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Background From 2019 to 2021, Rwandan residents of the border with the Democratic Republic of the Congo were offered the Ad26.ZEBOV (adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein) and MVA-BN-Filo (modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and nucleoprotein from Tai Forest viruses) Ebola vaccine regimen. Methods Nonpregnant persons aged ≥2 years were eligible. Unsolicited adverse events (UAEs) were reported through phone calls or visits, and serious adverse events (SAEs) were recorded per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Results Following Ad26.ZEBOV, UAEs were reported by 0.68% of 216 113 vaccinees and were more common in younger children (aged 2–8 years, 1.2%) compared with older children (aged 9–17 years, 0.4%) and adults (aged ≥18 years, 0.7%). Fever and headache were the most reported symptoms. All 17 SAEs related to vaccine were in children aged 2–8 years (10 postvaccination febrile convulsions ± gastroenteritis and 7 fever and/or gastroenteritis). The incidence of febrile seizures was 8 of 26 062 (0.031%) prior to initiation of routine acetaminophen in December 2020 and 2 of 15 897 (0.013%) thereafter. Nonobstetric SAEs were similar in males and females. All 20 deaths were unrelated to vaccination. Young girls and adult women with UAEs were less likely to receive the second dose than those without UAEs. Seven unrelated SAEs occurred in 203 267 MVA-BN-Filo recipients. Conclusions Postvaccination febrile convulsions in young children were rare but not previously described after Ad26.ZEBOV and were reduced with routine acetaminophen. The regimen was otherwise safe and well-tolerated.

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load., A single dose of a broadly neutralizing, HIV-specific antibody transiently reduces viral load in plasma, and in some individuals is associated with durable virus suppression in the absence of antiretroviral therapy.

Summary Background A preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV. Methods This first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18–45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4 × 10 12 vector genomes; group B, 4 × 10 13 vector genomes; group C, 8 × 10 13 vector genomes; and group D, 1·2 × 10 14 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov, number NCT01937455. Findings Between Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected. Interpretation Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies. Funding International AIDS Vaccine Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation, US National Institutes of Health.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.

IntroductionIntramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants.MethodsForty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally.ResultsAll 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection.ConclusionRepeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989.

Measuring PrEP adherence remains challenging. In 2009–2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP.

Summary Background More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. Methods We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18–50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 10 10 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 10 8 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 μg) or low-dose (50 μg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. Findings Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. Interpretation The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). Funding Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.

Background: A preventive vaccine for HIV is a critical public health need. Adeno-associated virus (AAV) mediated antibody gene delivery could be an alternative to immunization to induce sustained expression of neutralizing antibodies to prevent HIV. We conducted a first-in-human, phase 1 study of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralizing antibody against HIV. Methods: The trial was a phase 1, randomized, blinded, placebo-controlled, dose-escalation study at a single center in the UK. Healthy, HIV-uninfected men aged 18-45 were randomly assigned (3:1) to intervention or control in one of four dose-escalating cohorts (4x1012 vector genomes(vg), 4x1013 vg, 8x1013 vg or 1·2x1014 vg). Volunteers received intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps and were followed for 48 weeks. The primary objective was safety and tolerability. A secondary objective was to evaluate PG9 expression in serum and related HIV neutralization activity. This trial is registered with ClinicalTrials.gov, number NCT01937455. Findings: 21 volunteers were enrolled between February 10, 2014 and February 28, 2017 and completed 48 weeks follow-up. Reactogenicity was generally mild or moderate and self-limited. There were no probably or definitely related adverse events and no serious adverse events. We detected PG9 by HIV neutralization in serum of four volunteers, and by RT-PCR in muscle biopsies of four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in 10 volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1 specific T-cell responses were detected. Interpretation: Intramuscular administration of rAAV1-PG9DP in healthy men was safe and well-tolerated. Antibody expression was detected directly in muscle and indirectly in serum, and anti-drug antibodies were induced, indicating PG9 expression. Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralizing HIV antibodies. Trial Registration number: This trial is registered with ClinicalTrials.gov, number NCT01937455. Funding: International AIDS Vaccine Initiative, United States Agency for International Development (USAID), Bill & Melinda Gates Foundation, US National Institutes of Health Declaration of Interest: Jim Ackland reports receiving consulting fees from International AIDS Vaccine Initiative during the course of the study. Fraser Wright reports grants from National Institutes of Health during the conduct of the study. In addition, Dr. Wright has a patent US 9,408,904 licensed to Spark Therapeutics. Ethical Approval: The protocol was approved by the University of Surrey Ethics Committee, the NRES Bristol Research Ethics Committee and the UK Medicines and Healthcare products Regulatory Authority and conducted in compliance with Good Clinical Practices and the Declaration of Helsinki guidelines.

