HIV Vaccine Clinical Trials Research Articles

Why did I participate in an HIV vaccine study? Experiences of participation in the first phase II HIV vaccine trial in Mozambique: An ancillary study using a mixed-method approach

IntroductionThis study recognized the lack of information regarding recruitment and retention factors associated with implementing HIV vaccine trials from the perspective of de facto participants. It aimed to describe the motives and experiences of 31 young adults who participated in a phase II HIV vaccine clinical trial conducted in Maputo, Mozambique. MethodsThis was an ancillary study with a mixed-method approach that employed a convergent design, combining both quantitative and qualitative methodologies. Data collection involved questionnaire surveys, in-depth interviews, and focus group discussions. Participants were assessed before and after learning whether they received the experimental vaccine or placebo. Thematic analysis was used for qualitative data, while descriptive analysis and statistical tests such as Fischer’s test and McNemar’s exact test were applied to quantitative data. The study also utilized the Health Belief Model to understand the decision-making process of participating in an HIV vaccine study. ResultsMost of our participants were young females, single, with limited financial resources. Participants joined the trial with the belief that they had a unique opportunity to help the fight against HIV and contribute to the research for the discovery of an HIV vaccine. Positive experiences related to trial participation include gaining knowledge about HIV and personal health and receiving risk reduction counseling. Participants reported blood collection as a negative experience and that they suffered social harm because of trial participation. Participants felt abandoned after the trial ended. ConclusionPreventive HIV vaccine trials should integrate a social-behavioral component to assess reasons for participation and refusal in real-time. Providing ongoing personal attention is crucial for young individuals who have committed 1–2 years to trial participation, extending beyond the trial period. Implementing tailored strategies for HIV risk assessment and reduction during and after the trial is essential. Addressing these factors can enhance preventive HIV vaccine trial implementation.

Evaluating enrollment and representation in COVID-19 and HIV vaccine clinical trials.

Vaccine clinical trials should strive to recruit a racially, socioeconomically, and ethnically diverse range of participants to ensure appropriate representation that matches population characteristics. Yet, full inclusion in research is often limited. A single-center retrospective study was conducted of adults enrolled at Brigham and Women's Hospital (Boston, MA) between July 2020 and December 2021. Demographic characteristics, including age, race, ethnicity, ZIP code, and sex assigned at birth, were analyzed from both HIV and COVID-19 vaccine trials during the study period, acknowledging the limitations to representation under these parameters. We compared the educational attainment of vaccine trial participants to residents of the Massachusetts metropolitan area, geocoded participants' addresses to their census block group, and linked them to reported median household income levels from publicly available data for 2020. Frequency and quartile analyses were carried out, and spatial analyses were performed using ArcGIS Online web-based mapping software (Esri). A total of 1030 participants from four COVID-19 vaccine trials (n = 916 participants) and six HIV vaccine trials (n = 114 participants) were included in the analysis. The median age was 49 years (IQR 33-63) and 28 years (IQR 24-34) for the COVID-19 and HIV vaccine trials, respectively. Participants identifying as White were the majority group represented for both the COVID-19 (n = 598, 65.3%) and HIV vaccine trials (n = 83, 72.8%). Fewer than 25% of participants identified as Hispanic or Latin. Based on ZIP code of residence, the median household income for COVID-19 vaccine clinical trial participants (n = 846) was 102,088 USD (IQR = 81,442-126,094). For HIV vaccine clinical trial participants (n = 109), the median household income was 101,266 USD (IQR 75,052-108,832). We described the characteristics of participants enrolled for HIV and COVID-19 vaccine trials at a single center and found similitude in geographical distribution, median incomes, and proportion of underrepresented individuals between the two types of vaccine candidate trials. Further outreach efforts are needed to ensure the inclusion of individuals from lower educational and socioeconomic brackets. In addition, continued and sustained efforts are necessary to ensure inclusion of individuals from diverse racial and ethnic backgrounds.

Generating and measuring effective vaccine-elicited HIV-specific CD8 + T cell responses.

There is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials. Much progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials. Identifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV.

