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The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies., Competing Interests: Declaration of interests A.T. has received unrelated unrestricted research grants from the SNSF, Bill and Melinda Gates Foundation, Gilead Sciences, Novartis Biomedical Research Foundation, University of Zurich (UZH) Foundation, UZH Clinical Research Priority Program, the SHCS, honoraria from Roche Diagnostics and the Institute for biomedical research Bellinzona for consultant and scientific board activity, and directs the Swiss National Reference Center for Retroviruses together with M.H. H.F.G. has received unrelated unrestricted research grants from the SNSF, the SHCS, Yvonne Jacob Foundation, University of Zurich Clinical Research Priority Program, Systems.X, the National Institutes of Health, Gilead Sciences, and Roche. H.F.G. has further received personal fees from Merck, Gilead Sciences, ViiV, Janssen, GSK, Johnson and Johnson, and Novartis for consultancy or DSMB membership and a travel grant from Gilead. M.H. directs the Swiss National Reference Center for Retroviruses and has received unrelated unrestricted research grant from the UZH Clinical Research Priority Program, the SNSF, the SHCS, and the ETH PHRT. I.A.A. has received honoraria from MSD and Sanofi, a travel grant from Gilead Sciences, a grant from ProMedica Foundation, and she is member of the EKIF (Eidgenössische Kommission für Impffragen) of the Federal Office of Public Health. R.D.K. has received grants from SNSF, the National Institutes of Health, and Gilead Sciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The case-cohort design is a commonly used cost-effective sampling strategy for large cohort studies, where some covariates are expensive to measure or obtain. In this paper, we consider regression analysis under a case-cohort study with interval-censored failure time data, where the failure time is only known to fall within an interval instead of being exactly observed. A common approach to analyzing data from a case-cohort study is the inverse probability weighting approach, where only subjects in the case-cohort sample are used in estimation, and the subjects are weighted based on the probability of inclusion into the case-cohort sample. This approach, though consistent, is generally inefficient as it does not incorporate information outside the case-cohort sample. To improve efficiency, we first develop a sieve maximum weighted likelihood estimator under the Cox model based on the case-cohort sample and then propose a procedure to update this estimator by using information in the full cohort. We show that the update estimator is consistent, asymptotically normal, and at least as efficient as the original estimator. The proposed method can flexibly incorporate auxiliary variables to improve estimation efficiency. A weighted bootstrap procedure is employed for variance estimation. Simulation results indicate that the proposed method works well in practical situations. An application to a Phase 3 HIV vaccine efficacy trial is provided for illustration., Competing Interests: Declaration of conflicting interestsThe author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite a growing body of literature in the area of recruitment modeling for multicenter studies, in practice, statistical models to predict enrollments are rarely used and when they are, they often rely on unrealistic assumptions. The time-dependent Poisson-Gamma model (tPG) is a recently developed flexible methodology which allows analysts to predict recruitments in an ongoing multicenter trial, and its performance has been validated on data from a cohort study. In this article, we illustrate and further validate the tPG model on recruitment data from randomized controlled trials. Additionally, in the appendix, we provide a practical and easy to follow guide to its implementation via the tPG R package. To validate the model, we show the predictive performance of the proposed methodology in forecasting the recruitment process of two HIV vaccine trials conducted by the HIV Vaccine Trials Network in multiple Sub-Saharan countries., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite increased uptake of antiretroviral therapy (ART) among pregnant people living with human immunodeficiency virus (HIV), vertical transmission remains the most important route of pediatric HIV acquisition. The numbers of HIV acquisitions in infancy have remained alarmingly stagnant in recent years. It is evident that additional strategies that can synergize with ART will be required to end the pediatric HIV epidemic. In this review, we discuss the potential for immune-based interventions that can be administered in conjunction with current ART-based strategies to the birthing parent for prevention of vertical transmission of HIV-1, and the potential challenges associated with each approach., Competing Interests: Disclosure S.R. Permar serves as a consultant to Moderna, Merck, Pfizer, Dynavax, and GSK vaccine programs for CMV, and leads sponsored research programs with Moderna, United States, Dynavax, and Pfizer, United States on CMV vaccines. All other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Globally, the number of new HIV infections remains unacceptably high, and urgent new approaches are needed to advance HIV vaccine science. However, the development of a preventive HIV vaccine has proven to be an intractable scientific challenge. Recent advances in HIV immunogen design have taken the field a step closer to triggering the rare precursors of broadly neutralising antibodies, which are widely assumed to be necessary for a vaccine. Nonetheless, these same studies and previous studies in people living with HIV have also highlighted the major hurdles that must be overcome to boost the cross-reactivity and potency of these responses to sufficient levels. Here, we describe an opportunity for fast-tracking the evaluation of candidate preventive and therapeutic vaccines by immunising people with HIV who are antiretroviral therapy suppressed. We argue that such studies, unlike traditional studies of vaccines in participants not infected with HIV, will be faster and more informative and will allow the vaccine field to bypass multiple hurdles. This approach will accelerate the process of defining the capacity of immunogens to trigger relevant antibodies, currently an extremely slow and expensive pathway, and provide a quick path to creating an HIV vaccine., Competing Interests: Declaration of interests PLM is supported for unrelated HIV research by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa, the South African Medical Research Council, the Centre for the AIDS Program of Research, and the Duke Consortia for HIV/AIDS Vaccine Development. Through the International AIDS Vaccine Initiative, PLM is funded by the US Agency for International Development. PLM is also funded by the European & Developing Countries Clinical Trials Partnership and the Bill & Melinda Gates Foundation-funded Collaboration for AIDS Vaccine Discovery and Comprehensive Cellular Vaccine Immune Monitoring Consortium. AT is currently supported for unrelated HIV research by the Swiss National Science Foundation, the Swiss HIV Cohort Study, and the EU's Horizon 2020 research and innovation programme under grant agreement number 681032 and (through the State Secretariat for Education, Research and Innovation) grant agreement number 15.0337 from the Swiss Government. PLM and AT are planning to engage in RENEW trials in the future., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Informed consent as stipulated in regulatory human research guidelines requires volunteers to be well-informed about what will happen to them in a trial. However, researchers may be faced with the challenge of how to ensure that a volunteer agreeing to take part in a clinical trial is truly informed. This study aimed to find out volunteers' comprehension of informed consent and voluntary participation in Human Immunodeficiency Virus (HIV) clinical trials during the registration cohort., Methods: We conducted a qualitative study among volunteers who were enrolled in the registration cohort of HIV clinical trials in Dar es Salaam, Tanzania. A purposive sampling strategy was used to obtain twenty study participants. The data were collected between June and September 2020 using a semi-structured interview guide. In-depth interviews were used to collect the data to obtain deep insights of the individual study participants on the comprehension of informed consent and participation in the clinical trial. A thematic analysis approach was used to analyze the data. Themes and subthemes were supported by the quotes from the participants., Results: Volunteers described comprehension of informed consent from different perspectives. They reported that various components of the informed consent such as study procedure, confidentiality, risk and benefits were grasped during engagement meetings. Furthermore, the volunteers' decision to participate in the registration cohort was voluntary. However, trial aspects such as health insurance, free condoms, and medical checkups could have indirectly influenced their reluctance to withdraw from the study., Conclusion: Engagement meetings may increase the comprehension of informed consent among potential participants for HIV clinical trials. However, trial incentives may influence participation, and thus future research should focus on the challenges of giving incentives in the study. This will ensure comprehension and voluntary participation in the context of HIV clinical trials., (© 2024. The Author(s).)