Background Digital technologies, especially if used in novel ways, provide a number of potential advantages to clinical research in trials related to human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) and may greatly facilitate operations as well as data collection and analysis. These technologies may even allow answering questions that are not answerable with older technologies. However, they come with a variety of potential concerns for both the participants and the trial sponsors. The exact challenges and means for alleviation depend on the technology and on the population in which it is deployed, and the rapidly changing landscape of digital technologies presents a challenge for creating future-proof guidelines for technology application. Objective The aim of this study was to identify and summarize some common themes that are frequently encountered by researchers in this context and highlight those that should be carefully considered before making a decision to include these technologies in their research. Methods In April 2016, the Global HIV Vaccine Enterprise surveyed the field for research groups with recent experience in novel applications of digital technologies in HIV clinical research and convened these groups for a 1-day meeting. Real-world uses of various technologies were presented and discussed by 46 attendees, most of whom were researchers involved in the design and conduct of clinical trials of biomedical HIV prevention and treatment approaches. After the meeting, a small group of organizers reviewed the presentations and feedback obtained during the meeting and categorized various lessons-learned to identify common themes. A group of 9 experts developed a draft summary of the findings that was circulated via email to all 46 attendees for review. Taking into account the feedback received, the group finalized the considerations that are presented here. Results Meeting presenters and attendees discussed the many successful applications of digital technologies to improve research outcomes, such as those for recruitment and enrollment, participant identification, informed consent, data collection, data quality, and protocol or treatment adherence. These discussions also revealed unintended consequence of technology usage, including risks to study participants and risks to study integrity. Conclusions Key lessons learned from these discussions included the need to thoroughly evaluate systems to be used, the idea that early success may not be sustained throughout the study, that some failures will occur, and considerations for study-provided devices. Additionally, taking these key lessons into account, the group generated recommendations on how to move forward with the use of technology in HIV vaccine and biomedical prevention trials.

Background: Health-care providers form the backbone of health information and service delivery in many African communities. This study investigated health-care providers' (HCPs) attitudes towards a novel method of HIV prevention for women—a microbicide-embedded intravaginal ring (IVR). Methods: Qualitative interviews were conducted, covering initial attitudes towards IVRs, potential use among female sex workers, herbal practices for sexually transmitted infection (STI) management and the ways in which populations can access the rings should they become available. Twenty HCPs were interviewed in Mukuru and Kibera, which are informal settlements in Nairobi, Kenya, with high HIV prevalence, unemployment and commercial sex work. Results: The majority of HCPs had positive attitudes towards IVRs as a method of HIV prevention in this environment. HCPs liked that IVRs are female controlled and can be used covertly. Overall, HCPs reported a willingness to participate in the distribution of IVRs, and favoured distribution through health facilities at no cost. Conclusion: Findings from this study demonstrate that HCPs are willing to serve as the primary source of IVR information in target communities. However, they require adequate knowledge regarding microbicides and IVRs before these products reach the market.

While the long-term goal is to develop highly effective AIDS vaccines, first generation vaccines may be only partially effective. Other HIV prevention modalities such as preexposure prophylaxis with antiretrovirals (PrEP) may have limited efficacy as well. The combined administration of vaccine and PrEP (VAXPREP), however, may have a synergistic effect leading to an overall benefit that is greater than the sum of the individual effects. We propose two test-of-concept trial designs for an AIDS vaccine plus oral or topical ARV. In one design, evidence that PrEP reduces the risk of HIV acquisition is assumed to justify offering it to all participants. A two-arm study comparing PrEP alone to VAXPREP is proposed in which 30 to 60 incident infections are observed to assess the additional benefit of vaccination on risk of infection and setpoint viral load. The demonstrated superiority of VAXPREP does not imply vaccine alone is efficacious. Similarly, the lack of superiority does not imply vaccine alone is ineffective, as antagonism could exist between vaccine and PrEP. In the other design, PrEP is assumed not to be in general use. A 2 × 2 factorial design is proposed in which high-risk individuals are randomized to one of four arms: placebo vaccine given with placebo PrEP, placebo vaccine given with PrEP, vaccine given with placebo PrEP, or VAXPREP. Between 60 and 210 infections are required to detect a benefit of vaccination with or without PrEP on risk of HIV acquisition or setpoint viral load, with fewer infections needed when synergy is present.