HIV vaccines: Lessons from basic research, clinical trials, and public policy

Forty years since its discovery in 1983, HIV/AIDS still lacks a cure, despite advances in biomedicine that have dramatically improved global understanding of the virus’s biology. Decades of research and improvements to clinical trial infrastructure have promoted the development of novel vaccines for HIV, but these vaccines have shown limited efficacy. The landmark clinical trial “RV144” in Thailand (2003) showed modest efficacy of an HIV vaccine for the first time ever, sparking the formation of public-private partnerships and a wave of other HIV vaccine clinical trials. Around two decades later, the COVID-19 pandemic provided an impetus to move vaccine technology forward and exposed areas for improvement in vaccine and clinical-trial infrastructure. Looking at historical examples from both HIV and COVID-19 research, vaccine trials, and global statistics, it is clear that a successful vaccination campaign will require generous funding, collaboration, clinical trial infrastructure, sharing of data and resources amongst researchers, and policy based on scientific evidence and ethics. Such a successful campaign will also require overcoming several hurdles, such as delivering vaccines to individuals in countries with underdeveloped health care systems and both demographic and geographic disparities in access to care. The perspectives in this article are apropos given the recent development of HIV vaccines that have entered clinical trials.

Sexually transmitted infections amongst men who have sex with men (MSM) in South Africa.

There is limited data about bacterial STIs in MSM populations in sub-Saharan Africa. Our retrospective analysis used data from the HVTN 702 HIV vaccine clinical trial (October 2016 to July 2021). We evaluated multiple variables. Polymerase chain reaction testing was conducted on urine and rectal samples to detect Neisseria gonorrhoea (NG) and Chlamydia trachomatis (CT) every 6 months. Syphilis serology was conducted at month 0 and thereafter every 12 months. We calculated STI prevalence and the associated 95% confidence intervals until 24 months of follow-up. The trial enrolled 183 participants who identified as male or transgender female, and of homosexual or bisexual orientation. Of these, 173 had STI testing done at month 0, median age was 23 (IQR 20-25) years, with median 20.5 (IQR 17.5-24.8) months follow-up (FU). The clinical trial also enrolled and performed month 0 STI testing on 3389 female participants, median age 23 (IQR 21-27) years, median 24.8 (IQR 18.8-24.8) months FU and 1080 non-MSM males with a median age of 27 (IQR 24-31) years, median 24.8 (IQR 23-24.8) months FU. At month 0, CT prevalence was similar in MSM and females (26.0% vs 23.0%, p = 0.492) but was more prevalent in MSM compared to non-MSM males (26.0% vs 14.3%, p = 0.001). CT was the most prevalent STI among MSM at months 0 and 6 but declined from month 0 to month 6 (26.0% vs 17.1%, p = 0.023). In contrast, NG did not decline in MSM between months 0 and 6 (8.1% vs 7.1%, p = 0.680) nor did syphilis prevalence between months 0 and 12 (5.2% vs 3.8%, p = 0.588). Bacterial STI burden is higher in MSM compared to non-MSM males, and CT is the most prevalent bacterial STI amongst MSM. Preventive STI vaccines, especially against CT, may be helpful to develop.

A qualitative study of stakeholder and researcher perspectives of community engagement practices for HIV vaccine clinical trials in South Africa.

Community engagement increases community trust of research and improves trial participation. However, there is limited documented appraisal of community engagement practices. Several HIV vaccine efficacy trials have been conducted in South Africa, the country most affected by HIV, predominantly in collaboration with the HIV Vaccine Trials Network (HVTN). We explored stakeholder and researcher perspectives of the HVTN community engagement practices used in the Gauteng province of South Africa. In 2017, we conducted a qualitative study. Using semi-structured interview guides, we facilitated two group discussions with Community Advisory Board (CAB) members (n = 13), and 14 in-depth interviews with HVTN-affiliated employees (n = 8 in South Africa and n = 6 in the USA). Group discussions and in-depth interviews were audio-recorded, transcribed verbatim, translated into English, and coded using NVIVO 12 Plus software for thematic data analysis. Overall, median age of study participants was 22 (interquartile range 32-54) years, and 74% (n = 20) were female. Three main themes about community engagement emerged: (i) community engagement as an ongoing iterative relationship between researchers and community; (ii) methods of community engagement, encompassing community education by linking with external stakeholders and through awareness campaigns by pamphlet distribution and mass events, working with communities to develop recruitment messages, and working with CAB as a link to communities; and (iii) strategies to improve community engagement, for example, using simple language, linking with religious leaders and traditional healers, and communicating via conventional (newspapers, television, and radio) and social (videos and listicles) media. Our data indicate ways for researchers to improve relationships with community by understanding local needs, strengthening collaborations, and tailoring communication strategies. In this regard, CABs signify critical linkages between researchers and communities. CABs can relay relevant health research needs, advise on the creation of suitable materials, and link researchers more effectively with community leaders and media.

Developing capacity for implementation and evaluation of vaccine trials in Uganda: Perspective of the Makerere University Walter Reed Project.

Infectious diseases and neglected tropical diseases continue to be a major challenge in resource limited settings, causing significant morbidity and mortality. Although vaccines are a key biomedical prevention tool, resource limited settings often lack the infrastructure, regulatory frameworks, and skilled human resource to conduct vaccine clinical trials. To address this gap, the Makerere University Walter Reed Project (MUWRP) was established and has contributed to vaccine research in Uganda and globally. This was achieved through training a strong vaccine clinical trial workforce; development of requisite clinical trial infrastructure for research activities and management of investigational products; conducting phase I-III vaccine trials and contribution to national ethical and regulatory frameworks that protect participants. As of 2022, MUWRP had successfully conducted and completed five phase I/II HIV vaccine clinical trials, five for Ebola and Marburg, while one phase I/II Schistosomiasis and one phase III COVTD-19 vaccine clinical trial are ongoing. The completed vaccine trials provided critical scientific knowledge on the safety and immunogenicity of investigational products which informed the design of better vaccines for diseases of global health importance. Academia, through establishment of appropriate partnerships can contribute to the identification of solutions to complex public health challenges.

A varying-coefficient partially linear transformation model for length-biased data with an application to HIV vaccine studies.

Prevalent cohort studies in medical research often give rise to length-biased survival data that require special treatments. The recently proposed varying-coefficient partially linear transformation (VCPLT) model has the virtue of providing a more dynamic content of the effects of the covariates on survival times than the well-known partially linear transformation (PLT) model by allowing flexible interactions between the covariates. However, no existing analysis of the VCPLT model has considered length-biased sampling. In this paper, we consider the VCPLT model when the data are length-biased and right censored, thereby extending the reach of this flexible and powerful tool. We develop a martingale estimating function-based approach to the estimation of this model, provide theoretical underpinnings, evaluate finite sample performance via simulations, and showcase its practical appeal via an empirical application using data from two HIV vaccine clinical trials conducted by the U.S. National Institute of Allergy and Infectious Diseases.

Willingness to volunteer in future HIV vaccine clinical trials: A literature review and evidence synthesis

Context: Developing an effective vaccine for HIV/AIDS is a global endeavor requiring the participation of willing volunteers. Aims: To evaluate the willingness of the global population to undergo vaccination and participate in clinical trials. Methods: Following PRISMA guidelines, relevant studies published from January 2005 to December 2019 that reported quantitative, qualitative, and mixed analyses in peer-reviewed research papers were sought in the major databases. The inclusion criteria were that the studies be related to the willingness of participants to undergo HIV vaccination and submit to subsequent clinical trials, that they are in English, conducted in any geographic location, and published during the target period. The exclusion criteria were grey literature and studies involving the stakeholders, medical students or medical fraternities, seropositive parents with seronegative offspring, the vaccine’s biochemical, immunological, or financial aspects, and participants below the age of 16. Systematic reviews, letters to the editor, and case studies were also excluded. Results: The selected databases initially yielded 334 articles, of which 27 remained after applying the inclusion and exclusion criteria. Demographic data, motivating factors, and the volunteers’ willingness levels were collected and analyzed. Conclusions: This review offers guidance for future research, including a standardized scale to predict the willingness of potential volunteer groups.

"An Extra Variable to Consider"-Vaccine-Induced Seropositivity and Adolescent HIV Vaccine Clinical Trials.

Our study explores the understanding of vaccine-induced seropositivity (VISP) and its potential impact on US adolescents' and caregivers' willingness to participate in adolescent HIV vaccine clinical trials. Findings from in-depth interviews suggest that addressing concerns about VISP will be essential for future pediatric HIV vaccine trials in the United States.