Background: A cohort of female sex workers (FSWs) was established to determine HIV prevalence and incidence, and associated factors in preparation for a phase IIb HIV vaccine and pre-exposure prophylaxis trial (PrEPVacc)., Setting: A cohort of FSWs in Dar es Salaam, Tanzania., Methods: FSWs aged 18-45 years were recruited using a respondent-driven sampling method. Social demographic data, HIV risk behavioral assessments, and blood samples for testing of HIV, syphilis, hepatitis B (HBV), and hepatitis C (HCV) infections were collected at baseline and then at 3, 6, 9, and 12 months. Poisson regressions were used to estimate the prevalence ratios for factors associated with HIV prevalence and to estimate the 12-month HIV incidence rate., Results: Between October and December 2018, a total of 773 FSWs were screened for eligibility and 700 were enrolled. The baseline prevalence of HIV, syphilis, HBV, and HCV was 7.6%, 1.2%, 1.7%, and 1.0%, respectively. HIV prevalence was associated with older age, using illicit drugs, and being infected with syphilis, HBV, or HCV. Attendance at 12 months was 80% (562/700). Twenty-one FSWs seroconverted during follow-up, giving a 12-month HIV incidence rate of 3.45 per 100 person-years at risk (95% CI; 2.25-5.28/100 person-years at risk). The HIV incidence rate was higher among FSWs aged 18-24 years, FSWs who used drugs, and those diagnosed with syphilis, HBV, or HCV., Conclusion: The high HIV incidence rate and retention rate among FSWs enrolled into the cohort demonstrate that this population is suitable for participation in HIV prevention trials., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: PrEP literacy is influenced by many factors including the types of information available and how it is interpreted. The level of PrEP literacy may influence acceptability and uptake., Methods: We conducted 25 in-depth interviews in a HIV vaccine trial preparedness cohort study. We explored what participants knew about PrEP, sources of PrEP knowledge and how much they know about PrEP. We used the framework approach to generate themes for analysis guided by the Social Ecological Model and examined levels of PrEP literacy using the individual and interpersonal constructs of the SEM., Results: We found that PrEP awareness is strongly influenced by external factors such as social media and how much participants know about HIV treatment and prevention in the local community. However, while participants highlighted the importance of the internet/social media as a source of information about PrEP they talked of low PrEP literacy in their communities. Participants indicated that their own knowledge came as a result of joining the HIV vaccine trial preparedness study. However, some expressed doubts about the effectiveness of the drug and worried about side effects. Participants commented that at the community level PrEP was associated with being sexually active, because it was used to prevent the sexual transmission of HIV. As a result, some participants commented that one could feel judged by the health workers for asking for PrEP at health facilities in the community., Conclusion: The information collected in this study provided an understanding of the different layers of influence around individuals that are important to address to improve PrEP acceptability and uptake. Our findings can inform strategies to address the barriers to PrEP uptake, particularly at structural and community levels., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04066881., (© 2022. The Author(s).)

Purpose of the Review: To discuss main challenges of therapeutic vaccine clinical trials design, implementation and analyses in the HIV cure field., Recent Findings: Therapeutic vaccines are progressively being postulated as T-cell stimulating agents to use in combination HIV cure strategies, with the addition of immunomodulators, latency reversing agents and/or broadly neutralizing antibodies. Although promising strategies are rapidly evolving in preclinical studies using nonhuman primate models, translation into human testing in randomized controlled clinical trials is more challenging and expensive to conduct. Adaptive designs, access to cohorts of early-treated individuals, consensus on how to safely conduct analytical treatment interruptions, use of alternative statistical methods, development of point-of-care/home-based testing technologies and ensuring early engagement of communities where research is being developed are some of the critical aspects to consider to facilitate clinical trial development in the HIV cure field., Summary: Design and development of HIV therapeutic vaccine clinical trials poses many challenges, from Phase 0/pilot studies to Phase I/II trials in which efficacy of the intervention is being tested and antiretroviral therapy cessation is needed, complexity of cure trials progressively increases. Understanding fundamental issues and careful planning of therapeutic vaccine clinical trials is crucial to minimize design flaws, reduce loss of follow-ups and missing data while ensuring participant's safety and guarantee valid and accurate analyses and thus, better contribute towards an HIV cure., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Although highly active antiretroviral therapy has transformed HIV-1 infection into a manageable chronic disease, the development of an effective vaccine is still an important and challengeable research field of HIV-1 treatment. The challenge arises from an enormous diversity of HIV-1 strains and their rapid evolution ahead of effective immune responses. HIV-1 evasion from host immunity contributes to viral spread and pathogenesis, thus understanding the mechanisms of HIV-1 immune evasion is important. In this review, we summarized our present knowledge on the mechanisms how HIV-1 escapes immune responses. Such knowledge will help with the design of effective vaccines capable of inducing immune control of HIV-1.

Background: Daily oral pre-exposure prophylaxis (PrEP) use is highly effective against HIV infection. However, the uptake of PrEP among individuals at high-risk of HIV acquisition in sub-Saharan Africa varies because of availability and acceptability. We assessed the acceptability of PrEP among participants in a prospective HIV vaccine preparedness study in Masaka, southwestern Uganda., Methods: From November 2018 to August 2019, 20 participants (10 female) were purposively selected for in-depth interviews (IDIs) at 3 and 9 months' post-enrolment in the vaccine preparedness study. Four focus group discussions (FGD) (two among men) were conducted with 29 individuals categorized as: younger (18-24 years) men, younger (18-24 years) women, older (≥30 years) men, and older (≥30 years) women. Apart from IDI specific questions on recent life history including work experience, relationship history and places lived, topics for IDIs and FGDs included knowledge of HIV, perceptions of HIV risk (including own risk), knowledge of and use of PrEP. The Theoretical Framework of Acceptability was used to structure a thematic framework approach for data analysis., Results: Participants understood that PrEP was an oral pill taken daily by HIV negative individuals to prevent acquisition of HIV. Overall, interest in and acceptability of PrEP was high, more than half expressed positivity towards PrEP but were not ready to initiate taking it citing the burden of daily oral pill taking, related side effects, stigma and distrust of PrEP. Fourteen participants (from IDI and FGD) initiated PrEP, although some (one FGD and two IDI participants) stopped taking it due to side effects or perceived reduced risk., Conclusion: We observed a keen interest in PrEP initiation among our study participants. However, a limited understanding of PrEP and associated concerns impeded uptake and sustained use. Hence, interventions are needed to address end-user challenges to increase uptake and support adherence., Competing Interests: The authors have declared that no competing interests exist.