Standards of care provided to volunteers in HIV prevention research in developing countries are evolving. Inconsistency in standards, particularly within a research network highlights the need to balance volunteers' health and wellness with the efficient conduct of research. Ten research centers (RC's) in East and Southern Africa affiliated with the International AIDS Vaccine Initiative (IAVI) were studied using a mixed methods approach to understand variations, similarities and gaps in services provided, recipients of services, referral systems, and barriers to referral uptake. These data were then used to develop expected standards across the 10 RCs. Findings indicated that RCs consistently provided HIV risk reduction and family planning (FP) counseling, male condoms, management of sexually transmitted infections, CD-4 counts, and general medical care to volunteers and non-research volunteers. Services that were less consistently provided on-site included: female condoms, adult male circumcision (AMC), antiretroviral therapy (ART) and post-exposure prophylaxis (PEP) in case of rape. The FP options provided on-site varied, with few providing implants, intrauterine devices, tubal ligation, and vasectomy. Most RCs had established referral systems for ART, AMC, PEP, and FP, but few had referral points for psychosocial services. Few RCs had comprehensive guidelines on referrals other than those related to adverse events. Findings indicate that the greatest challenges for referral uptake were transportation and health care costs, poor quality and inconsistency of services at some referral points. Few RCs covered the cost of referrals for non-study related adverse events. A collaborative process between IAVI and the RCs was undertaken to reach consensus on expected standards of care. A set of required and recommended services to be provided on-site or by referral was developed. In developing such standards, we tried to balance scientific priorities, equity, contextual realities, community expectations, and cost-effectiveness.

Multiple intravaginal HIV prevention methods, including microbicide gels, barriers, and intravaginal rings, are in clinical development in Africa. Development of intravaginal HIV prevention products requires an understanding of sexual behavior, sexually transmitted infection (STI), and vaginitis prevalences, and sexual and vaginal practices in potential target populations. We assessed these factors in a cohort of Kenyan female sex workers (FSW). Women who reported exchanging sex for money/gifts at least three times in the past month and who were HIV uninfected were enrolled and followed for 6 months. STI prevalence and HIV incidence were analyzed by multivariate logistic regression analysis, controlling for demographic and behavioral factors. Thirty-seven percent (74/200) reported having had anal sex. Frequency of anal sex was higher with regular and casual partners than with primary partners. Women were less likely to use condoms for anal sex than for vaginal sex with regular or casual partners. Vaginal washing was universal (100%). HIV incidence was 5.6 per 100 person-years (95% CI 1.62, 11.67). HIV incidence was not associated with any demographic or risk behavior. The relatively high rate of anal sex and universal vaginal washing may complicate both safety and efficacy evaluation of intravaginal products and should be taken into account in trial design. This FSW population had significant HIV incidence and needs continued HIV prevention interventions.

Anti-HIV Antibodies One of the top priorities for an HIV vaccine is the ability to elicit a broadly neutralizing antibody response, which should provide the best protection against infection. In the 25 years since the discovery of HIV, very few broadly neutralizing antibodies have been identified, and those that do exist were discovered nearly two decades ago. Using a high-throughput culture system, Walker et al. (p. 285 ; published online 3 September) now identify two additional broadly neutralizing antibodies isolated from a clade A HIV-infected African donor. These antibodies exhibit great potency and, in contrast to other known broadly neutralizing antibodies, are able to neutralize a wide range of viruses from many different clades. The antibodies recognize a motif in the trimerized viral envelope protein that is found in conserved regions of the variable loops of the gp120 subunit. Identification of this motif provides an intriguing new target for vaccine development.

This study sought to determine if microdermabrasion can selectively remove stratum corneum to increase skin permeability. Although, microdermabrasion has been used for cosmetic treatment of skin for decades, no study has assessed the detailed effects of microdermabrasion conditions on the degree of skin tissue removal. Therefore, we histologically characterized the skin of rhesus macaques and human volunteers after microdermabrasion at different conditions. Using mobile tip microdermabrasion, an increase in the number of treatment passes led to greater tissue removal ranging from minimal effects to extensive damage to deeper layers of the skin. Of note, these data showed for the first time that at moderate microdermabrasion conditions selective yet full-thickness removal of stratum corneum could be achieved with little damage to deeper skin tissues. In the stationary mode of microdermabrasion, selective stratum corneum removal was not observed, but micro-blisters could be seen. Similar tissue removal trends were observed in human volunteers. As proof of concept for drug delivery applications, a model fluorescent drug (fluorescein) was delivered through microdermabraded skin and antibodies were generated against vaccinia virus after its topical application in monkeys. In conclusion, microdermabrasion can selectively remove full-thickness stratum corneum with little damage to deeper tissues and thereby increase skin permeability.

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC50) neutralization titers of ≥100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC50titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

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-gamma 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 titers200 versusor =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 titers200 versusor = 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 titers200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process. (c) 2007 Lippincott Williams & Wilkins.

Supplemental Digital Content is Available in the Text., Objective: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Design: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. Methods: At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Results: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41–0.86, all P < 0.001). Conclusions: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.

Background These two trials under Europe-Africa collaborations aim at addressing two factors relevant for Africa i.e helminth infections and HIV-1 diversity. EV06 used a novel combination of DNA expressing clade C Env, Gag and Pol-nef co-administered with AIDSVAX®B/E Env protein to study the effect of S. mansoni on vaccine responses. GREAT is a recently awarded trial using a 2nd generation improved conserved tHIVConsvX T-cell vaccine candidate combined with bivalent mosaic design to increase breadth and protective epitopes. Methods EV06 enrolled 72 males and females aged 18–45, half infected with S. mansoni (SM+). In each arm 30 received vaccine and 6 placebo at week 0, 4 and 24. Responses were evaluated at week 0, 6, 26 and 36. Humoral responses were measured as binding IgG against a panel of HIV-1 envelope glycoproteins and as neutralizing antibodies (Nabs), using TZM/ bl cells and tier 1 pseudoviruses. Cellular responses were measured as HIV-specific CD4+ and CD8+ T-cell by IFN-γ ELIS-pot and multi-cytokine intracellular staining flow cytometry. GREAT will be a phase IIa trial and preparation for efficacy trials in Kenya, Uganda and Zambia testing ChAdOx1.tHIVconsv5 and ChAdOx1.tHIVconsv6 followed by MVA.tHIVconsv3 and MVA.tHIVconsv4 on week 2 (Arm 1) or week 8 (Arm 2). Progress Differences in binding IgG response rates were observed in vaccinated participants against the vaccine matched clade C V1V2 (gp70–96ZM651.02 V1V2) at week 6: 56% among SM+ versus 86% among SM – (p=0.039). At week 36, response magnitudes were statistically lower in the SM+ against gp120 and gp140 proteins (p=0.04 for both). SM+ also had lower Nabs and ELISpot responses at various time points. Still blinded data on the first 20 volunteers show 80% responders for CD4 T cell at w26 and 70% CD8 responders at w36. These trials will provide more data on challenges facing HIV vaccine development in Africa.

Background Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens. Design Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment. Methods Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT. Results Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen. Conclusions Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing. Registration Clinicaltrials.gov number NCT00931346

This paper used qualitative methods to explore experiences of men who have sex with men and female sex workers in Nairobi and Mtwapa, Kenya, who used oral pre-exposure prophylaxis (PrEP) for HIV prevention as part of a four-month trial of safety, acceptability and adherence. Fifty-one of 72 volunteers who took part in a randomized, placebo-controlled, blinded trial that compared daily and intermittent dosage of PrEP underwent qualitative assessments after completing the trial. Analyses identified three themes: (i) acceptability of PrEP was high, i.e. side effects were experienced early in the study but diminished over time, however characteristics of pills could improve comfort and use; (ii) social impacts such as stigma, rumors, and relationship difficulties due to being perceived as HIV positive were prevalent; (iii) adherence was challenged by complexities of daily life, in particular post-coital dosing adherence suffered from alcohol use around time of sex, mobile populations, and transactional sex work. These themes resonated across dosing regimens and gender, and while most participants favored the intermittent dosing schedule, those in the intermittent group noted particular challenges in adhering to the post-coital dose. Culturally appropriate and consistent counseling addressing these issues may be critical for PrEP effectiveness.

