Dan H Barouch, M.D., PhD. - US grants

DESCRIPTION (provided by applicant): Dr. Dan Barouch received his D.Phil. from Oxford University prior to completing his M.D. at Harvard Medical School. He is currently in his final year of internal medicine residency training at Massachusetts General Hospital, after which he will be a fellow in infectious diseases. He plans a full-time career as an academic investigator with a special interest in translational research and AIDS vaccine development. During medical school and residency, Dr. Barouch worked part-time in the laboratory of Dr. Norman Letvin at the Beth Israel Deaconess Medical Center. His preliminary work showed that cytokine plasmids could augment DNA vaccine- elicited immune responses in both mice and rhesus monkeys. Moreover, he demonstrated that cytokine-augmented DNA vaccination could control viremia and prevent clinical AIDS following a pathogenic, homologous SHIV challenge. In the current studies, he will examine the immune correlates of long-term control of viremia in these animals. He will also examine the protective efficacy of cytokine-augmented DNA vaccination strategies and DNA/rMVA (recombinant modified vaccinia Ankara) prime-boost regimens against pathogenic, heterologous viral challenges. In addition, he will initiate a phase I clinical trial to assess the safety, tolerability, and immunogenicity of cytokine-augmented DNA vaccine strategies in humans. Dr. Norman Letvin, Chief of the Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, and Dr. Raphael Dolin, Dean for Clinical Programs, Harvard Medical School, will guide Dr. Barouch's development as an independent investigator. In addition, a committee of distinguished scientists will oversee his progress toward independence.

DESCRIPTION (provided by applicant): The development of a safe and effective HIV-1 vaccine is a global health priority. Plasmid DNA vaccines have elicited potent virus-specific cellular immune responses in animal models but have proven only marginally immunogenic in clinical trials to date. Strategies aimed at augmenting the immunogenicity of DNA vaccines are therefore an area of active investigation. We have recently demonstrated that co-administration of the combination of plasmid MIP-1alpha and plasmid GM-CSF with DNA vaccines resulted in the recruitment of large numbers of dendritic cells to the site of inoculation and a synergistic and durable augmentation of DNA vaccine-elicited immune responses in mice. We hypothesize that the immunogenicity of DNA vaccines is limited by the availability of professional antigen-presenting cells (APCs) at the site of inoculation. We further hypothesize that DNA vaccine-elicited immune responses in both mice and rhesus monkeys will be augmented by co-administration of plasmid-encoded chemoattractants that recruit APCs to the site of inoculation. To investigate these hypotheses, we propose: I. To investigate the immunogenicity, protective efficacy, and histopathology of a novel vaccine strategy consisting of GM-CSF/MIP-1alpha-augmented DNA vaccine priming followed by rAd5 boosting in rhesus monkeys; II. To construct plasmid chemokine/Ig fusions and to assess their ability to augment DNA vaccine-elicited immune responses in mice; III. To assess the ability of plasmid chemokines combined with plasmid costimulatory molecules to augment DNA vaccine-elicited immune responses in mice; and IV. To investigate the immunogenicity and protective efficacy of cytokine-augmented DNA vaccine priming followed by rAd5 boosting in rhesus monkeys with pre-existing anti-Ad5 immunity. The long-term objectives of these studies are to develop novel vaccine regimens that recruit APCs to the site of inoculation in animal models and to consider advancing the most promising strategies into clinical trials.

[unreadable] DESCRIPTION (provided by applicant): The development of a safe and effective HIV-1 vaccine is a global health priority. Recombinant adenovirus serotype 5 (rAd5) vector-based vaccines have been shown to elicit potent cellular immune responses in animal models and are being developed as candidate HIV-1 vaccines. However, the high prevalence of preexisting immunity to Ad5 in human populations will likely substantially limit the immunogenicity and clinical utility of rAd5 vaccines. Recombinant adenovirus serotype 35 (rAd35) vector-based vaccines are therefore being developed as potential alternatives to rAd5 vaccines. Our preliminary studies demonstrate that a rAd35-Gag vaccine effectively evades anti-Ad5 immunity but is substantially less immunogenic than a rAd5-Gag vaccine in mice. The development of improved vaccine vectors is therefore urgently needed. [unreadable] [unreadable] In this Innovation Grant, we propose to construct novel chimeric rAd vectors that combine the desirable properties of rAd5 and rAd35. The Ad5 fiber protein may be critical for rAd5 immunogenicity, whereas the Ad5 hexon protein is the primary target of Ad5-specific neutralizing antibodies. We therefore hypothesize that chimeric rAd vectors containing the Ad5 fiber and the Ad35 hexon will both retain the immunogenicity of rAd5 and effectively evade anti-Ad5 immunity. If successful, these novel vectors could be developed rapidly as improved adenovirus vaccines for HIV-1. We propose the following three Specific Aims: [unreadable] [unreadable] I. To construct and assess the immunogenicity of rAd35 vectors containing the Ad5 fiber in mice; [unreadable] II. To construct and assess the immunogenicity of rAd5 vectors containing the Ad35 hexon in mice; and [unreadable] III. To assess the immunogenicity of the optimal chimeric rAd vector in a pilot study in rhesus monkeys. [unreadable] [unreadable] This project is consistent with the goals of PA-03-082, which aims to support the entrance of innovative, exploratory, high risk/high impact prophylactic vaccine concepts into the research pipeline. Within the two-year time frame of this award, sufficient data will be generated with candidate chimeric rAd vaccines to justify further vaccine/challenge studies in rhesus monkeys. [unreadable] [unreadable]

A critical roadblock in the development of an HIV-1 vaccine is our current inability to deliver HIV-1 antigens efficiently to the immune system and to prime predictable, high frequency immune responses in humans. Recombinant Ad5 vector-based vaccines have elicited potent immune responses in preclinical studies. However, the high frequency of anti-Ad5 immunity in the developing world will likely limit the immunogenicity and clinical utility of rAd5 vaccines. We therefore propose the development of novel, replication-incompetent rAd vector-based vaccines for HIV-1. In this project, we will investigate the hypothesis that novel rAd vector-based vaccines derived from rare Ad serotypes and engineered for improved immunogenicity will elicit potent immune responses in rhesus monkeys with anti-Ad5 immunity. We further hypothesize that heterologous rAd prime-boost regimens utilizing these novel rAd vectors will prove substantially more immunogenic than traditional rAd5 vaccines in the presence of anti-Ad5 immunity. As a key component of these studies, we will systematically compare the immunogenicity and protective efficacy of various rAd vector combinations to determine the optimal vaccine regimen to advance into the clinical studies described in Project 2 of this IPCAVD grant. To investigate these hypotheses, we propose the following five Specific Aims: 1. To compare the immunogenicity of rAd5, rAd35, and capsid chimeric rAd5/rAd35 vectors in rhesus monkeys with anti-Ad5 immunity; 2. To compare the immunogenicity of various heterologous rAd prime-boost regimens in rhesus monkeys with anti-Ad5 immunity and to assess their protective efficacy against a SHIV-89.6P challenge; 3. To assess the immunogenicity and protective efficacy of the optimal heterologous rAd prime-boost regimen against an SIVmac251 challenge in rhesus monkeys with and without anti-Ad5 immunity; 4. To assess the immunogenicity and protective efficacy of limiting vaccine doses of the optimal heterologous rAd prime-boost regimen against a heterologous SIVmac251 challenge in rhesus monkeys with anti-Ad5 immunity; and 5. To determine the protective efficacy of the optimal heterologous rAd prime-boost regimen against repetitive, low-dose, mucosal, heterologous SIVmac251 challenges in rhesus monkeys with anti-Ad5 immunity.

Centralized administration is critical for efficient project management, coordination, and execution. Core A (Administrative Core) will provide all the logistic, scientific, managerial, financial, and biostatistics support to facilitate and to coordinate the studies described in this Consortium. The Administrative Core will ensure that all the Projects and Cores function optimally and adhere to the timelines described in the individual sections of this grant. The Administrative Core will establish a Scientific Leadership Committee as the primary decision making committee for this Consortium, organize conference calls every two weeks and regular in-person meetings, maintain regulatory approvals, provide fiscal and logistic oversight, manage subcontracts, and coordinate meetings with the Scientific Advisory Board and DAIDS Program Officials. This detailed administration and management structure will ensure that all the studies remain focused on the overall objective to evaluate the early events of acute mucosal SIV/SHIV infection and the capacity of vaccines to impact these events. To accomplish these goals, we propose the following five Specific Aims: 1. To coordinate communications, interactions, and operations among investigators, Projects, and Cores to facilitate the overall progress and goals of this Consortium; 2. To ensure and to maintain regulatory compliance; 3. To provide detailed financial oversight and management; 4. To coordinate meetings with the Scientific Advisory Board and DAIDS Program Officials; and 5. To provide biostatistics support for all Projects and Cores.

DESCRIPTION (provided by applicant): A critical roadblock in the development of an HIV-1 vaccine is our current inability to deliver HIV-1 antigens efficiently to the immune system and to prime predictable, high frequency immune responses in humans. Recombinant Ad5 vector-based vaccines have elicited potent immune responses in preclinical studies. However, the high frequency of anti-Ad5 immunity in the developing world will likely limit the immunogenicity and clinical utility of rAd5 vaccines. We therefore propose the development of novel, replication-incompetent rAd vector-based vaccines for HIV-1. In this IPCAVD grant, we propose a focused, timeline-driven, milestone-oriented, product development program to evaluate the utility of rare serotype and molecularly engineered Ad vectors as candidate HIV-1 vaccines. We will define the optimal heterologous rAd prime-boost regimen in preclinical studies and advance this regimen into phase I and phase II clinical trials. These studies will investigate the hypothesis that these novel rAd vaccines for HIV-1 are immunogenic in the presence of anti-Ad5 immunity in both rhesus monkeys and humans. In Project 1 (Preclinical Evaluation of Novel Adenovirus Vectors), we will compare various rAd primeboost regimens in rhesus monkeys with anti-Ad5 immunity and select the optimal regimen to advance into clinical studies. We hypothesize that the optimal vector combination will involve two heterologous serotype rAd vectors that are both rare in human populations, engineered for optimal immunogenicity, derived from different Ad subfamilies, and distinct from Ad5. In Project 2 (Clinical Evaluation of Novel Adenovirus Vectors), we will conduct two phase I dose-escalation studies and a phase II heterologous rAd prime-boost study in the developing world in collaboration with the HIV Vaccine Trials Network (HVTN). Core A (Administrative Core Facility) will provide all the logistic, scientific, managerial, and financial oversight to coordinate the studies described in this IPCAVD grant. Core B (Vector Core Facility) will manufacture research-grade and clinical-grade rAd vectors and will obtain the regulatory approvals required to initiate the clinical studies. An External Steering Committee consisting of senior and distinguished leaders in the field has been assembled to supervise and to guide the overall progress of the proposed studies. By the end of the proposed 5-year period of support, we predict that we will have generated sufficient preclinical and clinical data to determine whether this vaccine strategy should be advanced into expanded clinical trials.

[unreadable] DESCRIPTION (provided by applicant): A critical roadblock in the development of an HIV-1 vaccine is our current inability to deliver HIV-1 antigens efficiently to the immune system and to prime predictable, high frequency immune responses in humans. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 have elicited potent immune responses in preclinical studies. However, the high frequency of anti-Ad5 immunity in the developing world will likely limit the immunogenicity and clinical utility of rAd5 vaccines. We therefore propose the development of novel rAd vector-based vaccines for HIV-1. [unreadable] [unreadable] We hypothesize that rAd vector-based vaccines derived from rare Ad serotypes and engineered for improved immunogenicity will prove significantly more immunogenic than rAd5 vaccines in rhesus monkeys with anti-Ad5 immunity. We further hypothesize that the optimal rAd vaccine regimen will be a heterologous prime-boost regimen involving two different serotype vectors that are both rare in human populations, engineered for optimal immunogenicity, derived from different Ad subfamilies, and distinct from Ad5. [unreadable] [unreadable] To investigate these hypotheses, we propose the following four Specific Aims: [unreadable] 1. To compare the immunogenicity of rAd5, rAd35, and capsid chimeric rAd5/rAd35 vectors in rhesus monkeys with anti-Ad5 immunity; [unreadable] 2. To assess the immunogenicity of heterologous rAd prime-boost regimens involving vectors derived from two different Ad subfamilies in mice; [unreadable] 3. To assess the immunogenicity and protective efficacy of the optimal heterologous rAd prime-boost regimen against an SIVmac251 challenge in rhesus monkeys with and without anti-Ad5 immunity; and 4. To determine the immunogenicity and protective efficacy of the optimal heterologous rAd prime- boost regimen delivered by either systemic or mucosal routes against repetitive, low-dose, mucosal SIVmac251 challenges in rhesus monkeys with anti-Ad5 immunity. [unreadable] [unreadable] The overall goal of these studies is to develop a novel heterologous rAd prime-boost regimen for HIV-1 that is highly immunogenic in the presence of anti-Ad5 immunity and that can be advanced rapidly into clinical vaccine trials in the developing world. [unreadable] [unreadable]

Centralized administration is critical for efficient program management, coordination, and execution. Core A (Administrative Core) will provide all the logistic, scientific, managerial, financial, and biostatistics support to facilitate and to coordinate the studies described in this IPCAVD program. Core A will ensure that all the Projects and Cores function optimally and adhere to the timelines described in this grant. Core A will organize conference calls every two weeks and regular in-person meetings, maintain regulatory approvals, provide fiscal and logistic oversight, manage subcontracts, coordinate meetings with the Scientific Advisory Board (SAB) and NIAID Program Officials to support this IPCAVD program, and provide centralized biostatistics support for all preclinical and clinical studies for this IPCAVD program. This detailed administration and management structure will ensure that all the studies remain focused on the overall objective to develop Ad26/Env vaccines for HIV-1. To accomplish these goals, we propose the following five Specific Aims: Specific Aim 1. To coordinate communications, interactions, and operations among investigators, Projects, and Cores to facilitate the overall progress and goals of this IPCAVD program Specific Aim 2. To ensure and to maintain regulatory compliance Specific Aim 3. To provide detailed financial oversight and management Specific Aim 4. To coordinate meetings with the SAB and NIAID Program Officials Specific Aim 5. To provide centralized biostatistics support for this IPCAVD program

Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd Vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. We propose to develop a practical, two-injection, heterologous rAd26 prime, rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate HIV-1 vaccine. The goals of Project 1 are to select the optimal antigens for our multivalent HIV-1 vaccine candidate and to evaluate the immunogenicity and protective efficacy of the rAd26 prime, rAd5HVR48 boost regimen in rhesus monkeys to support the clinical program in Project 2 and the manufacturing program in Project 3. In Project 1, we hypothesize that M consensus or M mosaic HIV-1 antigens will prove superior to naturally occurring C clade and VRC multiclade antigens for immunologic coverage of diverse global virus sequences. We further hypothesize that the optimal vaccine regimen expressing SIV antigens will afford significant protection against both homologous and heterologous SIV challenges in rhesus monkeys. To explore these hypotheses, we propose the following four Specific Aims: 1. To compare the magnitude and breadth of immune responses elicited by optimal C clade, M consensus, M mosaic, and VRC multiclade antigens in rhesus monkeys; 2. To determine the protective efficacy of the optimal vaccine regimen expressing various sets of SIV antigens against homologous SIV challenges in rhesus monkeys with anti-Ad5 immunity; 3. To evaluate the protective efficacy of the optimal vaccine regimen against heterologous SIV challenges in rhesus monkeys with anti-Ad5 immunity;and 4. To assess the mucosal immunogenicity and protective efficacy of the optimal vaccine regimen against multiple, low-dose, mucosal SIV challenges in rhesus monkeys with anti-Ad5 immunity.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are [unreadable] promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. [unreadable] We therefore propose to develop a practical, two-injection, heterologous rAd26 prime, [unreadable] rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate [unreadable] HIV-1 vaccine. To accomplish this goal, we propose three Projects and one Core: [unreadable] Project 1 (Preclinical Evaluation of Novel Adenovirus Prime-Boost HIV-1 Vaccine) will determine the [unreadable] optimal antigens for our multivalent HIV-1 vaccine candidate and will evaluate the immunogenicity and [unreadable] protective efficacy of the rAd26 prime, rAd5HVR48 boost regimen against homologous and heterologous SIV challenges in rhesus monkeys. [unreadable] Project 2 (Clinical Evaluation of Novel Adenovirus Prime-Boost HIV-1 Vaccine) will assess the safety [unreadable] and immunogenicity of the optimal heterologous rAd26 prime, rAd5HVR48 boost regimen in phase 1 and international phase 2a clinical trials in collaboration with the HIV Vaccine Trials. Network (HVTN). [unreadable] Project 3 (Manufacturing of Novel Adenovirus Prime-Boost HIV-1 Vaccine) will manufacture and [unreadable] release trivalent, clinical-grade rAd26 and rAd5HVR48 vaccine products at Crucell Holland BV, Leiden, The Netherlands. [unreadable] Core A (Administrative Core) will provide all the logistic, scientific, managerial, and financial oversight [unreadable] to facilitate and to coordinate the studies described in this IPCAVD program. [unreadable] By the end of the proposed 5-year period of support, we plan to have sufficient preclinical and clinical [unreadable] data to determine whether this vaccine may be a promising candidate for further development into advanced phase clinical trials including potential efficacy studies. [unreadable] [unreadable] [unreadable] PROJECT 1: Preclinical Evaluation of Novel Adenovirus Prime-Boost HIV-1 Vaccine: Dan H. Barouch [unreadable] [unreadable] PROJECT 1 DESCRIPTION (provided by applicant): [unreadable] Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are [unreadable] promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd Vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. We propose to develop a practical, two-injection, heterologous rAd26 prime, rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate HIV-1 vaccine. The goals of Project 1 are to select the optimal antigens for our multivalent HIV-1 vaccine candidate and to evaluate the immunogenicity and protective efficacy of the rAd26 prime, rAd5HVR48 boost regimen in rhesus monkeys to support the clinical program in Project 2 and the manufacturing program in Project 3. [unreadable] In Project 1, we hypothesize that M consensus or M mosaic HIV-1 antigens will prove superior [unreadable] to naturally occurring C clade and VRC multiclade antigens for immunologic coverage of diverse [unreadable] global virus sequences. We further hypothesize that the optimal vaccine regimen expressing SIV [unreadable] antigens will afford significant protection against both homologous and heterologous SIV challenges in rhesus monkeys. To explore these hypotheses, we propose the following four Specific Aims: [unreadable] 1. To compare the magnitude and breadth of immune responses elicited by optimal C clade, M [unreadable] consensus, M mosaic, and VRC multiclade antigens in rhesus monkeys; [unreadable] 2. To determine the protective efficacy of the optimal vaccine regimen expressing various sets of SIV antigens against homologous SIV challenges in rhesus monkeys with anti-Ad5 immunity; [unreadable] 3. To evaluate the protective efficacy of the optimal vaccine regimen against heterologous SIV [unreadable] challenges in rhesus monkeys with anti-Ad5 immunity; and [unreadable] 4. To assess the mucosal immunogenicity and protective efficacy of the optimal vaccine regimen [unreadable] against multiple, low-dose, mucosal SIV challenges in rhesus monkeys with anti-Ad5 immunity. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): HIV-1 infection begins with the fusion of viral and target cell membranes, which is mediated by the viral envelope glycoprotein upon engagement with host cellular receptors. The HIV-1 envelope glycoprotein undergoes large structural rearrangements during viral entry. There are at least three distinct conformational states of the HIV-1 envelope protein: the prefusion, prehairpin intermediate, and postfusion conformations. Each conformation presents distinct antigenic surfaces to the immune system. In this proposal, we seek to assess the impact of HIV-1 envelope conformation on immunogenicity. We hypothesize that different functional conformers of the HIV-1 envelope protein elicit distinct profiles of antibody responses. A deeper understanding of the relationship between HIV-1 envelope structure and immunogenicity will likely facilitate future structure-based immunogen design strategies at a level of sophistication and structural detail that has not previously been possible. To explore this hypothesis, we propose the following three Specific Aims: 1. We will assess the immunogenicity of the three principal conformational states of gp41 corresponding to the prefusion, prehairpin intermediate, and postfusion conformations in guinea pigs;2. We will investigate the immunogenicity of uncleaved, precursor state (gp140)3 trimers and cleaved (gp120/gp41ecto)3 trimer complexes in guinea pigs;and, 3. We will determine the immunogenicity and protective efficacy of the optimal HIV-1 envelope immunogens in rhesus monkeys. An HIV-1 envelope immunogen with the ability to induce broadly reactive NAbs will likely be an essential component for any successful AIDS vaccine. Given the recent disappointing results from the Merck rAd5 vaccine trials aimed at eliciting T cell responses, the need to identify envelope immunogens that can elicit broadly reactive neutralizing antibodies has never been greater. In this proposal, we will assess the impact of HIV-1 envelope conformation on the profile of elicited neutralizing antibody responses.

The earliest events following mucosal HIV-1 exposure represent a critical window of opportunity for vaccine-elicited immune responses to impact the acquisition and propagation of HIV-1 infection. However, very little is known about the biology of the eclipse phase of HIV-1 infection in humans, particularly the immunologic and virologic events that occur at the mucosal site of transmission. Given the difficulties in studying the earliest mucosal events of HIV-1 infection in humans, modeling these events in nonhuman primates is required. Such studies will provide insight into the early events of virus transmission and the capacity of immune responses to block or to attenuate these events. In this Project, we hypothesize that SIV-specific immune responses elicited by adenovirus and poxvirus vaccine vectors will substantially impact the early events following intravaginal (IVAG) SIV infection of rhesus monkeys. In particular, we hypothesize that vaccine-elicited mucosal immune responses at the site of inoculation will limit the initial local amplification of virus at the mucosal portal of entry during the eclipse phase of infection prior to systemic virus dissemination. The goal is to define precisely when and where innate and adaptive immune responses intercept the virus following IVAG SIV infection of both .naive and vaccinated animals. To evaluate these hypotheses, we propose the following Specific Aims: 1. To define the early virologic, immunologic, and pathologic events following IVAG SIV infection of naive, unvaccinated rhesus monkeys; 2. To evaluate the capacity of adenovirus vector-based vaccines to impact the early events following IVAG SIV infection of rhesus monkeys; and 3. To assess the capacity of poxvirus vector-based vaccines to impact the early events following IVAG SIV infection of rhesus monkeys.

DESCRIPTION (provided by applicant): The earliest events following mucosal HIV-1 exposure represent a critical window of opportunity for vaccine-elicited immune responses to impact the acquisition and propagation of HlV-1 infection. However, opportunities to elucidate these early immunologic and virologic events in humans are extremely limited. Modeling these events in nonhuman primates will therefore likely be instrumental in the design and development of next generation HIV-1 vaccine strategies. Such studies will provide critical insights into the early events of virus transmission and the capacity of vaccine-elicited immune responses to block or to attenuate these events. In this Consortium, we have assembled many the of world's foremost experts in nonhuman primate research and HIV-1 vaccine development to analyze the virology and immunology of early SIV/SHIV infection in rhesus monkeys as well as to determine the mechanism by which cutting-edge vaccine approaches afford protection in these models. These studies will allow a detailed interrogation of the ability of different types of immune responses to intercept the virus and to control early infection. We hypothesize that certain vaccines and immunologic interventions will be able to attenuate or even abrogate the early events following mucosal SIV/SHIV infection, including the initial local amplification of virus at the mucosal portal of entry as well as the subsequent trajectory of virus spread that leads to systemic dissemination. During the proposed five year project period, we will explore in detail the mechanism of protection afforded by adenovirus vectors and poxvirus vectors (Barouch, Project 1), cytomegalovirus vectors (Picker, Project 2), live attenuated SIV (Johnson, Project 3), neutralizing antibodies (Burton, Project 4), and adeno-associated virus-mediated antibody delivery (Desrosiers, Project 5). These Projects will receive extensive support from the Administrative/Biostatistics (Barouch/Johnson, Core A), Pathology (Haase, Core B), Immunology (Johnson/Burton, Core C), Virology (Shaw/Lifson, Core D), Systems Biology (Sekaly, Core E), and Nonhuman Primate (Axthelm/Mansfield, Core F) core facilities.

DESCRIPTION (provided by applicant): The development of an HIV-1 vaccine is a critical global health priority. Yet, despite over 30 years of research, only three HIV-1 vaccine concepts have completed clinical efficacy testing in humans. The RV144 study showed that an ALVAC prime, gpl20 protein boost regimen afforded 31% protection against acquisition of HIV-1 infection in a community-based study in Thailand, suggesting that the development of an HIV-1 vaccine is possible. However, additional novel vaccine concepts need to be tested in clinical trials, including clinical efficacy trials. In this IPCAVD program, we propose to evaluate our Ad26/MVA and Ad26/Protein vaccine candidates in SIV challenge studies in rhesus monkeys and in phase 1 clinical trials in humans. Specifically, we hypothesize that a heterologous prime-boost regimen combining novel serotype adenovirus vectors with poxvirus vectors and/or Env gp140 trimers will induce potent and protective antitbody and T lymphocyte responses. The goal of these studies is to define the optimal vaccine candidate for potential phase 2 clinical development. To accomplish this goal, we propose the following Projects and Cores: Project 1: Preclinical Evaluation of Novel Ad/MVA and Ad/Protein l-IIV-1 Vaccines Project 2: Clinical Evaluation of Novel Ad/MVA and Ad/Protein HIV-1 Vaccines Project 3: Manufacturing and Regulatory Support of Ad/MVA and Ad/Protein HIV-1 Vaccines Core A: Administrative Core; Core B: Immune Monitoring Core. Project 1: Preclinical Evaluation of Novel Ad/MVA and Ad/Protein HIV-1 Vaccines Project 1 Leader (PL): Dan H. Barouch DESCRIPTION (provided by applicant): Adenovirus vectors have proven highly potent for inducing both humoral and cellular immune responses. The failure of an Ad5-Gag/Pol/Nef vaccine in the Step study has led to the development of novel serotype Ad vectors, which are biologically very different and arguably substantially superior to Ad5 in terms of seroepidemiology, cellular receptor usage, in vivo tropism, innate immune responses, transcriptional profiles, adaptive immune phenotypes, and protective efficacy against SIV in rhesus monkeys. Moreover, the inclusion of Env may be critical for an HIV-1 vaccine. Based on our preclinical and clinical preliminary data, we have prioritized Ad26/MVA and Ad26/Protein regimens for further development. In Project 1, we will conduct the key preclinical studies to inform the clinical development program described in Project 2. These studies will help define the lead vaccine candidate and will help determine the mechanism of protection afforded by our optimal vaccine regimen. Specifically, we will test the hypothesis that adding a gp140 trimer protein boost will augment the partial protection afforded by our optimal vaccine vectors against acquisition of highly stringent, heterologous SIV challenges. We will also test the hypothesis that vaccine-elicited Env-specific antibodies are critical for this protection. To evaluate these hypotheses, we propose the following two Specific Aims: 1. To compare the immunogenicity and protective efficacy of Ad26/Ad26 and Ad26/MVA vector regimens with and without a gp140 trimer protein boost against repetitive, heterologous, neutralization-resistant, intrarectal SIV challenges in rhesus monkeys; and 2. To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys.

PROJECT SUMMARY (See instructions): Adenovirus vectors have proven highly potent for inducing both humoral and cellular immune responses. The failure of an Ad5-Gag/Pol/Nef vaccine in the Step study has led to the development of novel serotype Ad vectors, which are biologically very different and arguably substantially superior to Ad5 in terms of seroepidemiology, cellular receptor usage, in vivo tropism, innate immune responses, transcriptional profiles, adaptive immune phenotypes, and protective efficacy against SIV in rhesus monkeys. Moreover, the inclusion of Env may be critical for an HIV-1 vaccine. Based on our preclinical and clinical preliminary data, we have prioritized Ad26/MVA and Ad26/Protein regimens for further development. In Project 1, we will conduct the key preclinical studies to inform the clinical development program described in Project 2. These studies will help define the lead vaccine candidate and will help determine the mechanism of protection afforded by our optimal vaccine regimen. Specifically, we will test the hypothesis that adding a gp140 trimer protein boost will augment the partial protection afforded by our optimal vaccine vectors against acquisition of highly stringent, heterologous SIV challenges. We will also test the hypothesis that vaccine-elicited Env-specific antibodies are critical for this protection. To evaluate these hypotheses, we propose the following two Specific Aims: 1. To compare the immunogenicity and protective efficacy of Ad26/Ad26 and Ad26/MVA vector regimens with and without a gp140 trimer protein boost against repetitive, heterologous, neutralization-resistant, intrarectal SIV challenges in rhesus monkeys; and 2. To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys.

Infection of rhesus macaques with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) is a key animal model for HIV-1 infection. The Nonhuman Primate (NHP) Scientific Research Support Component (SRSC) aims to support this CHAVI-ID by providing all the expertise, infrastructure, reagents, personnel, and animals for the conduct of complex in vivo immunogenicity and challenge studies in NHPs. This SRSC will involve leadership from both Beth Israel Deaconess Medical Center and the Yerkes National Primate Research Center (Emory University) and is well positioned to meet the CHAVI-ID goals. This SRSC leadership will work closely with the research discovery teams responsible for the studies described in Scientific Foci #1 and#2 and participate actively in the scientific mission of this CHAVI-ID. The main role of this SRSC is to provide leadership and technical expertise to ensure consistency and quality control in animal selection, execution of study protocols, experimental procedures, sample acquisition and distribution, immunologic and virologic studies, and data collection and analysis. The Specific Aims are: 1. To support this CHAVI-ID by selecting and providing rhesus macaques, providing exceptional animal care, conducting experimental studies with monoclonal antibodies (MAbs) and vaccines, collecting samples for immunologic and virologic testing, and performing necropsy studies. These studies will initially evaluate: A. Protective efficacy of HIV-1 Env-specific MAbs against SHIV challenge; B. Immunogenicity and protective efficacy of novel HIV-1 Env immunogens and immunization strategies; 2. To support this CHAVI-ID by providing blood and tissue samples from SIV/SHIV-infected and uninfected NHPs to collaborating investigators to underpin basic research studies. These samples will support studies of neutralizing Abs in Focus #1 and will help elucidate the characteristics of virus-specific CD4+ follicular helper T cell (Tfh) responses in Focus #2, with an initial emphasis on the development of Tfh cells during vaccine-induced immune responses and the role of Tfh cells in promoting the affinity maturation of antibodies.

SUMMARY The overall goal of our Consortium is to elucidate the immunologic mechanisms of leading HIV-1 prophylactic vaccines and eradication strategies. Our overall hypothesis is that understanding the mechanism of action of these immunologic interventions will facilitate the clinical development of these concepts and will also lead to the next generation of vaccines and eradication strategies. Focus 1: Understanding Mechanisms of Prophylactic SIV Vaccine Efficacy. We have developed two prophylactic vaccines with distinct and potentially complementary modes of protection against highly pathogenic mucosal SIV challenges. In Focus 1, we will explore the hypothesis that Ad26/Env and CMV vector vaccines protect by distinct and potentially complementary mechanisms. The major objectives are to determine the component or components of the humoral and/or cellular immune responses responsible for the efficacy of the Ad26/Env and CMV vector vaccines, the mechanisms by which these components prevent or control/clear infection, and their potential for combinatorial enhancement of efficacy. Specific Aim 1: To determine the nature and functional characteristics of antibodies responsible for protection against acquisition of infection in monkeys vaccinated with the Ad26/Env regimen. Specific Aim 2: To determine the cell type(s) (CD8+ T cells, CD4+ T cells, NK cells) responsible for CMV vector-mediated early control and eventual clearance of SIV infection, and the immunobiologic basis of protection vs. non-protection. Specific Aim 3: To determine whether combination of an acquisition-preventing Ab-targeted vaccine and an infection-controlling/clearing cellular immunity-targeted vaccine will add or synergize in protection. Focus 2: Development of Immunologic Strategies for SIV Remission/Eradication. Functional HIV cure will likely require both viral reservoir reduction and potent, long-term anti-viral immunity such that the viral reactivation that occurs after cART cessation can be eliminated or stringently controlled over a lifetime. In Focus 2, we will explore the hypothesis that therapeutic vaccines and engineered T cells, together with sanctuary disruption and potentially latency reversal, can contribute to virus eradication strategies. Specific Aim 1: To develop vaccine vector-based strategies to elicit T cell responses able to destroy reactivating virus during cART therapy and/or control viral relapse after cART cessation. Specific Aim 2: To develop engineered autologous T cell-based strategies to destroy reactivating virus during cART therapy and facilitate control of viral relapse after cART cessation. Specific Aim 3: To determine whether 2nd generation therapeutic vaccines combined with optimized latency reversal/sanctuary therapy can enhance SIV reservoir depletion and/or control post-cART viral relapse.

SUMMARY The goal of our Collaboratory is to develop novel combined immunologic approaches to cure HIV-1 through a highly collaborative and multifaceted research program involving leading investigators in academia, government, and industry. Our overall hypothesis is that a combined immunologic approach that optimizes antiviral humoral and cellular immune responses, together with latency reversal and possibly lymphoid sanctuary disruption, will effectively reduce or control the viral reservoir in ART- suppressed, SHIV-infected rhesus monkeys and in ART-suppressed, HIV-1-infected humans to achieve a functional cure. We propose two interactive Research Foci and five Scientific Research Support Sections (Clinical, Nonhuman Primate, Virology, Immunology, and Biostatistics and Bioinformatics). Focus 1: Efficacy of Combined Immunologic Approaches to Target the Viral Reservoir In this Focus, we will evaluate the efficacy of best-in-class broadly neutralizing monoclonal antibodies (bnMAbs), therapeutic vaccines, and latency reversing agents (LRAs) in both SHIV-infected rhesus monkeys and HIV-1-infected humans. These studies will fill a critical knowledge gap by defining the capacity of leading immunologic interventions to target viral reservoirs and to contribute to an HIV-1 cure. Specific Aim 1. To evaluate two leading therapeutic vaccines in ART-suppressed, HIV-1-infected humans treated during acute HIV-1 infection; Specific Aim 2. To evaluate the combination of bnMAbs and a therapeutic vaccine in ART-suppressed, SHIV- infected rhesus monkeys; and Specific Aim 3. To evaluate the combination of optimal bnMAbs and a therapeutic vaccine in ART- suppressed, HIV-1-infected humans treated during both acute and chronic HIV-1 infection. Focus 2: Mechanisms and Next Generation Strategies to Target the Viral Reservoir A major knowledge gap is that we currently do not know which anatomic viral sanctuary gives rise to viral rebound following discontinuation of ART. In this Focus, we will evaluate the impact of bnMAbs, therapeutic vaccines, and LRAs on the viral reservoir, and we will define the anatomic location of the residual viral reservoir that persists despite these interventions with the goal of developing next generation HIV-1 cure strategies. Specific Aim 1. To define the mechanism of action of leading bnMAbs, therapeutic vaccines, and LRAs in depleting the viral reservoir in ART-suppressed, SHIV-infected rhesus monkeys; Specific Aim 2. To develop more effective bnMAbs for reservoir depletion; and Specific Aim 3. To test an improved HIV-1 cure strategy in ART-suppressed, SHIV-infected rhesus monkeys.

SUMMARY One of the current leading HIV cure approaches is the ?shock and kill? strategy. This approach takes into account that virus reactivation alone will not likely lead to eradication of the reservoir, and that an additional immunologic effector mechanism will almost certainly be required to eliminate reactivated cells. While cytotoxic T cells have frequently been proposed as potential killers that may be recruited for such a strategy, broadly neutralizing antibodies (bNAbs) can also induce rapid destruction of target cells by directing the cytotoxic and antiviral activity of the innate immune system. This has been widely exploited by the monoclonal antibody therapeutics community in developing improved antibodies for cancer but has not yet been explored for HIV. Antibody Fc-engineering efforts have modified antibodies to ensure that they are able to drive killing of the targets, and not only bind them. Point mutations have been introduced to selectively and specifically drive relevant effector functions, bi- and tetra-specific antibodies have been engineered to broaden and optimize targeting, and natural Fc-optimization strategies via glycan engineering have been utilized to collectively tune and promote more effective Fc-effector function for target cell elimination. In this proposal, we hypothesize that rational antibody engineering will result in functional optimization of bNAbs that will more effectively eliminate the viral reservoir for HIV eradication. Specific Aim 1: Design and down-select a panel of Fc point mutants and/or glycan variants that drive reservoir clearance. Specific Aim 2: Develop a bi- or tetra-specific antibody that drives reservoir eradication. Specific Aim 3: Evaluate the efficacy of the optimized bNAbs for virus eradication in ART-suppressed, SHIV-infected rhesus monkeys.

The goal of this IPCAVD program is to develop Ad26/Env vaccines for HIV-1 by a highly collaborative and multifaceted research program involving leading investigators in academia and industry. Our overall hypothesis is that an optimized Ad26/Env mosaic vaccine will induce highly functional antibodies that will protect humans against acquisition of multiple HIV-1 clades. The significance of this program is the potential actual development of a safe and effective global HIV-1 vaccine, the unparalleled commitment of a major pharmaceutical company to this HIV-1 vaccine, and the opportunity for major scientific advances in our understanding of immune correlates of protection. In our current IPCAVD program (U19 AI096040), we have developed alternative serotype adenovirus vectors, bioinformatically optimized HIV-1 mosaic antigens, and stable Env gp140 protein immunogens. We have shown that the Ad26-Env/Gag/Pol prime, Env gp140 protein boost (Ad26/Env) vaccine afforded unprecedented protective efficacy against acquisition of infection following heterologous SIVmac251 challenges in rhesus monkeys, as well as robust protection against SHIV-SF162P3 challenges. Protection correlated with polyfunctional antibody responses as determined by systems serology. We have also advanced the Ad26/Env, Ad26/MVA, and Ad26/MVA/Env mosaic vaccines into phase 1/2a clinical trials in the United States, East Africa, South Africa, and Thailand. Over the next 5 years of this IPCAVD program, we propose to define the extent and mechanism of protection achieved by our lead Ad26/Env vaccine regimen in rhesus monkeys, to advance our lead vaccine regimen into phase 2b/3 efficacy studies in humans, and to develop an improved next generation HIV-1 vaccine candidate. To accomplish the goals of this IPCAVD program, we propose the following Projects and Cores: Project 1. Preclinical Development of Ad26/Env Vaccines for HIV Project 2. Manufacturing and Clinical Development of Ad26/Env Vaccines for HIV Core A. Administrative Core Core B. Immunology Core Core C. NHP Core

Infection of rhesus monkeys with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) is a key animal model for HIV-1 infection. Nonhuman primates (NHP) are complex, higher order species that require specialized infrastructure and experienced staff in a research setting. Core C (NHP Core) aims to support this IPCAVD program by providing all the expertise, infrastructure, reagents, personnel, animals, and logistics for the conduct of complex in vivo studies in rhesus monkeys. Core C will involve leadership from Beth Israel Deaconess Medical Center and Bioqual and is well positioned to meet program objectives. The goal of Core C is to provide leadership and technical expertise to ensure consistency and quality control in animal selection, execution of study protocols, experimental procedures, sample acquisition and distribution, and data collection and analysis. To accomplish this goal, we propose three Specific Aims: Specific Aim 1. To support this IPCAVD program by selecting and providing rhesus monkeys, providing exceptional animal care, and conducting experimental vaccine studies Specific Aim 2. To provide facilities for the receipt, cataloging, processing, storage, and distribution of blood and tissue samples in compliance with Good Clinical Laboratory Practice Specific Aim 3. To obtain and to maintain all required regulatory approvals for the proposed studies

In our current IPCAVD program (U19 AI096040), we have developed alternative serotype adenovirus vectors, bioinformatically optimized HIV-1 mosaic antigens, and stable Env gp140 protein immunogens. We have shown that the Ad26-Env/Gag/Pol prime, Env gp140 protein boost (Ad26/Env) vaccine afforded unprecedented protective efficacy against acquisition of infection following heterologous SIVmac251 challenges in rhesus monkeys, as well as robust protection against SHIV-SF162P3 challenges. Protection correlated with polyfunctional antibody responses as determined by systems serology. We have also advanced the Ad26/Env, Ad26/MVA, and Ad26/MVA/Env mosaic vaccines into phase 1/2a clinical trials in the United States, East Africa, South Africa, and Thailand. Over the next 5 years of this IPCAVD program, we propose to define the extent and mechanism of protection achieved by our lead Ad26/Env vaccine regimen in rhesus monkeys, to advance our lead vaccine regimen into phase 2b/3 efficacy studies in humans, and to develop an improved next generation HIV-1 vaccine candidate. In this Project, we hypothesize that our current Ad26/Env mosaic vaccine as well as simplified vaccine regimens will protect against SHIVs derived from diverse clades by a consistent mechanism involving polyfunctional non-neutralizing antibodies. We further hypothesize that a next generation HIV-1 vaccine candidate that elicits augmented NAb magnitude and breadth will improve protective efficacy against SHIV challenges in rhesus monkeys. To test these hypotheses we propose the following Specific Aims: Specific Aim 1. To define the protective efficacy and protective mechanism of our Ad26/Env mosaic vaccine and simplified vaccine regimens against SHIVs derived from diverse clades in rhesus monkeys Specific Aim 2. To develop an improved HIV-1 vaccine strategy that elicits augmented NAb responses in rhesus monkeys

The goal of therapeutic vaccination is to increase host immune control of HIV-1 to achieve durable virologic control in the absence of ART, which is defined as a ?functional cure?. However, therapeutic vaccine studies in humans have to date been largely unsuccessful. We speculate that this may reflect the fact that prior vaccines (i) have failed to induce sufficient breadth of cellular immune responses and (ii) have not effectively activated or targeted the latent viral reservoir. We hypothesize that a therapeutic vaccine that induces potent and broad immune responses and that activates the latent viral reservoir will reduce the size of the replication- competent viral reservoir and will enhance virologic control following ART discontinuation. We have shown that Ad26/MVA therapeutic vaccination together with innate immune stimulation with a TLR7 agonist resulted in virologic control in a subset of SIV-infected rhesus monkeys following ART discontinuation. We therefore propose to evaluate the immunogenicity and efficacy of the Ad26/MVA + TLR7 agonist vaccine in HIV-1-infected humans to define its ability to control viral replication following discontinuation of ART. We also hypothesize that the addition of broadly neutralizing antibodies (bNAbs) may augment the antiviral efficacy of a therapeutic vaccine. To optimize both active and passive immunity, we propose a follow-up study to evaluate the optimal therapeutic vaccine together with bNAbs in HIV-1-infected humans. We therefore propose the following two Specific Aims: Specific Aim 1. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with TLR7 agonist administration in HIV-1-infected humans Specific Aim 2. To evaluate the safety, immunogenicity, and efficacy of Ad26/MVA therapeutic vaccination with broadly neutralizing antibodies (bNAbs) and a TLR7 agonist in HIV-1-infected humans

SUMMARY The viral reservoir in latently infected CD4+ T lymphocytes represents the key challenge for achieving an HIV-1 cure. We recently reported that the combination of the broadly neutralizing antibody (bNAb) PGT121 together with a TLR7 agonist resulted in a substantial delay or prevention of viral rebound following ART discontinuation in SHIV-infected rhesus monkeys. However, the biology and heterogeneity of the viral reservoir, as well as the mechanism(s) by which these immunotherapeutic strategies target the reservoir, remain to be determined. We hypothesize that there is substantial heterogeneity in the anatomic locations, cellular phenotypes, host transcriptomes, and viral sequences of the viral reservoir, and that certain subsets of reservoir cells are more susceptible to immune-mediated destruction. An improved understanding of the different cellular subsets that comprise the viral reservoir will be essential for understanding the partial efficacy of current interventions and for developing improved next-generation HIV-1 cure strategies. In this proposal, we will continue an ongoing collaboration between Alex K. Shalek at Massachusetts Institute of Technology (MIT), who is an expert in single-cell genomic profiling approaches, and Dan H. Barouch at Beth Israel Deaconess Medical School (BIDMC), who is an expert in conducting HIV-1 cure studies in rhesus monkeys and humans. This unique and synergistic partnership will apply the most insightful, cutting-edge, single-cell `-omics' assays to the most relevant blood and tissue specimens from both monkeys and humans, leading to a deeper understanding of the viral reservoir. Overall, we will utilize these cutting-edge, single-cell `-omics' technologies to define, at multiple levels, the functional heterogeneity of the viral reservoir and to evaluate the mechanism by which current immunotherapeutic interventions target subsets of replication-competent reservoir cells. Such knowledge will be leveraged to define the susceptibility of reservoir subpopulations to immune-mediated destruction by comparing reservoir identity and phenotype following distinct immunotherapy protocols, and to refine and develop next generation HIV-1 cures. To accomplish this goal, we propose the following two Specific Aims: Aim 1: To evaluate the anatomic, cellular, molecular, and viral heterogeneity of the viral reservoir in ART- suppressed rhesus monkeys using single-cell and population genomic profiling strategies Aim 2: To determine the extent to which current immunotherapeutic interventions target various subpopulations of the viral reservoir in rhesus monkeys

SUMMARY The goals of I4C 2.0 are to advance our scientific understanding of the viral reservoir and to develop immunologic strategies for HIV-1 remission and eradication by a highly collaborative and multifaceted research program involving partnerships among academia, industry, government, and the community. Our overall hypothesis is that multiple immunologic strategies will need to be explored and combined to achieve long-term, ART- free virologic control or complete virus eradication, with the goal of selecting combination regimens to advance into clinical development by the end of the proposed period of support. We propose three Research Foci, a Management and Operations Section, and a Community Engagement Section. Focus 1 (Mechanistic Basis of Reservoir Targeting and Viral Persistence) Aim 1. To define a virologic, immunologic, and transcriptomic signature of viral persistence and rebound and to determine how immunologic strategies target the viral reservoir in NHPs and humans Aim 2. To define drivers of clonal expansion and persistence of the replication-competent viral reservoir in NHPs and humans to enhance reservoir control and elimination Focus 2 (Novel Strategies for Sustained Virus Remission) Aim 1. To evaluate innovative immune engineering strategies that provide long-term T cell or Env-directed immune control, including therapeutic vaccines, CAR-T cells, and engineered B cells Aim 2. To combine approaches that augment humoral and cellular immune responses to achieve sustained immunosurveillance and long-term ART-free virologic control Focus 3 (Novel Strategies for Virus Eradication) Aim 1. To evaluate innovative strategies for rapid elimination of the majority of the viral reservoir, including improved LRAs combined with bNAbs, activated NK cells, and CAR-T cells Aim 2. To combine the most effective approach to rapidly eliminate the majority of the viral reservoir with sustained immunosurveillance to eliminate the residual viral reservoir Management and Operations (MO) Section Community Engagement (CE) Section

This proposal outlines the scientific agenda of the Leadership and Operations Center of the HIV Vaccine Trials Network (HVTN), the collaboration of physician scientists at 64 clinical trial sites in 15 countries on 4 continents dedicated to developing a globally effective HIV vaccine. During the current funding period, the HVTN has transformed HIV prevention science by taking two HIV vaccine concepts and the broadly neutralizing monoclonal antibody (mAb) VRC01 from phase 1 to efficacy evaluation. We have added over 35 clinical trial sites in sub- Saharan Africa and now have over 12,500 participants enrolled in randomized controlled efficacy trials. We propose to continue our scientific leadership in HIV vaccines. The scientific pipeline for vaccines with the potential to induce broadly neutralizing antibodies (bnAbs) to HIV has markedly expanded. This proposal describes a novel fast-track phase 1 program to assess, in an iterative fashion, candidate trimers, germline or lineage-based vaccines designed to elicit bnAbs in adults. A phase 1 program to investigate these vaccines in HIV-1?exposed infants is also proposed. The HVTN currently has five HIV efficacy trials in place. Two vaccine trials (HVTN 702 & 705) are in progress; a third (HVTN 706) will start in August 2019; and we are collaborating with the HIV Prevention Trials Network (HPTN) on two antibody-mediated prevention (AMP) trials evaluating the infusion of passively administered mAbs. These efficacy trials will define the potential of neutralizing and/or non- neutralizing antibodies to prevent HIV acquisition. The samples and statistical design of the efficacy trials are developed around correlates of protection; we will continue to develop the robust integrated laboratory, statistical and computational platform needed to define these correlates. We will also continue to expand our behavioral sciences program to enhance our already successful recruitment and retention programs, and to continue to expand the enrollment of persons of color and transgender persons into HVTN trials. Vaccine clinical trials involve a complex interplay between clinical trial sites, HVTN laboratories, computational scientists, and our operational, training, mentoring, and fiscal management teams; these interactions are described in the application. The clinical, laboratory and statistical infrastructure we have built for HIV vaccines will also be used to assist in tuberculosis (TB) vaccine development. Importantly, we will build on our success in the unique community-based programs and integration of community representatives and community advisory boards into HVTN research process and conduct. We will also continue to develop the next generation of vaccine scientists and expand our scientific collaborations to engage the scientific community to utilize the extensive specimen and data repositories we have established. The overall goal of the HVTN in this proposal is to develop a vaccine regimen or combination mAb regimen that will reduce HIV acquisition in adults and infants by more than 60 percent.