HIV Vaccine Trials Research Articles

Analysis of Informatively Interval-Censored Case–Cohort Studies with the Application to HIV Vaccine Trials

Analysis of Informatively Interval-Censored Case–Cohort Studies with the Application to HIV Vaccine Trials

Mixed Origins: HIV gp120-Specific Memory Develops from Pre-Existing Memory and Naive B Cells Following Vaccination in Humans.

The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naive B cell receptor, fail to bind Env, suggesting that the initial responding B cell population not only exclusively comprises a naive population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing, focused on immunoglobulin G (IgG), IgA, and IgM, VH-lineage tracking, we identified four of these mAb lineages in pre-immune peripheral blood. We also looked through the ∼7 month postvaccination bone marrow, and interestingly, several of these lineages that were found in prevaccination blood were still persistent in the postvaccination bone marrow, including the CD138+ long-lived plasma cell compartment. The majority of the pre-immune lineage members included IgM, however, IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naive and cross-reactive memory B cells. ClinicalTrials.gov NCT02207920.

Efficient Estimation under Data Fusion.

We aim to make inferences about a smooth, finite-dimensional parameter by fusing data from multiple sources together. Previous works have studied the estimation of a variety of parameters in similar data fusion settings, including in the estimation of the average treatment effect and average reward under a policy, with the majority of them merging one historical data source with covariates, actions, and rewards and one data source of the same covariates. In this work, we consider the general case where one or more data sources align with each part of the distribution of the target population, for example, the conditional distribution of the reward given actions and covariates. We describe potential gains in efficiency that can arise from fusing these data sources together in a single analysis, which we characterize by a reduction in the semiparametric efficiency bound. We also provide a general means to construct estimators that achieve these bounds. In numerical simulations, we illustrate marked improvements in efficiency from using our proposed estimators rather than their natural alternatives. Finally, we illustrate the magnitude of efficiency gains that can be realized in vaccine immunogenicity studies by fusing data from two HIV vaccine trials.

Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?

Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.

Exploring a community’s understanding of HIV vaccine‑induced seropositivity in a South African research setting

The high HIV prevalence and incidence in South Africa makes it suitable for recruitment of participants for large-scale HIV preventive vaccine trials. However, fear of vaccine-induced seropositivity (VISP) may be a barrier for community acceptability of the trial, for volunteers to participate in HIV preventive vaccine trials and for uptake of an efficacious vaccine. Prior to 2015, when the first phase 1 safety HIV vaccine trial was undertaken at Setshaba Research Centre, Soshanguve, the local community stakeholders and healthcare workers were naive about HIV vaccine research and HIV preventive vaccines. To explore knowledge and perceptions regarding VISP among community stakeholders and healthcare workers in peri-urbanb Soshanguve, Tshwane. Using a quantitative-qualitative mixed-methods study design, surveys (n=50) and in-depth interviews (n=18) were conducted during July - August 2015. Participants included community stakeholders, community advisory board members and healthcare workers, who were >18 years old and had attended community educational workshops during September 2014 - May 2015. Audio recordings of interviews were transcribed verbatim and coded using content thematic analysis. Data were further analysed by sex, age and educational level. Of a maximum score of 2 on knowledge on VISP, the 50 survey participants (mean age 33.78 years; 45 females) obtained an average of 0.88 (44%). Of 17 in-depth interviewees (one interview could not be transcribed; mean age 30.9 years; 12 females), 8 (47%) displayed some knowledge about VISP, of whom only 5 defined VISP correctly. Women were more knowledgeable about VISP than men; 5 of 12 women (42%) came close to defining VISP correctly, while none of the 5 men did so. The main fear of trial participation expressed by most participants (n=6) was testing HIV-positive as a result of the vaccine. While some participants believed that the community's perceptions of VISP would negatively affect HIV vaccine trial support and recruitment efforts, others noted that if trial participants understand the concept of VISP and are part of support groups, then they would have the information to combat negative attitudes within their community. Most participants had an inaccurate and incomplete understanding of VISP. Many feared testing HIV-positive at clinics; therefore, education on improving a basic understanding of how vaccines work and why VISP occurs is essential. In addition, assessing participant understanding of HIV testing, transmission and VISP is critical for recruitment of participants into HIV vaccine trials and may improve acceptability of an HIV preventive vaccine.