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up (LTFU) in an HIV vaccine-preparedness study in Masaka, Uganda., Methods: Between July 2018 and March 2021, HIV sero-negative adults (18-45 years) at high risk of HIV infection were identified through HIV counselling and testing (HCT) from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria. Study procedures included collection of baseline socio-demographic data, quarterly HCT, and 6-monthly collection of sexual risk behaviour data. Retention strategies included collection of detailed locator data, short clinic visits (1-2 h), flexible reimbursement for transport costs, immediate (≤7 days) follow-up of missed visits via phone and/or home visits, and community engagement meetings. LTFU was defined as missing ≥2 sequential study visits. Poisson regression models were used to identify baseline factors associated with LTFU., Results: 672 participants were included in this analysis. Of these, 336 (50%) were female and 390 (58%) were ≤24 years. The median follow-up time was 11 months (range: 0-31 months). A total 214 (32%) participants were LTFU over 607.8 person-years of observation (PYO), a rate of 35.2/100 PYO. LTFU was higher in younger participants (18-24 years versus 35-45 years, adjusted rate ratio (aRR) = 1.29, 95% confidence interval (CI) 0.80-2.11), although this difference was not significant. Female sex (aRR = 2.07, 95% CI, 1.51-2.84), and recreational drug use (aRR = 1.61, 95% CI, 1.12-2.34) were significantly associated with increased LTFU. Engagement in transactional sex was associated with increased LTFU (aRR = 1.36, 95% CI, 0.97-1.90) but this difference was not significant. LTFU was higher in 2020-2021 (the period of COVID-19 restrictions) compared to 2018-2019 (aRR = 1.54, 1.17-2.03). Being Muslim or other (aRR = 0.68, 95% CI 0.47-0.97) and self-identification as a sex worker (aRR = 0.47, 95% CI, 0.31-0.72) were associated with reduced LTFU., Conclusion: We observed a high LTFU rate in this cohort. LTFU was highest among women, younger persons, recreational drug users, and persons who engage in transactional sex. Efforts to design retention strategies should focus on these subpopulations.

Since the beginning of the HIV/AIDS epidemy in the eighties, hundreds of phase I human immunization studies were performed, however, only nine tested efficacy in phase IIb/III clinical trials. While immunogens for SARS-CoV-2 did move along the development and clinical trial pipeline at unprecedent speed, two HIV immunization vaccine trials, started in 2016 and 2017, did meet non-efficacy criteria at the interim analysis and were thus, halted by the Data and Safety Monitoring Boards. The challenges in the quest to develop a safe, effective and durable HIV vaccine are unchanged. However, as research on HIV vaccine discovery moves forward there are many new tools and platform technologies to iterate vaccine strategies faster. Among these, there is a growing interest to conduct experimental medicine approaches where product development is directly informed by human data at an early stage of product development.

Due to the success of combined antiretroviral therapy (cART) in recent years, the pathological outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved substantially, achieving undetectable viral loads in most cases. Nevertheless, the presence of a viral reservoir formed by latently infected cells results in patients having to maintain treatment for life. In the absence of effective eradication strategies against HIV-1, research efforts are focused on obtaining a cure. One of these approaches is the creation of therapeutic vaccines. In this sense, the most promising one up to now is based on the establishing of the immunological synapse between dendritic cells (DCs) and T lymphocytes (TL). DCs are one of the first cells of the immune system to encounter HIV-1 by acting as antigen presenting cells, bringing about the interaction between innate and adaptive immune responses mediated by TL. Furthermore, TL are the end effector, and their response capacity is essential in the adaptive elimination of cells infected by pathogens. In this review, we summarize the knowledge of the interaction between DCs with TL, as well as the characterization of the specific T-cell response against HIV-1 infection. The use of nanotechnology in the design and improvement of vaccines based on DCs has been researched and presented here with a special emphasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Espinar-Buitrago and Muñoz-Fernández.)

Introduction: Vaccine efficacy testing requires engagement of willing volunteers with high disease incidence. We evaluated factors associated with willingness to participate in potential future HIV vaccine trials in Maputo, Mozambique., Methods: Adults aged 18-35 years without HIV and who reported at least two sexual partners in the 3 months prior to screening were enrolled into a 24-month observational study. They were asked at screening and exit if they would be willing to participate in a theoretical HIV vaccine study. Bivariate and multivariate logistic regression analyses were done between willingness to participate, demographic, sexual behavior, and motivational factors for screening visit data. Logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for factors potentially associated with willingness to participate for data from both visits., Results: A total of 577 participants without HIV were eligible, including 275 (48%) women. The mean age was 22.2 (SD ± 3.9) years. At screening 529 (92%) expressed willingness to participate and the proportion remained stable at 378 (88%) of the 430 participants retained through the exit visit (p = 0.209). Helping the country (n = 556) and fear of needles (n = 26) were the top motive and barrier for willingness to participate, respectively. Results from the GEE binary logistic regression (screening visit and exit visit) showed that wanting to learn how to avoid risk behaviors (aOR 3.33, 95% CI: 1.61-6.86) and feeling protected against HIV infection (aOR 2.24, 95% CI: 1.07-4.7) were associated with willingness to participate in HIV vaccine studies., Conclusion: The majority of our study population in Mozambique expressed willingness to participate in a theoretical HIV vaccine trial. Participation in a HIV vaccine trial was seen as a way to contribute to the fight against HIV but was associated with some unrealistic expectations such as protection against HIV. This reinforces the need for continuous mobilization and awareness of potential participants to HIV vaccine trial., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The broadly neutralizing antibody PG9 recognizes a unique glycopeptide epitope in the V1V2 domain of HIV-1 gp120 envelope glycoprotein. The present study describes the design, synthesis, and antibody-binding analysis of HIV-1 V1V2 glycopeptide-Q β conjugates as a mimic of the proposed neutralizing epitope of PG9. The glycopeptides were synthesized using a highly efficient chemoenzymatic method. The alkyne-tagged glycopeptides were then conjugated to the recombinant bacteriophage (Q β ), a virus-like nanoparticle, through a click reaction. Antibody-binding analysis indicated that the synthetic glycoconjugates showed significantly enhanced affinity for antibody PG9 compared with the monomeric glycopeptides. It was also shown that the affinity of the Q β -conjugates for antibody PG9 was dependent on the density of the glycopeptide antigen display. The glycopeptide-Q β conjugates synthesized represent a promising candidate of HIV-1 vaccine.

Identification of vulnerable sites defined by broadly neutralizing antibodies (bNAbs) on HIV-1 envelope (Env) is crucial for vaccine design, and we present here a vulnerable site defined by bNAb M4008_N1, which neutralizes about 40% of a tier-2 virus panel. A 3.2 Å resolution cryo-EM structure of M4008_N1 in complex with BG505 DS-SOSIP reveals a large, shallow protein epitope surface centered at the V3 crown of gp120 and surrounded by key glycans. M4008_N1 interacts with gp120 primarily through its hammerhead CDR H3 to form a β-sheet interaction with the V3 crown hairpin. This makes M4008_N1 compatible with the closed conformation of the prefusion Env trimer, and thus distinct from other known V3 crown mAbs. This mode of bNAb approaching the immunogenic V3 crown in the native Env trimer suggests a strategy for immunogen design targeting this site of vulnerability., (© 2021. The Author(s).)

