisition. Here, respondent-driven sampling was shown to be an efficient method for reaching marginalized populations of MSM living with HIV in Nigeria, and engaging them in universal HIV treatment services.