Methods Seventy-two HIV-uninfected partners (50% women) in Uganda were randomized to daily or intermittent (Monday, Friday and within 2 hours after sex, not exceeding 1 dose/day) oral emtricitabine/tenofovir or placebo in a 2:1:2:1 ratio for four months. Adherence was assessed monthly by MEMS and self-reported taken or missed doses by timeline follow-back calendar. MEMS data was adjusted for extra openings without pill removal and removal of multiple pills. Non-fixed days within intermittent regimen were classified as adherent/non-adherent based on self-reported sex by SMS. Adherence rates by taken/missed doses were compared to raw MEMS data using Spearman correlation.

Background: This mixed methods study reports on product acceptance from a Phase I clinical trial of a candidate non-nucleoside reverse transcriptase inhibitor (NNRTI) vaginal microbicide product (UC781). The product was evaluated in the context of a Phase I clinical trial in an area characterized by high HIV prevalence among minority women. The findings will inform the development of an acceptable microbicide that will address the needs of diverse women and their partners. Methods: This is a mixed methods study of 34 racially and ethnically diverse female participants and 10 male partners in Atlanta, Georgia. Chi-square tests for marginal homogeneity and kappa statistics were calculated to analyze differences between groups on product attributes and use intention. ANOVA was used to examine difference between the treatment groups. Qualitative data were analyzed via constant comparative methodology. Results: Thirty-four out of the original female cohort of 36 completed the questionnaire. Approval of future microbicide development was high at 91.2% (n=31) despite a lack of enthusiasm for the placebo and UC781 formulations. Overall female acceptability was correlated with personal protection motivation (r=1.00, p

Background Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). Methods/Principal Findings MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2∶1∶2∶1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Conclusions/Significance Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens. Trial Registration ClinicalTrials.gov NCT00971230

Objectives To assess the burden of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in high-risk HIV-1 negative men who have sex with men (MSM) in Africa. Methods Before the start of a pre-exposure prophylaxis trial, HIV-1 negative volunteers were screened for sexually transmitted infection (STI) including CT and NG, using a highly sensitive and specific nucleic acid amplification test. Samples positive for CT by Aptima testing, were evaluated for the presence of lymphogranuloma venereum (LGV) serovars using an in-house PCR assay. All men were asked to submit a urine specimen, and all had a rectal swab collected by a clinician. Men were asked if they had dysuria, urethral or rectal discharge, or rectal pain. Results 43 HIV-1 negative MSM were screened, of whom 13 reported sex with men only; the majority (27/43) reported sex work. One volunteer had dysuria and another, rectal pain. Eleven MSM (26%, 95% CI 14% to 41%) had infections with either or both pathogens. Homosexual men had a higher prevalence of any infection than bisexual men (46% vs 17%, p=0.04), and all cases of rectal infections, including one with CT, two with NG and two with CT/NG co-infection. All patients with CT were negative for LGV. One patient with a rectal NG infection reported rectal pain. Conclusions A remarkably high burden of STI infection was found among HIV-1 negative MSM. Most (12/13) infections, including three of four rectal NG infections, were subclinical. These findings suggest that high-risk MSM will benefit from effective STI screening in Kenya.

Yellow fever is a mosquitoborne hemorrhagic disease that is endemic in sub-Saharan Africa and tropical South America. The etiologic agent, the yellow fever virus (YFV) is a single-stranded RNA virus in the family Flaviviridae, which also includes the dengue and West Nile viruses. After a natural YFV infection, viral replication initially occurs in tissues at the site of infection, but it rapidly spreads to the lymph nodes, blood, and liver [1]. The live attenuated yellow fever vaccine (YF-17D) was developed in the 1930s through experimental attenuation of the Asibi strain of YFV by serial passaging in cell culture [2]. The vaccine is considered safe and extremely effective, and it has been administered to >500 million people worldwide [3, 4]. Protection is achieved in >98% of recipients, with a duration of at least 10 years and probably much longer, given that significant neutralizing antibody titers may persist for ≥35 years after a single vaccination [3, 4]. Although YF-17D is usually a well-tolerated vaccine, in rare cases (approximately 1 in 250,000 vaccinees) individuals develop severe viscerotropic adverse reactions within 2 to 5 days after vaccination; these reactions are sometimes fatal [5–8]. Yellow fever vaccine–associated viscerotropic disease is characterized by the failure of multiple organ systems [5–8]. Within 2–5 days after vaccination, patients develop high fever, malaise, and myalgia, followed by jaundice, oliguria, cardiovascular instability, hemorrhage, and renal and respiratory failure. The case fatality rate is over 50%, and large amounts of YFV antigen may be found in the liver, heart, and other organs, primarily in tissue-associated macrophages [5–9]. The syndrome was first described in 2001, but cases in 1975 and the 1990s were identified retrospectively. To date, a total of 36 cases have been reported worldwide. Genetic mutations in the YFV do not seem to be the cause of the adverse reactions, because in several instances YFV isolated from subjects has had the same consensus nucleotide sequence as the original vaccine strain virus [8]. Furthermore, the YFV isolates recovered from the subjects showed no reversion to virulence in animal models, suggesting that host factors may be involved in disease [8].