A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates., Competing Interests: SS, PE, AG, LY, GK, KM, SF, KN, LW, SS, EL, PP, SN, SC, SR, MR, DD, PG, GT, NM, SV, RT No competing interests declared

Background: Pregnancies occur during HIV-1 vaccine clinical trials, despite requirements for women of reproductive potential to use effective contraception. Deployment of an effective HIV-1 vaccine regimen will likely target adolescents and young adults and therefore safety for pregnant and breastfeeding women will need to be addressed., Methods: We performed a retrospective, cross-protocol analysis to identify and compare pregnancy outcomes reported in 53 Phase 1 and Phase 2a HIV-1 vaccine clinical trials conducted by the HIV Vaccine Trials Network (HVTN)., Results: Two thousand six hundred seventy-three women of reproductive potential were identified and 193 pregnancies were reported. 39 of 53 (74%) studies had at least one pregnancy reported with an overall pregnancy rate of 3.15 per 100 woman-years (w-yr). While active contraception use was required during study participation, 13 of the 53 studies also contained a long-term follow up period during which pregnancy was no longer discouraged. The pregnancy rate during main study participation was 3.09 per 100 w-yr, while pregnancies occurred at a slightly greater rate in the long-term follow up period (3.22 per 100 w-yr). Adverse pregnancy outcomes were reported at similar rates between vaccinees and placebo recipients when vaccine vectors, adjuvant used, or geographic region were examined., Conclusion: Although there is considerable heterogeneity amongst the different vaccine trials, there appears to be no obvious indication of increased risk of adverse pregnancy or birth outcomes in these early phase HIV-1 vaccine studies. More complete data on pregnancy outcomes should be collected in early phase HIV-1 vaccine clinical trials to better inform subsequent efficacy trials., (© 2021. The Author(s).)

Background: HIV Vaccine Trials Network 703/HIV Prevention Trials Network 081 is a phase 2b randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 years at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania, and Zimbabwe. It is one of the 2 Antibody Mediated Prevention efficacy trials, with HIV Vaccine Trials Network 704/HIV Prevention Trials Network 085, evaluating VRC01 for HIV prevention., Methods: Intense community engagement was used to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every 8 weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion., Results: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 years (interquartile range: 22-30), and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%), and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%., Conclusions: This proof-of-concept, large-scale monoclonal antibody study demonstrates the feasibility of conducting complex trials involving intravenous infusions in high incidence populations in sub-Saharan Africa., Competing Interests: J.R.M. reports an NIH patent for VRC01. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vaccination is crucial for human immunodeficiency virus (HIV)-exposed children because of their increased risk of morbidity and mortality from various vaccine-preventable diseases. However, studies have shown that they are at high risk of incomplete vaccination. Although China has developed prevention of mother-to-child transmission (PMTCT) of HIV programs substantially over the past decades, few studies have investigated the immunization levels of Chinese HIV-exposed children. Therefore, we aimed to evaluate vaccination coverage and its associated factors among HIV-exposed children in China during 2016‒2018., Methods: We conducted a retrospective cohort review of all cases of Chinese HIV-exposed children born between July 1, 2016 and June 30, 2018 recorded in the Chinese information system on PMTCT. The vaccination coverage indicators refer to the percentage of children who received recommended basic vaccines, including Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), polio, measles-containing vaccine (MCV), and diphtheria-tetanus-pertussis-containing (DTP) vaccine. Univariate and multivariate logistic regression analyses expressed as crude odds ratios (cORs) and adjusted odds ratios (aORs), each with 95% confidence intervals (95% CI), were performed to compare the proportional differences of factors associated with vaccine coverage., Results: Among the enrolled 10 033 children, the vaccination rate was 54.1% for BCG, 84.5% for complete HepB vaccination, 54.5% for complete polio vaccination, 51.3% for MCV, and 59.5% for complete DTP vaccination. Children with perinatally acquired HIV (PHIV) were 2.46‒3.82 times less likely to be vaccinated than HIV-exposed uninfected children. Multivariate logistic regression indicated that children of Han ethnicity (aOR = 1.33‒2.04), children with early infant diagnosis (EID) of HIV (aOR = 1.86‒3.17), and children whose mothers had better education (college or above, aOR = 1.63‒2.51) had higher odds of being vaccinated. Most of the deceased children (aOR = 4.28‒21.55) missed vaccination, and PHIV (aOR = 2.46‒3.82) significantly affected immunization., Conclusions: Chinese HIV-exposed children had low vaccination coverage, which is a serious health challenge that needs to be addressed thoroughly. Interventions should be developed with a focus on minority HIV-exposed children whose mothers do not have formal education. Particularly, more attention should be paid to EID to increase access to immunization.

Background: The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention., Methods: In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector., Results: All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61)., Conclusions: Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired., Clinical Trials Registration: South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969)., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

The human IgG3 subclass is conspicuously absent among the formats for approved monoclonal antibody therapies and Fc fusion protein biologics. Concern about the potential for rapid degradation, reduced plasma half-life, and increased immunogenicity due to marked variation in allotypes has apparently outweighed the potential advantages of IgG3, which include high affinity for activating Fc γ receptors, effective complement fixation, and a long hinge that appears better suited for low abundance targets. This review aims to highlight distinguishing features of IgG3 and to explore its functional role in the immune response. We present studies of natural immunity and recombinant antibody therapies that elucidate key contributions of IgG3 and discuss historical roadblocks that no longer remain clearly relevant. Collectively, this body of evidence motivates thoughtful reconsideration of the clinical advancement of this distinctive antibody subclass for treatment of human diseases. Abbreviations: ADCC - Antibody-Dependent Cell-mediated CytotoxicityADE - Antibody-dependent enhancementAID - Activation-Induced Cytidine DeaminaseCH - Constant HeavyCHF - Complement factor HCSR - Class Switch RecombinationEM - Electron MicroscopyFab - Fragment, antigen bindingFc - Fragment, crystallizableFcRn - Neonatal Fc ReceptorFcγR - Fc gamma ReceptorHIV - Human Immunodeficiency VirusIg - ImmunoglobulinIgH - Immunoglobulin Heavy chain geneNHP - Non-Human Primate.

We proposed a new HIV-1 therapeutic vaccine based on conserved cytotoxic T lymphocyte (CTL) epitopes of archived HIV-1 DNA according to their affinity to the dominant HLA-A and -B alleles of the population investigated. Our proposal (Hla Fitted VAC, HFVAC) was composed of 15 peptides originating from the RT, gag and nef parts of proviral DNA. Our aim was to investigate baseline immune reactivity to the vaccine in HIV-1 chronically infected patients at success of antiretroviral therapy (ART) who would be eligible for a therapeutic vaccine. Forty-one patients were tested. Most of them had been infected with HIV-1 subtype B and all had been receiving successful ART for 2 to 20 years. The predominant HLA-A and -B alleles were those of a Caucasian population. ELISPOT was carried out using the HFVAC peptides. In 22 patients, the PD-1 marker was investigated on CD4+ and CD8+ T cells by flow cytometry in order to evaluate global T cell exhaustion. ELISPOT positivity was 65% overall and 69% in patients exhibiting at least one HLA allele fitting with HFVAC. The percentages of CD4+ and CD8+ T cells expressing PD-1 were high (median values 23.70 and 32.60, respectively), but did not seem to be associated with an impairment of the immune response investigated in vitro. In conclusion, reactivity to HFVAC was high in this ART-treated population with dominant HLA alleles, despite potential cellular exhaustion associated with the PD-1 marker.

Following the discovery of HIV as a causative agent of AIDS, the expectation was to rapidly develop a vaccine; but thirty years later, we still do not have a licensed vaccine. Progress has been hindered by the extensive genetic variability of HIV and our limited understanding of immune responses required to protect against HIV acquisition. Nonetheless, valuable knowledge accrued from numerous basic and translational science research studies and vaccine trials has provided insight into the structural biology of the virus, immunogen design and novel vaccine delivery systems that will likely constitute an effective vaccine. Furthermore, stakeholders now appreciate the daunting scientific challenges of developing an effective HIV vaccine, hence the increased advocacy for collaborative efforts among academic research scientists, governments, pharmaceutical industry, philanthropy, and regulatory entities. In this review, we highlight the history of HIV vaccine development efforts, highlighting major challenges and future directions., (Copyright © 2020 Ng’uni, Chasara and Ndhlovu.)

Competing Interests: GST has patent applications for HIV immunogen design and HIV incidence assays. GST received a research contract through Duke University from GSK.

The development of an HIV vaccine has been a major challenge for several decades already. In order to cope with the large diversity and mutation rate of the virus, a vaccine needs to offer extraordinarily broad protection. In recent years, a large number of clinical studies all over the world have been investigating promising new vaccine strategies. Findings of these studies will provide important guidance for further optimisation of vaccine candidates, excipients and vaccination schedules in the near future. Vaccines currently under investigation are stimulating either the development of antibodies against HIV or antiviral T-cell immunity. In order to provide broad and long-lasting protection, an effective vaccine should induce both humoral and cellular responses, which could be achieved with sequential immunisations as well as a combination of several different vaccine strategies.

Despite the success of anti-retroviral therapy (ART) in transforming HIV into a manageable disease, it has become evident that long-term ART will not eliminate the HIV reservoir and cure the infection. Alternative strategies to eradicate HIV infection, or at least induce a state of viral control and drug-free remission are therefore needed. Therapeutic vaccination aims to induce or enhance immunity to alter the course of a disease. In this review we provide an overview of the current state of therapeutic HIV vaccine research and summarize the obstacles that the field faces while highlighting potential ways forward for a strategy to cure HIV infection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Induction of persistent HIV-1 Envelope (Env) specific antibody (Ab) is a primary goal of HIV vaccine strategies; however, it is unclear whether HIV Env immunization in humans induces bone marrow plasma cells, the presumed source of long-lived systemic Ab. To define the features of Env-specific plasma cells after vaccination, samples were obtained from HVTN 105, a phase I trial testing the same gp120 protein immunogen, AIDSVAX B/E, used in RV144, along with a DNA immunogen in various prime and boost strategies. Boosting regimens that included AIDSVAX B/E induced robust peripheral blood plasmablast responses. The Env-specific immunoglobulin repertoire of the plasmablasts is dominated by VH1 gene usage and targeting of the V3 region. Numerous plasmablast-derived immunoglobulin lineages persisted in the bone marrow >8 months after immunization, including in the CD138 + long-lived plasma cell compartment. These findings identify a cellular linkage for the development of sustained Env-specific Abs following vaccination in humans., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

In the RV144 trial, to date the only HIV-1 vaccine efficacy trial demonstrating a modestly reduced risk of HIV-1 acquisition, antibody responses toward the HIV Envelope protein (Env) variable (V) 2 and V3 regions were shown to be correlated with a reduced risk of infection. These potentially protective antibody responses, in parallel with the vaccine efficacy, however, waned quickly. Dissecting vaccine-induced IgG recognition of antigenic regions and their variants within the HIV-1 Env from different vaccine trials will aid in designing future HIV-1 immunogens and vaccination schedules. We, therefore, analyzed the IgG response toward linear HIV-1 Env epitopes elicited by a multi-clade, multigene HIVIS-DNA priming, and heterologous recombinant modified vaccinia virus Ankara (MVA-CMDR) boosting regimen (HIVIS03) and assessed whether a late MVA-CMDR boost 3 years after completion of the initial vaccination schedule (HIVIS06) restored antibody responses toward these epitopes. Here we report that vaccination schedule in the HIVIS03 trial elicited IgG responses against linear epitopes within the V2 and V3 tip as well as against the gp41 immunodominant region in a high proportion of vaccinees. Antibodies against the V2 and gp41 Env regions were restricted to variants with close homology to the MVA-CMDR immunogen sequence, while V3 responses were more cross-reactive. Boosting with a late third MVA-CMDR after 3 years effectively restored waned IgG responses to linear Env epitopes and induced targeting of identical antigenic regions and variants comparable to the previous combined HIVIS-DNA/MVA-CMDR regimen. Our findings support the notion that anti-HIV-1 Env responses, associated with a reduced risk of infection in RV144, could be maintained by regular boosting with a single dose of MVA-CMDR., (Copyright © 2020 Joachim, Ahmed, Pollakis, Rogers, Hoffmann, Munseri, Aboud, Lyamuya, Bakari, Robb, Wahren, Sandstrom, Nilsson, Biberfeld, Geldmacher and Held.)

Antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) infection. Research seeking to transform viral suppression into elimination has generated novel immune, chemical and molecular antiviral agents. However, none, to date, have excised latent integrated proviral DNA or removed infected cells from infected persons. These efforts included, but are not limited to, broadly neutralizing antibodies, "shock" and "kill" latency-reversing agents, innate immune regulators, and sequential long-acting antiretroviral nanoformulated prodrugs and CRISPR-Cas9 gene editing. While, the latter, enabled the complete excision of latent HIV-1 from the host genome success was so far limited. We contend that improvements in antiretroviral delivery, potency, agent specificity, or combinatorial therapies can provide a pathway towards complete HIV elimination., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: HVTN 100 evaluated the safety and immunogenicity of an HIV subtype C pox-protein vaccine regimen, investigating a 12-month booster to extend vaccine-induced immune responses., Methods and Findings: A phase 1-2 randomized double-blind placebo-controlled trial enrolled 252 participants (210 vaccine/42 placebo; median age 23 years; 43% female) between 9 February 2015 and 26 May 2015. Vaccine recipients received ALVAC-HIV (vCP2438) alone at months 0 and 1 and with bivalent subtype C gp120/MF59 at months 3, 6, and 12. Antibody (IgG, IgG3 binding, and neutralizing) and CD4+ T-cell (expressing interferon-gamma, interleukin-2, and CD40 ligand) responses were evaluated at month 6.5 for all participants and at months 12, 12.5, and 18 for a randomly selected subset. The primary analysis compared IgG binding antibody (bAb) responses and CD4+ T-cell responses to 3 vaccine-matched antigens at peak (month 6.5 versus 12.5) and durability (month 12 versus 18) timepoints; IgG responses to CaseA2&#95;gp70&#95;V1V2.B, a primary correlate of risk in RV144, were also compared at these same timepoints. Secondary and exploratory analyses compared IgG3 bAb responses, IgG bAb breadth scores, neutralizing antibody (nAb) responses, antibody-dependent cellular phagocytosis, CD4+ polyfunctionality responses, and CD4+ memory sub-population responses at the same timepoints. Vaccines were generally safe and well tolerated. During the study, there were 2 deaths (both in the vaccine group and both unrelated to study products). Ten participants became HIV-infected during the trial, 7% (3/42) of placebo recipients and 3% (7/210) of vaccine recipients. All 8 serious adverse events were unrelated to study products. Less waning of immune responses was seen after the fifth vaccination than after the fourth, with higher antibody and cellular response rates at month 18 than at month 12: IgG bAb response rates to 1086.C V1V2, 21.0% versus 9.7% (difference = 11.3%, 95% CI = 0.6%-22.0%, P = 0.039), and ZM96.C V1V2, 21.0% versus 6.5% (difference = 14.5%, 95% CI = 4.1%-24.9%, P = 0.004). IgG bAb response rates to all 4 primary V1V2 antigens were higher 2 weeks after the fifth vaccination than 2 weeks after the fourth vaccination: 87.7% versus 75.4% (difference = 12.3%, 95% CI = 1.7%-22.9%, P = 0.022) for 1086.C V1V2, 86.0% versus 63.2% (difference = 22.8%, 95% CI = 9.1%-36.5%, P = 0.001) for TV1c8.2.C V1V2, 67.7% versus 44.6% (difference = 23.1%, 95% CI = 10.4%-35.7%, P < 0.001) for ZM96.C V1V2, and 81.5% versus 60.0% (difference = 21.5%, 95% CI = 7.6%-35.5%, P = 0.002) for CaseA2&#95;gp70&#95;V1V2.B. IgG bAb response rates to the 3 primary vaccine-matched gp120 antigens were all above 90% at both peak timepoints, with no significant differences seen, except a higher response rate to ZM96.C gp120 at month 18 versus month 12: 64.5% versus 1.6% (difference = 62.9%, 95% CI = 49.3%-76.5%, P < 0.001). CD4+ T-cell response rates were higher at month 18 than month 12 for all 3 primary vaccine-matched antigens: 47.3% versus 29.1% (difference = 18.2%, 95% CI = 2.9%-33.4%, P = 0.021) for 1086.C, 61.8% versus 38.2% (difference = 23.6%, 95% CI = 9.5%-37.8%, P = 0.001) for TV1.C, and 63.6% versus 41.8% (difference = 21.8%, 95% CI = 5.1%-38.5%, P = 0.007) for ZM96.C, with no significant differences seen at the peak timepoints. Limitations were that higher doses of gp120 were not evaluated, this study was not designed to investigate HIV prevention efficacy, and the clinical significance of the observed immunological effects is uncertain., Conclusions: In this study, a 12-month booster of subtype C pox-protein vaccines restored immune responses, and slowed response decay compared to the 6-month vaccination., Trial Registration: ClinicalTrials.gov NCT02404311. South African National Clinical Trials Registry (SANCTR number: DOH--27-0215-4796)., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: CAD is a full-time employee at Sanofi Pasteur, shareholder Sanofi. SP is a full-time employee and shareholder at Sanofi Pasteur at the time of the study, now full-time employee at GSK group companies. MK is a full-time employee of GSK group companies, having GSK shares and stock options. OVDM is a full-time employee of GSK group companies, having GSK shares. MA, MNP, VLM are full-time employee of NIH/NIAID, which is the clinical trial sponsor. ZM is a a paid statistical advisor for PLOS Medicine.

Various long-awaited efficacy studies of vaccines and broadly neutralising antibodies for prevention of HIV are now well underway in highly endemic settings. One broadly neutralising monoclonal antibody is being assessed for proof of concept, and combinations are in the pipeline. Two multicomponent prime-and-boost vaccine regimens are being evaluated, one of which is designed for global coverage. These multicomponent vaccines present a new level of complexity that will challenge health delivery systems. We recommend that while awaiting the results, which will appear in 2020-22, the target product profiles and full public value proposition for both categories of products should be defined, and the regulatory, policy, and implementation pathways should be prepared. Economic and health benefits, cost of goods, administrative complexity, and user perspectives will be key considerations for the roll-out of effective products. Investments in manufacturing capacity and public-sector delivery systems will be needed to prepare for product introduction and scale-up. We propose a prioritisation of activities on the basis of a broad stakeholder consultation organised by WHO and UNAIDS., (Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Complement C3d receptor 2 (CR2) is the main receptor for complement protein C3d and plays an important role in adaptive immune responses. CR2 genetic variants are associated with susceptibility to systemic lupus erythematosus as well as to HIV-1 infection. In addition, CR2 function can be subverted by HIV-1 for an efficient entry into target cells; in a process known as antibody-dependent enhancement of viral infection. We sought to determine the association between CR2 gene variants with HIV-1 acquisition after vaccination with recombinant gp120 protein (Vax004 clinical trial)., Design and Methods: This is a retrospective cross-sectional study, comprising male volunteers of European ancestry including infected (n = 273) and uninfected (n = 402) vaccinees and placebo, who were genotyped for three single nucleotide polymorphisms (SNPs) in the CR2 gene region., Results: An interaction was observed between the baseline sexual behavior and the SNP rs3813946 for higher risk of infection in vacinees (interaction term P = 0.02). This SNP was associated with increased susceptibility to HIV-1 infection after vaccination in volunteers with low behavioral risk odds ratio (95% confidence interval): 5.5 (1.4-21.7) P = 0.006 but not vaccinees with high behavioral risk or volunteers given placebo (P = 0.7). Moreover, CR2 genotype was strongly associated with the rate of HIV-1 acquisition after vaccination in low-risk volunteers [hazard odds ratio (95% confidence interval): 3.3 (1.6-7.0), P = 0.001]., Conclusion: The current study suggests that CR2 may play a role in HIV-1 acquisition after vaccination with rgp120 proteins.

The vast genetic variability of HIV has impeded efforts towards a cure for HIV. Lifelong administration of combined antiretroviral therapy (cART) is highly effective against HIV and has markedly increased the life expectancy of HIV infected individuals. However, the long-term usage of cART is associated with co-morbidities and the emergence of multidrug-resistant escape mutants necessitating the development of alternative approaches to combat HIV/AIDS. In the past decade, the development of single-cell antibody cloning methods has facilitated the characterization of a diverse array of highly potent neutralizing antibodies against a broad range of HIV strains. Although the passive transfer of these broadly neutralizing antibodies (bnAbs) in both animal models and humans has been shown to elicit significant antiviral effects, long term virologic suppression requires repeated administration of these antibodies. Adeno-associated virus (AAV) mediated antibody gene transfer provides a long-term expression of these antibodies from a single administration of the recombinant vector. Therefore, this vectored approach holds promises in the treatment and prevention of a chronic disease like HIV infection. Here, we provide an overview of HIV genetic diversity, AAV vectorology, and anti-HIV bnAbs and summarize the promises and challenges of the application of AAV in the delivery of bnAbs for HIV prevention and therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

South African (SA) researchers have made both national and global contributions to HIV prevention and treatment. Research conducted in SA has contributed markedly to improved survival in HIV-infected infants, children and adults. The translation of clinical research into practice has enabled the curtailment of paediatric HIV in SA. Along with international collaborators, SA has made pivotal contributions to biomedical prevention modalities including medical male circumcision and oral and topical microbicides, and is undertaking pivotal HIV vaccine research. Research into the structural and psychosocial drivers of HIV infection will be critical for sustaining biomedical interventions, and necessary to end AIDS.