Strengthening laboratory capacity for HIV vaccine clinical trials and epidemiological studies in Eastern and Southern Africa

Background: Conducting successful HIV vaccine clinical trials in resource-limited settings is hampered by lack of adequate laboratory capacity at trial sites, poor infrastructure, lack of well-trained technical personnel, and inadequate laboratory quality management Systems. We describe our approach to establishing sustainable laboratory capacity for clinical trials in Africa. Methods: IAVI identified 9 CRCs where a capacity building program that supports immunology and clinical testing was established. Information from the 9 CRCs was collected retrospectively and compiled in Microsoft excel for descriptive statistics. Mapping was done in Quantum Geographic information system. Results: Newly built and refurbished laboratories have been equipped with the required testing laboratory equipment. All CRC laboratories (n=10, 100%) received Good Clinical Laboratory Practice (GCLP) accreditation between 2004 and 2016, and accreditation maintained annually. A total of 89 audits were done between 2005-2019. KAVI and KEMRI had the highest number of audits (n=11, 12.4%). IAVI successfully trained a total of 1811 individual, of which (n=1130, 62.7%) trained on GCLP, (n=330, 18.3%) Quality Management Systems, (n=311, 17,2%) laboratory techniques and (n=32,1.8%) between 2004 and 2021. All the 13 Assays were registered in either College of American pathologist (CAP) or Royal college of pathologists of Australasia (RCPA) for Proficiency testing. Conclusion: The establishment of GCLP accredited laboratories and well-trained personnel has created centers of excellence and it has enabled them to attract independent competitive research funding. The GCLP accreditation and standardized testing procedures ensured reliable and accurate data, especially important for multi-country and multi-center studies.

Current approaches to HIV vaccine development: a narrative review.

IntroductionThe development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the execution of vaccine efficacy testing in the context of evolving biomedical prevention interventions. This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps.MethodsWe conducted a targeted peer‐reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors’ own experience and engagement with collaborators in HIV vaccine research.DiscussionThe HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime‐boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates.ConclusionsHIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. These strategies have yielded novel mosaic antigen constructs now in efficacy testing, produced a diverse pipeline of early‐stage immunogens and novel adjuvants, and advanced the field towards a globally effective HIV vaccine.

Performance of International AIDS Vaccine Initiative African clinical research laboratories in standardised ELISpot and peripheral blood mononuclear cell processing in support of HIV vaccine clinical trials.

BackgroundStandardisation of procedures for performing cellular functional assays across laboratories participating in multicentre clinical trials is key for generating comparable and reliable data.ObjectiveThis article describes the performance of accredited laboratories in Africa and Europe on testing done in support of clinical trials.MethodsFor enzyme-linked immunospot assay (ELISpot) proficiency, characterised peripheral blood mononuclear cells (PBMCs) obtained from 48 HIV-negative blood donors in Johannesburg, South Africa, were sent to participating laboratories between February 2010 and February 2014. The PBMCs were tested for responses against cytomegalovirus, Epstein Barr and influenza peptide pools in a total of 1751 assays. In a separate study, a total of 1297 PBMC samples isolated from healthy HIV-negative participants in clinical trials of two prophylactic HIV vaccine candidates in Kenya, Uganda, Rwanda and Zambia were analysed for cell viability, cell yield and cell recovery from frozen PBMCs.ResultsMost (99%) of the 1751 ELISpot proficiency assays had data within acceptable ranges with low responses to mock stimuli. No significant statistical difference were observed in ELISpot responses at the five laboratories actively conducting immunological analyses. Of the 1297 clinical trial PBMCs processed, 94% had cell viability above 90% and 96% had cell yield above 0.7 million per mL of blood in freshly isolated cells. All parameters were within the predefined acceptance criteria.ConclusionWe demonstrate that multiple laboratories can generate reliable, accurate and comparable data by using standardised procedures, having regular training, having regular equipment maintenance and using centrally sourced reagents.

Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial.

Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007–2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20–26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21–30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625–2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265–2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126–4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3–20.1) vs. 16.5 (95% CI: 14.6–18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3–29.2) vs. 14.8 (95% CI: 13.0–16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.

Advances in HIV Vaccine Clinical Trials

Advances in HIV Vaccine Clinical Trials

Coronavirus Disease 2019 and Vaccination of Children and Adolescents: Prospects and Challenges

Coronavirus Disease 2019 and Vaccination of Children and Adolescents: Prospects and Challenges

Exploring the Engagement of Racial and Ethnic Minorities in HIV Treatment and Vaccine Clinical Trials: A Scoping Review of Literature and Implications for Future Research.