We sought to assess the potential acceptability of intravaginal rings (IVRs) as an HIV prevention method among at-risk women and men.We conducted a qualitative assessment of initial attitudes toward IVRs, current HIV prevention methods, and common behavioral practices among female sex workers (FSWs) and men who frequent FSWs in Mukuru, an urban slum community in Nairobi, Kenya. Nineteen women and 21 men took part in six focus group discussions.Most participants, both male and female, responded positively to the concept of an IVR as a device for delivering microbicides. Women particularly liked the convenience offered by its slow-release capacity. Some female respondents raised concerns about whether male customers would discover the ring and respond negatively, whereas others thought it unlikely that their clients would feel the ring. Focus groups conducted with male clients of FSWs suggested that many would be enthusiastic about women, and particularly sex workers, using a microbicide ring, but that women's fears about negative responses to covert use were well founded. Overall, this high-risk population of FSWs and male clients in Nairobi was very open to the IVR as a potential HIV prevention device.Themes that emerged from the focus groups highlight the importance of understanding attitudes toward IVRs as well as cultural practices that may impact IVR use in high-risk populations when pursuing clinical development of this potential HIV prevention device.

Few studies have examined the influence of pregnancy and hormonal contraception on HIV-related deaths in African women. Rwanda is a country with high fertility, high HIV prevalence, and frequent use of hormonal contraception in urban areas.Data from a prospective cohort study of 460 HIV-infected urban childbearing (18-35 years) women followed at 6-monthly intervals for 6 years in Kigali, Rwanda, were analyzed. The relationship of time-dependent measures of pregnancy and hormonal contraceptive use to death from HIV disease was assessed with multivariate models.Incident pregnancy was not associated with elevated risk of death among HIV-infected women. Oral and injectable hormonal contraceptive use had borderline protective effects associated with reduced mortality (HR 0.40, 95% CI 0.15-1.07 and HR 0.48, 95% CI 0.21-1.08 for mortality, respectively) in a multivariate model including time-dependent measures.The results point to the benefits of integrating family planning and HIV services. In a highly pronatalist society, such as Rwanda, which is experiencing high HIV prevalence, service integration affords an opportunity to provide HIV testing to women at risk of pregnancy and to promote family planning among HIV-positive women.

The southeastern United States has an increasing burden of HIV, particularly among blacks, women, and men who have sex with men. To evaluate HIV nucleic acid amplification testing (NAAT) and antibody-based algorithms in determination of HIV incidence, detection of acute HIV infections, and surveillance of drug-resistant virus transmission in the urban southeastern United States, we conducted a cross-sectional analysis of prospectively collected data from 2202 adults receiving HIV testing and counseling at 3 sites in Atlanta, GA from October 2002 through January 2004. After standard testing with an HIV enzyme immunoassay (EIA) and Western blot confirmation, HIV-positive specimens were tested with 2 standardized assays to detect recent infection. HIV antibody-negative specimens were pooled and screened for HIV using NAAT. Seventy (3.2%) of 2202 subjects were HIV infected. Only 66 were positive on the standard HIV antibody test; 4 were antibody-negative but acutely HIV infected. The overall annual HIV incidence was 1.1% (95% confidence interval [CI]: 0.4 to 1.8) based on the Vironostika-LS assay and 1.3% (95% CI: 0.6 to 2.1) based on the BED Incidence Enzyme Immunoassay (EIA). The prevalence of acute HIV infection was 1.8 per 1000 persons (95% CI: 0.7 to 4.6). The sensitivity of the current testing algorithm using an EIA and Western blot test for detectable infections was only 94.3% (95% CI: 86.2 to 97.8). All 3 of the acutely infected subjects genotyped had drug resistance mutations, and 1 had multiclass resistance. Adding NAAT-based screening to standard HIV antibody testing increased case identification by 6% and uncovered the first evidence of multidrug-resistant HIV transmission in Atlanta. Antibody tests alone are insufficient for public health practice in high-risk urban HIV testing settings.

