Testing the waters: Ethical considerations for including PrEP in a phase IIb HIV vaccine efficacy trial.

BACKGROUND: The field of HIV prevention research has recently experienced some mixed results in efficacy trials of pre-exposure prophylaxis, vaginal microbicides, and HIV vaccines. While there have been positive trial results in some studies, in the near term, no single method will be sufficient to quell the epidemic. Improved HIV prevention methods, choices among methods, and coverage for all at-risk populations will be needed. The emergence of partially effective prevention methods that are not uniformly available raises complex ethical and scientific questions regarding the design of ongoing prevention trials. METHODS: We present here an ethical analysis regarding inclusion of pre-exposure prophylaxis in an ongoing phase IIb vaccine efficacy trial, HVTN 505. This is the first large vaccine efficacy trial to address the issue of pre-exposure prophylaxis, and the decisions made by the protocol team were informed by extensive stakeholder consultations. The key ethical concerns are analyzed here, and the process of stakeholder engagement and decision-making described. DISCUSSION: This discussion and analysis will be useful as current and future research teams grapple with ethical and scientific study design questions emerging with the rapidly expanding evidence base for HIV prevention.

Exploring barriers and facilitators to participation of male-to-female transgender persons in preventive HIV vaccine clinical trials.

Observed seroincidence and prevalence rates in male-to-female (MTF) transgender individuals highlight the need for effective targeted HIV prevention strategies for this community. In order to develop an effective vaccine that can be used by transgender women, researchers must understand and address existing structural issues that present barriers to this group's participation in HIV vaccine clinical trials. Overcoming barriers to participation is important for ensuring HIV vaccine acceptability and efficacy for the MTF transgender community. To explore barriers and facilitators to MTF transgender participation in preventive HIV vaccine clinical trials, the HIV Vaccine Trials Network conducted focus groups among transgender women in four urban areas (Atlanta, Boston, Philadelphia, and San Francisco). Barriers and facilitators to engagement of transgender women in preventive HIV vaccine clinical trials led to the following recommendations: (a) transgender cultural competency training, (b) creating trans-friendly environments, (c) true partnerships with local trans-friendly organizations and health care providers, (d) protocols that focus on transgender specific issues, and (e) data collection and tracking of transgender individuals. These results have implications for the conduct of HIV vaccine trials, as well as engagement of transgender women in research programs in general.

Rapid Development of a Registry to Accelerate COVID-19 Vaccine Clinical Trials.

Background: The unprecedented scientific response to the SARS-Cov-2 pandemic in 2020 required the rapid development and activation of extensive clinical trial networks to study vaccines and therapeutics. The COVID-19 Prevention Network (CoVPN) coordinated hundreds of sites conducting phase 2 and 3 clinical trials of vaccines and antibody therapeutics. To facilitate these clinical trials, the CoVPN Volunteer Screening Registry (VSR) was created to collect volunteer information at scale, identify volunteers at risk of COVID-19 who met enrollment criteria, distribute candidates across clinical trial sites, and enable monitoring of volunteering and enrollment progress. Methods: We developed a secure database to support three primary web-based interfaces: a national volunteer questionnaire intake form, a clinical trial site portal, and an Administrative Portal. The Site Portal supported filters based on volunteer attributes, visual analytics, enrollment status tracking, geographic search, and clinical risk prediction. The Administrative Portal supported oversight and development with pre-specified reports aggregated by geography, trial, and trial site; charts of volunteer rates over time; volunteer risk score calculation; and dynamic, user-defined reports. Findings: Over 650,000 volunteers joined the VSR, and 1094 users were trained to utilize the system. The VSR played a key role in recruitment for the Moderna, Oxford-AstraZeneca, Janssen, and Novavax vaccine clinical trials, provided support to the Pfizer and Sanofi vaccine and prophylactic antibody clinical trials, and enhanced the diversity of trial participants. Clinical trial sites selected 166,729 volunteer records for follow-up screening, and of these 47·7% represented groups prioritized for increased enrollment. Despite the unprecedented urgency of its development, the system maintained 99·99% uptime. Interpretation: The success of the VSR demonstrates that information tools can be rapidly yet safely developed through a public-private partnership and integrated into a distributed and accelerated clinical trial setting. We further summarize the requirements, design, and development of the system, and discuss lessons learned for future pandemic preparedness.

Increasing Black, Indigenous and People of Color participation in clinical trials through community engagement and recruitment goal establishment.

Longstanding social and economic inequities elevate health risks and vulnerabilities for Black, Indigenous and People of Color (BIPOC) communities. Engagement of BIPOC communities in infectious disease research is a critical component in efforts to increase vaccine confidence, acceptability, and uptake of future approved products. Recent data highlight the relative absence of BIPOC communities in vaccine clinical trials. Intentional and effective community engagement methods are needed to improve BIPOC inclusion. We describe the methods utilized for the successful enrollment of BIPOC participants in the U.S. Government (USG)-funded COVID-19 Prevention Network (CoVPN)-sponsored vaccine efficacy trials and analyze the demographic and enrollment data across the efficacy trials to inform future efforts to ensure inclusive participation. Across the four USG-funded COVID-19 vaccine clinical trials for which data are available, 47% of participants enrolled at CoVPN sites in the US were BIPOC. White enrollment outpaced enrollment of BIPOC participants throughout the accrual period, requiring the implementation of strategies to increase diverse and inclusive enrollment. Trials opening later benefitted considerably from strengthened community engagement efforts, and greater and more diverse volunteer registry records. Despite robust fiscal resources and a longstanding collaborative and collective effort, enrollment of White persons outpaced that of BIPOC communities. With appropriate resources, commitment and community engagement expertise, the equitable enrollment of BIPOC individuals can be achieved. To ensure this goal, intentional efforts are needed, including an emphasis on diversity of enrollment in clinical trials, establishment of enrollment goals, ongoing robust community engagement, conducting population-specific trials, and research to inform best practices.

Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody.

BACKGROUND: The Antibody-Mediated Prevention trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody targeting the CD4-binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland, and the United States. METHODS: Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of 10 infusions. Participants were followed for 104 weeks after first infusion. RESULTS: The median HVTN 704/HPTN 085 participant age was 28 years; 99% were assigned male sex; 90% identified as cisgender men, 5% as TG women and the remaining as other genders. Thirty-two percent were White, 15% Black, and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. More than 23,000 infusions were administered with no serious IV administration complications. Overall, retention and adherence to the study schedule exceeded 90%, and the dropout rate was below 10% annually (7.3 per 100 person-years) through week 80, the last visit for the primary end point. CONCLUSIONS: HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale monoclonal antibody trials for HIV prevention and/or treatment.

Standardized metrics can reveal region-specific opportunities in community engagement to aid recruitment in HIV prevention trials.

Good Participatory Practice (GPP) guidelines support and direct community engagement practices in biomedical HIV prevention trials, however no standardized metrics define the implementation and evaluation of these practices. Collaboratively, the Community Program staff of the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) created a metric to describe, monitor, and evaluate one component of GPP, recruitment practices, in two HIV monoclonal Antibody Mediated Prevention (AMP) clinical trials, HVTN 703/HPTN 081 and HVTN 704/HPTN 085. Through consultation with community representatives from each clinical research site (hereafter "site(s)"), who made up the study Community Working Groups, recruitment strategy descriptors were developed for both trials to characterize responses to "How did you hear about the AMP study?" The Community Working Groups also helped to define and establish time points that were selected to allow comparisons across sites. Data were collected by 43 of 46 clinical research sites from January 1, 2017 to February 28, 2018. All 43 sites used multiple recruitment strategies successfully, but strategies varied by region. Globally, referrals was the most efficient and effective recruitment strategy as evidenced by the screening: enrollment ratio of 2.2:1 in Africa, and 2.1:1 in the Americas/Switzerland. Print materials were also valuable globally (3:1 Africa, 4.2:1 Americas/Switzerland). In Africa, in-person outreach was also quite effective (2.3:1) and led to the most enrollments (748 of 1186, 63%). In the Americas/Switzerland, outreach was also effective (2.6:1), but internet use resulted in the most screens (1893 of 4275, 44%) and enrollments (677 of 1531, 44%), compared to 12 of 2887 (0.4%) and 2 of 1204 (0.1%) in Africa, respectively. Standardized metrics and data collection aid meaningful comparisons of optimal community engagement methods for trial enrollment. Internet strategies had better success in the Americas/Switzerland than in sub-Saharan African countries. Data are essential in outreach staff efforts to improve screening-to-enrollment ratios. Because the effectiveness of recruitment strategies varies by region, it is critical that clinical research sites tailor community engagement and recruitment strategies to their local environment, and that they are supported with resources enabling use of a range of approaches.