Can HIV vaccines be shared fairly? Perspectives from Tanzania

BackgroundFor over 35 years, Africa has continued to host HIV vaccine trials geared towards overturning the HIV/AIDs pandemic in the continent. However, the methods of sharing the vaccines, when available remain less certain. Therefore, the study aims to explore stakeholders’ perspectives in the global South, in this case, Tanzania, on how HIV vaccines ought to be fairly shared.MethodsThe study deployed a qualitative case study design. Data were collected through in-depth interviews and focus group discussions with a total of 37 purposively selected participants. This included researchers, institutional review board members, a policymaker, HIV/AIDS advocates, and community advisory board members. The data obtained were inductively and deductively analyzed.ResultsFindings indicate that HIV vaccines can be shared fairly under the principles of distributive justice (contribution, need and equality). Thus, contribution-based sharing ought to be utilized upon the necessity to prioritize vaccine access or subsidized trial benefits to host communities. Need-based sharing ought to be considered for non-host communities that are at an increased risk of HIV infection. Lastly, equal-based sharing would be useful at later stages of vaccine distribution or when the aforementioned principles are deemed morally inappropriate. However, none of the benefit-sharing approaches is free of limitations and a counterbalancing sense of unfairness.ConclusionFair sharing of HIV vaccines, when available, ought to be informed by the contribution, need and equality principles of distributive justice. Countries in the global south including Tanzania are likely to be prioritized during the distribution of the HIV vaccines due to their participation in HIV vaccine trials and due to the disproportionate HIV burden evident in the region.

HIV Vaccine Trials in Thailand and Path to HIV Cure

Thailand has had over 30 years of experiences and development in fighting HIV/AIDS with successful results in terms of providing access to revention, testing, antiretroviral treatment (ART) and care for over 90% of the affected patients. As a consequence, approximately 400,000 patients on ART currently have undetectable viral load, lead normal lives, and are untransmittable. However, ART must remain in place forever or else the viral load in blood will rebound. Recent advance in stem cell transplant, gene editing, and therapeutic HIV vaccine development yields hope on designing novel approach for an HIV elimination or functional cure. The National AIDS Prevention and Alleviation Committee of Thailand has set up the Subcommittee on HIV Vaccine Trials to oversee and endorse experimental vaccine regimen with sound and adequate scientific background to be tested in Thailand. So far, at least 23 small and large studies have been conducted in collaboration with the international organizations and at least 10 articles were published after the studies ended and cited over 2,726 times. One landmarked trial using notable vaccine regimen, evaluated in the RV144 trial, has shown effectiveness in reducing new infections by 31.2%. The conduction of these research in Thailand have facilitated the development of infrastructure, networking, and experience sufficiently to further support future field trial with a notable HIV cure approach. Since there are over 400,000 HIV cases with undetectable viral load in Thailand, this condition poses an excellent opportunity for testing a novel HIV cure approaches to eliminate HIV or functional HIV cure. The Subcommittee has reviewed current novel methods in this regard and strongly welcomed international organizations with similar aim, to test an innovative therapeutic HIV vaccine or a combination therapy to finally end HIV/AIDS in Thailand by the year 2030. Keywords: HIV vaccine; HIV cure; Latent HIV reservoir; mRNA vaccine; Gene therapy; Stem cell transplantation

Examining oral pre-exposure prophylaxis (PrEP) literacy among participants in an HIV vaccine trial preparedness cohort study

BackgroundPrEP 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.MethodsWe 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.ResultsWe 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.ConclusionThe 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 registrationhttps://clinicaltrials.gov/ct2/show/NCT04066881

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.

Multi-trial analysis of HIV-1 envelope gp41-reactive antibodies among global recipients of candidate HIV-1 vaccines.

Many participants in HIV-1 vaccine trials, who have not previously been exposed to or vaccinated against HIV-1, display serum immunoglobulin antibodies that bind the gp41 region of HIV-1 envelope prior to vaccination. Previous studies have hypothesized that these pre-existing antibodies may be cross-reactive and may skew future vaccine responses. In 12 large studies conducted by the HIV Vaccine Trial Network (HVTN) (n=1470 individuals), we find wide variation among participants in the pre-vaccine levels of gp41-reactive antibodies as measured by the binding antibody multiplex assay (BAMA). In the absence of exposure to the gp41 immunogen, anti-gp41 IgG levels were temporally stable over 26-52 weeks in repeated measures of placebo recipients. The analysis revealed that the geometric mean of pre-vaccine anti-gp41 IgG response was greater among participants in South Africa compared with participants in the United States. With gene-level metagenomic sequencing of pre-vaccination fecal samples collected from participants in one trial (HVTN 106), we detected positive associations between pre-vaccine anti-gp41 IgG and abundance of genes from multiple taxa in the Eubacteriales order. The genes most strongly associated with higher baseline anti-gp41 IgG mapped to a clade containing Blautia wexlerae and closely related strains. In trials with vaccine products containing the full or partial portion of gp41 immunogen alongside a gp120 immunogen, we did not find evidence that individuals with higher baseline anti-gp41 IgG had different levels of anti-gp120 IgG after vaccination compared to individuals with lower pre-vaccine anti-gp41 levels (pooled estimate of standardized mean difference -0.01 with a 95% CI [-0.37; 0.34]).