Background Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses. Methods In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured. Results The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration. Conclusion Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses. Trial Registration ClinicalTrials.gov NCT01264445

Racial/ethnic minorities in the Southeastern USA are disproportionately affected by HIV, and would benefit from a preventive vaccine. We conducted a cross-sectional survey of 220 community college students in Atlanta to evaluate racial/ethnic differences in knowledge and willingness to participate in HIV vaccine trials. Willingness to participate did not differ by race/ethnicity, age, or gender, and was not associated with knowledge. African-Americans and Asians were more likely than Whites to: believe that an HIV vaccine exists, but is being withheld from the public; believe that AIDS was caused by a government conspiracy; feel that having other participants and investigators of their ethnic background in the trial was important. Misconceptions regarding HIV vaccines are common and differ by race/ethnicity. However, willingness to participate was not associated with knowledge or race/ethnicity. Efforts to increase participation should address the ethnic diversity of the trial personnel, and education to eliminate misconceptions about HIV vaccines and trials.

The potential medical transmission of HIV through unsafe medical injections was evaluated in 16 rural health institutions in Ethiopia. Most institutions reported re-using disposable needle/syringes, and 12% of observed injections were given with used, disposable syringes prepared for re-use. Analysis of used needle flushes showed no HIV RNA; however, the sensitivity of our method was limited. Despite the re-use of disposable needles, medical injection practices are not likely to contribute significantly to HIV transmission in this region.

During the first decade of the AIDS epidemic the outcome for nearly every person infected with HIV around the world was virtually the same: most of those who became infected with HIV eventually died as a result of AIDS. However this began to change in 1996 with the advent of protease inhibitors and HAART. In a very short time we saw dramatic decreases in the morbidity and mortality associated with HIV infection throughout the developed world and as a result the gap between outcomes for HIV-infected persons in the developed world and outcomes for those in the developing world began to widen. This unacceptable inequity between the countries that bear the greatest burden of disease and those that benefit the most from therapy is now beginning to change thanks largely to the efforts of nongovernmental organizations such as Medecines Sans Frontieres (MSF) and initiatives such as the President’s Emergency Plan For AIDS Relief and the “3 by 5” strategy of the World Health Organization (WHO). The WHO estimates that as a result of such programs the estimated number of people receiving antiretroviral therapy in the developing world increased from 400000 to 700000 during the second half of 2004. However this number still represents only ~12% of the nearly 6 million people who are in dire need of antiretroviral treatment. (excerpt)

Background Assessments of understanding (AoUs) in clinical trials are often composed of true/false multiple choice questions, however, these tools can be difficult for volunteers with limited education or without prior testing experience. Methods 35 adults were recruited at two research centers in Southern Africa. A within-subjects, repeated measures design was used, whereby each volunteer served as his/ her own control. An AoU tool with closed- and openended questions was administered within a hypothetical AIDS vaccine trial setting. Performance on closed- and open-ended questions was compared using correlations and repeated-measure t-tests, limited to 4 complex concepts: false sense of security, risk of false positive test, need for contraception, and potentially enhanced susceptibility.

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a “relaxed” definition (accounting for off-prescription dosing) and 40 % per a “strict” definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP. Electronic supplementary material The online version of this article (doi:10.1007/s10461-014-0958-x) contains supplementary material, which is available to authorized users.

Background Compliance with ethical, regulatory, and scientific guidelines does not always guarantee consideration of external stakeholders’ concerns in research. In 2007, UNAIDS and AVAC: Global Advocacy for HIV Prevention developed the Good Participatory Practice (GPP) Guidelines to ensure community and stakeholder engagement in biomedical HIV prevention research. In 2010-2011, the International AIDS Vaccine Initiative (IAVI) and AVAC conducted the first comprehensive evaluation of perceptions, practices and recommendations for improvement of participatory practice at eight IAVI-sponsored research centers (RCs) in Eastern and Southern Africa.