A Demographic Analysis of Racial/Ethnic Minority Enrollment Into HVTN Preventive Early Phase HIV Vaccine Clinical Trials Conducted in the United States, 2002-2016.

OBJECTIVES: Racial/ethnic minority communities in the United States are overrepresented among new HIV diagnoses, yet their inclusion in preventive HIV vaccine clinical trials is inadequate. An analysis of enrollment demographic characteristics from US preventive HIV vaccine clinical trials from 1988 through 2002 showed that enrollment of racial/ethnic minority groups increased. We analyzed enrollment in preventive HIV vaccine clinical trials from 2002 through 2016 and compared our data with data from the previous study, described demographic characteristics of trial participants, and assessed how well this distribution reflected the racial/ethnic distribution of new HIV diagnoses in the United States. METHODS: We examined data on demographic characteristics from 43 Phase 1 and Phase 2A preventive HIV vaccine clinical trials conducted in the United States and compared the results with those of the previous study. We also compared racial/ethnic distributions from 2011 through 2015 with Centers for Disease Control and Prevention data on the number of new HIV diagnoses during the same period. RESULTS: Of 3469 participants, 1134 (32.7%) identified as a racial/ethnic minority, a 94% increase from the previous period (634/3731; 17.0%). Percentage annual enrollment of all racial/ethnic minority participants fluctuated from 17% to 53% from mid-2002 to 2016. Percentages of new HIV diagnoses among the general population were 1.9 to 2.9 times the percentage enrollment of black participants and 1.3 to 6.6 times the percentage enrollment of Hispanic/Latino participants in clinical trials for the same period. CONCLUSIONS: Although enrollment of racial/ethnic minority groups into HIV vaccine clinical trials has increased, it is not proportional to the number of new HIV diagnoses among these groups. To enhance recruitment of racial/ethnic minority groups, the HIV Vaccine Trials Network has prioritized community partnerships and invested resources into staff training.

A descriptive analysis of transgender participants in phase 1-2a trials of the HIV Vaccine Trials Network (HVTN) in the United States and Peru.

BACKGROUND: HIV disproportionately impacts transgender populations globally, creating challenges to inclusion in trials requiring low HIV risk profiles (LHRP) for acquisition. Our knowledge of transgender individuals with LHRP is limited. We conducted an analysis of transgender and cisgender individuals in HVTN trials enrolling individuals with LHRP. METHODS: We analyzed data from 694 participants enrolled in the phase 1-2a HVTN trials in the US and Peru from 2009 to 2014 that included individuals who reported gender identity (GI) differing from assigned birth sex (transgender [TG]), and compared them with those who reported a congruent GI (cisgender [CG]). RESULTS: 681 participants (98%) were CG and 13 (2%) were TG. Mean age was 25 years. 16% were Hispanic and most (69%) were White. Reasons for enrolling included to help find an effective vaccine (TG 100%; CG 98%) and help their community (TG 100%; CG 96%). Significant differences by GI were observed in reported pre-existing conditions (p = 0.004); however, approximately 10% of pre-existing conditions reported by TG were GI-related (e.g., gender dysphoria). Significant differences were observed in hormone therapy use (p < 0.001) and mental health medications (p = 0.007). Retention was excellent with 2.1% missed visits and no discontinuations of vaccination for TG and 3% missed visits and 7.1% discontinuations among CG. There was no statistically significant difference in HIV incidence. CONCLUSIONS: Primary reasons for participation were altruistic for all participants. Comparable to CG counterparts, TG participants maintained LHRP, followed trial procedures, and had high retention, facilitating meaningful early phase HIV preventive vaccine trial contributions.

Engaging Transgender People in NIH-Funded HIV/AIDS Clinical Trials Research.

In 2009, the National Institutes of Health recognized the need to expand knowledge of lesbian, gay, bisexual, and transgender (LGBT) health and commissioned the Institute of Medicine to report on the health of these populations in the United States. The resulting Institute of Medicine publication called for more knowledge of the health of LGBT populations, as well as improved methodologies to reach them, more LGBT-focused research, and enhanced training programs and cultural competency of physicians and researchers. Several of the National Institutes of Health-funded HIV/AIDS clinical trials networks, including the Adolescent Medicine Trials Network for HIV/AIDS Interventions, HIV Prevention Trials Network, HIV Vaccine Trials Network, and Microbicide Trials Network, have focused attention on engaging transgender (TG) individuals in research. They have identified issues that transcend the nature of research (ie, treatment or prevention, adult or adolescent) and have adopted various approaches to effectively engage the TG community. Each network has recognized the importance of developing partnerships to build trust with and seek input from TG individuals on research plans and policies. They have established standing advisory groups and convened consultations for this purpose. To ensure that trial data are reflective of the participants they are seeking to enroll, they have reviewed and revised data collection forms to incorporate the 2-step method of collecting sex at birth and gender identity as 2 independent variables, and some have also revised research protocol templates and policies for concept development to ensure that they are appropriate for the inclusion of TG participants. The networks have also initiated trainings to enhance cultural sensitivity and developed a range of materials and resources for network and clinical research site staff. They continue to identify TG-specific research needs in an effort to be more responsive to and improve the health of TG individuals, particularly related to HIV/AIDS.

First-in-Human Evaluation of the Safety and Immunogenicity of a Recombinant Vesicular Stomatitis Virus Human Immunodeficiency Virus-1 gag Vaccine (HVTN 090).

Background. We report the first-in-human safety and immunogenicity evaluation of a highly attenuated, replication-competent recombinant vesicular stomatitis virus (rVSV) human immunodeficiency virus (HIV)-1 vaccine. Methods. Sixty healthy, HIV-1-uninfected adults were enrolled in a randomized, double-blinded, placebo-controlled dose-escalation study. Groups of 12 participants received rVSV HIV-1 gag vaccine at 5 dose levels (4.6 × 10(3) to 3.4 × 10(7) particle forming units) (N = 10/group) or placebo (N = 2/group), delivered intramuscularly as bilateral injections at 0 and 2 months. Safety monitoring included VSV cultures from blood, urine, saliva, and swabs of oral lesions. Vesicular stomatitis virus-neutralizing antibodies, T-cell immunogenicity, and HIV-1 specific binding antibodies were assessed. Results. Local and systemic reactogenicity symptoms were mild to moderate and increased with dose. No severe reactogenicity or product-related serious adverse events were reported, and all rVSV cultures were negative. All vaccine recipients became seropositive for VSV after 2 vaccinations. gag-specific T-cell responses were detected in 63% of participants by interferon-γ enzyme-linked immunospot at the highest dose post boost. Conclusions. An attenuated replication-competent rVSV gag vaccine has an acceptable safety profile in healthy adults. This rVSV vector is a promising new vaccine platform for the development of vaccines to combat HIV-1 and other serious human diseases.

Intentions to use preexposure prophylaxis among current phase 2B preventive HIV-1 vaccine efficacy trial participants.

In November 2010, the iPrEx study reported that preexposure prophylaxis (PrEP) with daily tenofovir disoproxil fumarate/emtricitabine reduced HIV infections by 44% among men who have sex with men and subsequent trials corroborated efficacy among heterosexual men and women. During regularly scheduled follow-up visits from January to March 2011, participants in an ongoing phase 2b vaccine efficacy trial completed an anonymous Web survey about PrEP. Among 376 respondents, 17% reported they were very likely to use PrEP in the next year. Nonwhite participants were more likely to use PrEP. Among those with some level of interest, intent to use PrEP was greatest if the drug were available through the clinical trial or health insurance. Most (91%) believed taking PrEP would not change their willingness to stay in the vaccine trial and few thought it would affect recruitment. As key stakeholders, currently enrolled trial participants can offer vital input about emerging prevention technologies that may affect the design of future HIV vaccine and nonvaccine prevention trials.