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8 + T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8 + T cell responses relatively infrequently during infection, CD8 + T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Despite the present HIV preventive and treatment programs, the prevalence of HIV is still high in eastern and southern Africa, among young women and populations at high. risk for HIV transmission such as sex workers. There is a need to prepare a suitable population that will participate in efficacy HIV vaccine trials to determine the efficacy of HIV vaccines that had proven to be safe and immune potent., Methods: It was a cross-sectional study that recruited 600 female sex workers using respondent-driven sampling in Dar es Salaam. The study examined recruitment approaches, risk behaviors and willingness of young female sex workers to participate in an HIV vaccine trial. Descriptive statistics described risk behaviors and willingness of the participants to participate in efficacy HIV vaccine trials. The logistic regression model computed the likelihood of willingness to participate in the trials with selected variables., Results: The study demonstrated 53% were less than 20 years old, 96% were single, and 22% lived in brothels. Eighty percent of the participants started selling sex at the age between 15 and 19 years old, 61% used illicit drugs for the first time when they were less than 20 years old, 24% had anal sex ever. Eighty-nine percent had more than 20-lifetime sexual partners, and 56% had unprotected sexual intercourse with sex clients. Ninety-one percent expressed a willingness to participate in the HIV vaccine trial. Sixty-one percent did not need permission from anyone for participating in a trial. Ninety-one percent expressed willingness to participate in the efficacy of HIV vaccine trial. In the logistic regression model, willingness was significantly associated with the need to ask permission for participation in HIV vaccine trial from sex agent., Conclusion: Respondent-driven sampling provided a rapid means of reaching young female sex workers who reported high-risk behaviors. The majority expressed a high level of willingness to participate in the HIV vaccine trial which was marginally correlated to the need to seek consent for participation in the trial from the sex brokers. Future HIV vaccine trials involving this population should consider involving the brokers in the trials because they form an essential part of the community for the participants.

Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic adenovirus 26 (Ad26)-based HIV-1 vaccine candidate. To investigate the basis of this protection, we performed whole transcriptomics profiling by RNA sequencing (RNA-seq) in sorted lymphocytes from peripheral blood samples taken during these studies at different time points after vaccination but before challenge. We observed a transcriptional signature in B cells that associated with protection from acquisition of simian immunodeficiency virus (SIV) or the simian-human immunodeficiency virus (SHIV) in both studies. Strong antibody responses were elicited, and genes from the signature for which expression was enriched specifically associated with higher magnitude of functional antibody responses. The same gene expression signature also associated with protection in RV144 in the only human HIV vaccine trial to date that has shown efficacy and in two additional NHP studies that evaluated similar canarypox-based vaccine regimens. A composite gene expression score derived from the gene signature was one of the top-ranked correlates of protection in the NHP vaccine studies. This study aims to bridge preclinical and clinical data with the identification of a gene signature in B cells that is associated with protection from SIV and HIV infection by providing a new approach for evaluating future vaccine candidates., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Introduction: Promising HIV vaccine candidates are steadily progressing through the clinical trial pipeline. Once available, HIV vaccines will be an important complement but also potential competitor to other biomedical prevention tools such as pre-exposure prophylaxis (PrEP). Accordingly, the value of HIV vaccines and the policies for rollout may depend on that interplay and tradeoffs with utilization of existing products. In this economic modelling analysis, we estimate the cost-effectiveness of HIV vaccines considering their potential interaction with PrEP and condom use., Methods: We developed a dynamic model of HIV transmission among the men who have sex with men population (MSM), aged 15-64 years, in Seattle, WA offered PrEP and HIV vaccine over a time horizon of 2025-2045. A healthcare sector perspective with annual discount rate of 3% for costs (2017 USD) and quality-adjusted life years (QALYs) was used. The primary economic endpoint is the incremental cost-effectiveness ratio (ICER) when compared to no HIV vaccine availability., Results: HIV vaccines improved population health and increased healthcare costs. Vaccination campaigns achieving 90% coverage of high-risk men and 60% coverage of other men within five years of introduction are projected to avoid 40% of new HIV infections between 2025 and 2045. This increased total healthcare costs by $30 million, with some PrEP costs shifted to HIV vaccine spending. HIV vaccines are estimated to have an ICER of $42,473/QALY, considered cost-effective using a threshold of $150,000/QALY. Results were most sensitive to HIV vaccine efficacy and future changes in the cost of PrEP drugs. Sensitivity analysis found ranges of 30-70% HIV vaccine efficacy remained cost-effective. Results were also sensitive to reductions in condom use among PrEP and vaccine users., Conclusions: Access to an HIV vaccine is desirable as it could increase the overall effectiveness of combination HIV prevention efforts and improve population health. Planning for the rollout and scale-up of HIV vaccines should carefully consider the design of policies that guide interactions between vaccine and PrEP utilization and potential competition., (© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Antigenic mimicry is a fundamental tenet of structure-based vaccinology. Vaccine strategies for the human immunodeficiency virus type 1 (HIV-1) focus on the mimicry of its envelope spike (Env) due to its exposed location on the viral membrane and role in mediating infection. However, the virus has evolved to minimize the immunogenicity of conserved epitopes on the envelope spike. This principle is starkly illustrated by the presence of an extensive array of host-derived glycans, which act to shield the underlying protein from antibody recognition. Despite these hurdles, a subset of HIV-infected individuals eventually develop broadly neutralizing antibodies that recognize these virally presented glycans. Effective HIV-1 immunogens are therefore likely to involve some degree of mimicry of both the protein and glycan components of Env. As such, considerable efforts have been made to characterize the structure of the envelope spike and its glycan shield. This review summarizes the recent progress made in this field, with an emphasis on our growing understanding of the factors shaping the glycan shield of Env derived from both virus and soluble immunogens. We argue that recombinant mimics of the envelope spike are currently capable of capturing many features of the native viral glycan shield. Finally, we explore strategies through which the immunogenicity of Env glycans may be enhanced in the development of future immunogens., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mucosal-associated invariant T (MAIT) cell populations are reduced in frequency in HIV-1+ patients, and this disruption is associated with systemic immune activation. Reconstitution of MAIT frequency may benefit HIV-1-infected individuals; however, only recently has in vivo work been endeavored. Treatment with interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), and recombinant human growth hormone (rhGH) immunotherapy combined with an HIV-1 vaccine in the context of antiretroviral therapy (ART) has shown to reconstitute CD4 T cell population numbers and function. In this study cryopreserved peripheral blood mononuclear cells (PBMCs) from 12 HIV-1+ patients who were undergoing a combination of HIV-1 vaccine and/or IL-2, GM-CSF and rhGH immunotherapy in conjunction with ART were analyzed to assess the potential of this treatment to promote MAIT cell proliferation. PBMCs were thawed from study baseline, weeks 2 and 48 time points, fluorescently stained for MAIT cell markers, and assessed by flow cytometric analysis. Matched pairs and intergroup results were statistically compared using appropriate methods. MAIT cell frequency was increased from baseline at 48 weeks in participants who received vaccine only, whereas individuals receiving IL-2, GM-CSF, and rhGH immunotherapy with or without vaccine did not show additional benefit. Although IL-2, GM-CSF, and rhGH treatment promotes CD4 T cell reconstitution and HIV-1-specific T cell function, it does not support MAIT cell recovery in patients on suppressive ART. Therapeutic immunization however has a positive effect, highlighting the importance of aiming for balanced promotion of T cell population reconstitution to impact on HIV-1 transmission and pathogenesis.

Background: Among the various types of pharmaceuticals, vaccines have a special place. However, in the case of HIV, nearly after 40 years of its discovery, an effective vaccine still is not available. The reason lies in several facts mainly the variability and smartness of HIV as well as the complexity of the interaction between HIV and immune responses. A robust, effective, and longterm immunity is undoubtedly what a successful preventive vaccine should induce in order to prevent the infection of HIV. Failure of human trials to this end has led to the idea of developing therapeutic vaccines with the purpose of curing already infected patients by boosting their immune responses against the virus. Nevertheless, the exceptional ability of the virus to escape the immune system based on the genetically diverse envelope and variable protein products have made it difficult to achieve an efficient therapeutic vaccine., Objective: We aimed at studying and comparing different approaches to HIV therapeutic vaccines., Methods: In this review, we summarized the human trials undergoing on HIV therapeutic vaccination which are registered in the U.S. clinical trial database (clinicaltrials.gov). These attempts are divided into different tables, according to the type of formulation and application in order to classify and compare their results., Result/conclusion: Among several methods applied in studied clinical trials which are mainly divided into DNA, Protein, Peptide, Viral vectors, and Dendritic cell-based vaccines, protein vaccine strategy is based on Tat protein-induced anti-Tat Abs in 79% HIV patients. However, the studies need to be continued to achieve a durable efficient immune response against HIV-1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Human immunodeficiency virus (HIV) has infected 76 million people and killed an estimated 35 million. During its 40-year history, remarkable progress has been made on antiretroviral drugs. Progress toward a vaccine has also been made, although this has yet to deliver a licensed product. In 2007, I wrote a review, HIV AIDS Vaccines: 2007. This review, HIV AIDS Vaccines: 2018, focuses on the progress in the past 11 years. I begin with key challenges for the development of an AIDS vaccine and the lessons learned from the six completed efficacy trials, only one of which has met with some success., (© 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: High retention (follow-up) rates improve the validity and statistical power of outcomes in longitudinal studies and the effectiveness of programs with prolonged administration of interventions. We assessed participant retention in a potential HIV vaccine trials population of fishing communities along Lake Victoria, Uganda., Methods: In a community-based individual randomized trial, 662 participants aged 15-49 years were randomized to either mobile phone or physical contact tracing reminders and followed up at months 1, 2, 3, 6, 12 and 18 post-enrolment. The visit schedules aimed at mimicking a vaccine efficacy trial representing an early interval (months 1-6) where most vaccinations would be administered and a later period of post-vaccination follow-up. The primary outcome was retention measured as the proportion of post-baseline follow up visits completed by a participant. Retention was estimated in early and later follow-up intervals, and overall for all the six follow-up visits. Adjusted differences in retention between the study arms were determined by multivariable logistic regression using Stata® 14. One participant was later dropped from the analysis because of age ineligibility discovered after enrolment., Results: Of the expected total follow up visits of 3966 among 661 participants, 84.1% (3334) were attained; 82.1% (1626/1980) in the phone arm and 86% (1708/1986) in the physical tracing arm (p = 0.001). No statistically significant differences in retention were observed between the study arms in the first 6 months but thereafter, retention was significantly higher for physical contact reminders than mobile phones; 91.5% versus 82.1% (p < 0.0001) at month 12 and 82.8% versus 75.4%, (p = 0.021) at month 18. Controlling for sex, age, education, occupation, community location, length of stay and marital status, the odds of good retention (completing 5 out of 6 follow-up visits) were 1.56 (95% CI;1.08-2.26, p = 0.018) for physical contact tracing compared to mobile phone tracing. Other statistically significant predictors of good retention were residing on islands and having stayed in the fishing communities for 5 or more years., Conclusions: Among fishing communities of Lake Victoria, Uganda, 84% of follow-up visits can be attained and participant retention is higher using physical contact reminders than mobile phones., Trial Registration Number: PACTR201311000696101 ( http://www.pactr.org/ ). retrospectively registered on 05 November, 2013.

Background: Live, attenuated viral vectors that express HIV-1 antigens are being investigated as an approach to generating durable immune responses against HIV-1 in humans. We recently developed a replication-competent, highly attenuated Ad26 vector that expresses mosaic HIV-1 Env (rcAd26.MOS1.HIV-Env, "rcAd26"). Here we present the results of a first-in-human, placebo-controlled clinical trial to test the safety, immunogenicity and mucosal shedding of rcAd26 given orally., Methods: Healthy adults were randomly assigned to receive a single oral dose of vaccine or placebo at 5:1 ratio in a dosage escalation of 10^8 to 10^11 rcAd26 VP (nominal doses) at University of Rochester Medical Center, Rochester, NY, USA. Participants were isolated and monitored for reactogenicity for 10 days post-vaccination, and adverse events were recorded up to day 112. Rectal and oropharyngeal secretions were evaluated for shedding of the vaccine. Humoral and cellular immune responses were measured. Household contacts were monitored for secondary vaccine transmission., Results: We enrolled 22 participants and 11 household contacts between February 7 and June 24, 2015. 18 participants received one dose of HIV-1 vaccine and 4 participants received placebo. The vaccine caused only mild to moderate adverse events. No vaccine-related SAEs were observed. No infectious rcAd26 viral particles were detected in rectal or oropharyngeal secretions from any participant. Env-specific ELISA and ELISPOT responses were undetectable. No household contacts developed vaccine-induced HIV-1 seropositivity or vaccine-associated illness., Conclusions: The highly attenuated rcAd26.MOS1.HIV-Env vaccine was well tolerated up to 10^11 VP in healthy, HIV-1-uninfected adults, though the single dose was poorly immunogenic suggesting the replicative capacity of the vector was too attenuated. There was no evidence of shedding of infectious virus or secondary vaccine transmission following the isolation period. These data suggest the use of less attenuated viral vectors in future studies of live, oral HIV-1 vaccines., Trial Registration: ClinicalTrials.gov NCT02366013., Competing Interests: The authors Christopher Yallop and Menzo Havenga are employees of Batavia Biosciences B.V., Leiden, The Netherlands. This employment does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.