HIV disproportionately impacts US racial and ethnic minorities but they participate in treatment and vaccine clinical trials at a lower rate than whites. To summarize barriers and facilitators to this participation we conducted a scoping review of the literature guided by the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Studies published from January 2007 and September 2019 were reviewed. Thirty-one articles were identified from an initial pool of 325 records using three coders. All records were then assessed for barriers and facilitators and summarized. Results indicate that while racial and ethnic minority participation in these trials has increased over the past 10 years, rates still do not proportionately reflect their burden of HIV infection. While many of the barriers mirror those found in other disease clinical trials (e.g., cancer), HIV stigma is a unique and important barrier to participating in HIV clinical trials. Recommendations to improve recruitment and retention of racial and ethnic minorities include training health care providers on the importance of recruiting diverse participants, creating interdisciplinary research teams that better represent who is being recruited, and providing culturally competent trial designs. Despite the knowledge of how to better recruit racial and ethnic minorities, few interventions have been documented using these strategies. Based on the findings of this review, we recommend that future clinical trials engage community stakeholders in all stages of the research process through community-based participatory research approaches and promote culturally and linguistically appropriate recruitment and retention strategies for marginalized populations overly impacted by HIV.

Post-randomization Biomarker Effect Modification Analysis in an HIV Vaccine Clinical Trial.

While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, markers measuring immune response to vaccination were strongly correlated with infection. This finding generated the hypothesis that some marker-defined vaccinated subgroups were partially protected whereas others had their risk increased. This hypothesis can be assessed using the principal stratification framework (Frangakis and Rubin, 2002) for studying treatment effect modification by an intermediate response variable, using methods in the sub-field of principal surrogate (PS) analysis that studies multiple principal strata. Unfortunately, available methods for PS analysis require an augmented study design not available in HVTN 505, and make untestable structural risk assumptions, motivating a need for more robust PS methods. Fortunately, another sub-field of principal stratification, survivor average causal effect (SACE) analysis (Rubin, 2006) - which studies effects in a single principal stratum - provides many methods not requiring an augmented design and making fewer assumptions. We show how, for a binary intermediate response variable, methods developed for SACE analysis can be adapted to PS analysis, providing new and more robust PS methods. Application to HVTN 505 supports that the vaccine partially protected individuals with vaccine-induced T-cells expressing certain combinations of functions.

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

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. 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. 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. 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.

Regulatory T cell abundance and activation status before and after priming with HIVIS-DNA and boosting with MVA-HIV/rgp140/GLA-AF may impact the magnitude of the vaccine-induced immune responses

BackgroundLittle is known about regulatory CD4 T cells (Tregs) in the context of HIV vaccines. Tregs can be differentiated into resting (FoxP3+CD45RA+ – rTregs), activated (FoxP3HighCD45RA− – aTregs) and memory (FoxP3LowCD45RA− – mTregs). Tregs, as CD4 T cells, are also frequent targets for HIV infection. We studied how the abundance and phenotypes of Tregs in terms of activation status and expression of HIV-1 binding molecules would have changed during vaccination in healthy volunteers participating in a phase IIa HIV vaccine clinical trial. Subjects were primed three times with HIVIS-DNA and boosted twice with MVA-CMDR-HIV alone (n = 12) or MVA-CMDR combined with protein CN54rgp140 (n = 13). The proportions of β7 integrin in all CD4 T cells and in the Tregs subset decreased moderately after the final vaccination (p = 0.001 and p = 0.033, respectively) and the rTregs proportion within the total Tregs were also decreased after the final vaccination (p = 0.038). All these proportions returned to normal values within the three months after the final vaccination. The magnitude of HIV-Envelope-specific IFNγ + T cells after vaccination (r = 0.66; p = 0.021) correlated directly with the proportion of Tregs, and correlated inversely correlated with ratios of Th17/Tregs (r = −0.75; p = 0.0057) and Th17/mTregs (r = −0.78; p = 0.0065). Higher titers of IgG gp140 antibodies were observed in subjects with higher mTregs proportions (r = 0.52; p = 0.022). Interestingly, pre-vaccination levels of mTregs correlated with vaccine-induced Env-binding antibodies (r = 0.57; p = 0.01) and presence of neutralizing antibodies (r = 0.61; p = 0.01), while the pre-vaccination Th17/mTregs ratio correlated inversely with the magnitude of cellular IFN-γ ELISpot responses (r = −0.9; p = 0.002). Taken together, these results suggest that pre- and post-vaccination Tregs, their activation status, the Th17/Tregs ratio and other host factors affecting Treg abundance, have an impact on the magnitude of HIV vaccine-induced immune responses. Moreover, the DNA-HIVIS/MVA-HIV regimen, alone or in combination with CN54rgp140 induced moderate and temporary alterations of the Tregs activation status. We also show a decrease in expression of the HIV-1 ligand β7 integrin on Tregs and all CD4 T cells.