Baseline host determinants of robust human HIV-1 vaccine-induced immune responses: A meta-analysis of 26 vaccine regimens.

SummaryBackgroundThe identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders.MethodsThis was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered.FindingsOverall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status.InterpretationThe identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power.FundingNational Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources.

The Prevalence, Incidence, and Risk Factors for HIV Among Female Sex Workers-A Cohort Being Prepared for a Phase IIb HIV Vaccine Trial in Dar es Salaam, Tanzania.

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). A cohort of FSWs in Dar es Salaam, Tanzania. 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. 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. 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.

Achieving intracellular cytokine staining assay concordance on two continents to assess HIV vaccine-induced T-cell responses.

The HIV Vaccine Trials Network (HVTN) conducts clinical trials on 4 continents in pursuit of a safe and effective HIV vaccine. Cellular immune responses to vaccination that define vaccine immunogenicity and/or immune correlates of protection can be measured using multiparameter intracellular cytokine staining (ICS) assays. The HVTN cellular immunology laboratory, located in Seattle, WA, conducts ICS assays for vaccine trials according to Good Clinical Laboratory Practices (GCLP). In 2013, the HVTN established a second GCLP compliant cellular immunology laboratory in Cape Town, South Africa to assess vaccine immunogenicity for HVTN trials conducted on the African continent. To ensure ICS readouts in the 2 laboratories were directly comparable, we conducted concordance testing using PBMC from healthy controls and vaccine trial participants. Despite standardized procedures and instrumentation, shared quality control measures and quality assurance oversight, several factors impacted our ability to obtain close agreement in T-cell responses measured in the 2 laboratories. One of these was the type of fetal bovine serum (FBS) used in the assay, which impacted lymphocyte cell viability and background responses. In addition, the differences in supernatant removal technique also significantly affected our ability to detect positive responses to vaccine antigens. Standardization of these factors allowed us to achieve and maintain ICS assay concordance across the 2 laboratories over multiple years, accelerating our efforts to evaluate HIV vaccines. The insights gained in this process are valuable for assay transfer efforts by groups of investigators that need to directly compare data generated in different laboratories around the globe.

Vaccine-Induced Seroreactivity Impacts the Accuracy of HIV Testing Algorithms in Sub-Saharan Africa: An Exploratory Study.

The detection of vaccine-induced HIV antibody responses by rapid diagnostic tests (RDTs) may confound the interpretation of HIV testing results. We assessed the impact of vaccine-induced seroreactivity (VISR) on the diagnosis of HIV in sub-Saharan Africa. Samples collected from healthy participants of HIVIS and TaMoVac HIV vaccine trials after the final vaccination were analyzed for VISR using HIV testing algorithms used in Mozambique and Tanzania that employ two sequential RDTs. The samples were also tested for VISR using Enzygnost HIV Integral 4 ELISA and HIV western blot assays. Antibody titers to subtype C gp140 were determined using an in-house enzyme-linked immunosorbent assay (ELISA). The frequency of VISR was 93.4% (128/137) by Enzygnost HIV Integral 4 ELISA, and 66.4% (91/137) by western blot assay (WHO interpretation). The proportion of vaccine recipients that would have been misdiagnosed as HIV-positive in Mozambique was half of that in Tanzania: 26.3% (36/137) and 54.0% (74/137), respectively, p < 0.0001. In conclusion, the HIV RDTs and algorithms assessed here will potentially misclassify a large proportion of the HIV vaccine recipients if no other test is used. Increased efforts are needed to develop differential serological or molecular tools for use at the point of care.

Analysis of the HIV Vaccine Trials Network 702 Phase 2b–3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk

Analysis of the HIV Vaccine Trials Network 702 Phase 2b–3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk

"By only considering the end product it means that our participation has always been in vain": Defining benefits in HIV vaccine trials in Tanzania.

Debates about what constitutes benefits in human research continue to be less informed due to a lack of empirical evidence from the developing world. This study aimed to explore what constitutes benefits in HIV vaccine trials in Tanzania and examine inherent ethical implications. A qualitative case study design was deployed and a total of 29 purposively selected study participants comprising of experienced researchers, institutional review board members and community advisory board members were included. Collected data were analyzed by thematic analysis aided by computer software: MAXQDA version 20.4.0. The study findings indicate that there is a growing appreciation of benefits beyond actual vaccines to include 1) capacity building at individual, community, institutional and regulatory levels; and 2) non-capacity building related benefits such as strengthened collaborations, ancillary care and employment opportunities. So, as the struggle for viable HIV vaccines continues, other benefits that have accrued from such trials are not to be blindsided especially for developing countries like Tanzania.

Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices—United States, 2022

Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices—United States, 2022

A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination.

Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.

"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.

Structure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s.

Passive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes.