Vaccine targeting HIV sites of vulnerability

针对艾滋病毒易感部位的疫苗

• 批准号: 10512063
• 负责人: Catarina E Hioe
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512063
• 关键词: 2019-nCoV; AIDS prevention; Adherence; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody Response; Antigens; Biomanufacturing; COVID-19; Caring; Cells; Clinical Trials; Collaborations; Complement Activation; DNA; Data; Development; Disease; Epitopes; Escherichia coli; Future; Glycoproteins; Goals; Good Manufacturing Process; HIV; HIV Envelope Protein gp120; HIV Infections; HIV envelope protein; HIV vaccine; Healthcare Systems; Home; Human; Immune; Immune response; Immunization; Immunize; Immunodominant Epitopes; Immunoglobulin G; In Vitro; Individual; Infection; Laboratories; Lead; Legal patent; Macaca mulatta; Mediating; Medical center; Methods; Monkeys; Monoclonal Antibodies; Oryctolagus cuniculus; Outcome; Pathway interactions; Phase; Phase I Clinical Trials; Plasma; Plasmids; Production; Protein Analysis; Proteins; Provider; Publishing; RNA Splicing; Recombinants; Regimen; Research; Risk; SIV; Scaffolding Protein; Site; Supervision; Testing; Transfection; United States Department of Veterans Affairs; United States Dept. of Health and Human Services; Universities; Vaccination; Vaccine Clinical Trial; Vaccines; Vagina; Validation; Veterans; Veterans Health Administration; Viral Physiology; Virion; Virus; Virus Diseases; Wisconsin; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; cross reactivity; design; economic impact; efficacy clinical trial; env Gene Products; glycosylation; immunogenic; immunogenicity; improved; in vivo; medical schools; monomer; nonhuman primate; novel; novel vaccines; pandemic disease; pathogen; plasmid DNA; prevent; protein purification; prototype; rational design; scaffold; simian human immunodeficiency virus; standard of care; vaccine candidate; vaccine efficacy; vaccine strategy; vaccine trial; vaccine-induced antibodies; virus envelope

Project Summary/Abstract Effective HIV vaccines are not yet available. Of the phase 2b/3 vaccine trials, only the Thai RV144 trial showed efficacy (31%, p=0.04), and high levels of antibodies (Abs) against the V1V2 domain of HIV envelope (Env) were found to be the only primary immune correlate of reduced virus acquisition. Studies of vaccines in SIV or SHIV-challenged monkeys have since recapitulated these findings. To improve upon the RV144 vaccine, we have designed V1V2-targeted vaccine candidates and identified the most immunogenic: V1V2/A244-2J9C, a protein with V1V2 of CRF_01.AE strain A244 spliced into a bacterial trimeric protein scaffold, 2J9C. With our unique vaccine strategy centered on targeting V1V2 using novel recombinant subunit immunogens, we have demonstrated the capacity to induce an Ab response in plasma and vaginal secretion that was focused on V1V2 and diverted from other more immunodominant sites on Env. The elicited Abs displayed cross-reactivity with strains from multiple clades, durability of 1-2 years after the last boost, and antiviral functions including Ab- dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and complement activation—activities that are not readily achieved by immunization with intact gp120. V1V2/A244-2J9C DNA has also been shown as an effective prime, focusing the Ab response on the specific V2 region that accounted for reduced infection in RV144. Altogether these data provide evidence supporting the validation of our lead vaccine candidate and vaccination approach. A US patent has been issued for our V1V2-scaffold designs, with the VA as one of the assignees. This application proposes to produce the lead immunogen V1V2/A244-2J9C under cGMP (current Good Manufacturing Practice) as both DNA plasmid and protein, and test its optimized delivery in order to pave the way toward a human phase I clinical trial. To accomplish this goal, four specific aims are proposed. Aim 1 is to generate a master bank of E. coli transformed with the V1V2/A244-2J9C-expressing DNA plasmid. In Aim 2 we will test the cGMP-grade V1V2/A244-2J9C-encoding DNA for protein production in transiently transfected 293T cells and for immunogenicity in rabbits. In vitro protein analysis will include expression efficiency, mass, oligomerization, glycosylation, stability, and reactivity with a panel of monoclonals Abs (mAbs). Aim 3 is to produce a master bank of HEK293T GnTi-/- cells and a pilot batch of V1V2/A244-2J9C protein using the plasmid from Aim 1. Finally, Aim 4 will test purification methods and conduct in vitro analysis for V1V2/A244-2J9C protein from Aim 3 and then perform in vivo rabbit immunogenicity testing with V1V2/A244-2J9C DNA and protein. The cGMP production will be done by Waisman BioManufacturing, associated with the University of Wisconsin-Madison, under the supervision of Drs. Carl A. Ross and Brian M. Dattilo. In vitro immunogen analysis, protein purification, rabbit vaccination, and immune assessment will be performed in the laboratory of Dr. Catarina Hioe (PI, James J. Peters VA Medical Center, JJP VAMC) in collaboration with Dr. Susan Zolla-Pazner (Mount Sinai School of Medicine, MSSM). The V1V2/A244-2J9C DNA and protein immunogens will be the first of their kind to move toward clinical trials. An effective vaccine to prevent HIV infection and/or disease is an essential portion of the Strategic National Vaccine Plan of the Departments of Health and Human Services and Veterans Affairs. An HIV vaccine is invaluable to protect Veterans who are at risk at home and abroad. This vaccine could as well serve as a prototype for vaccines against other diseases, like COVID19, where a focused Ab response to specific epitopes is requisite for protection.

项目总结/文摘