Nucleoside-modified mRNA vaccine for prevention and treatment of genital herpes

用于预防和治疗生殖器疱疹的核苷修饰mRNA疫苗

基本信息

  • 批准号:
    10734345
  • 负责人:
  • 金额:
    $ 81.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-15 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Abstract Genital herpes affects 650 million people globally. Vaccines are urgently needed to prevent infection and treat individuals already infected. During the current funding cycle, we developed a candidate vaccine for preventing genital herpes that uses nucleoside-modified mRNA encapsulated within lipid nanoparticles (LNP) to express herpes simplex virus type 2 (HSV-2) glycoproteins C, D, and E (gC2, gD2, gE2). The vaccine targets an entry molecule, gD2, and two immune evasion molecules, gC2 and gE2. Our vaccine candidate will enter phase 1 human trials in December 2022. Our new goals are to define the immune correlates of protection for the trivalent vaccine using sera we collected from immunized mice and guinea pigs during this grant cycle, and to develop an mRNA-based vaccine as immunotherapy. In Aim 1, we will define the immune correlates of protection. Our hypothesis is that by defining immune correlates, we will better understand the mechanisms of vaccine protection and the immune responses required for success in human trials. We will use high throughput biosensor technology and our extensive panel of gC2, gD2, and gE2 monoclonal antibodies to determine whether the trivalent vaccine produces antibodies to crucial epitopes on gC2, gD2 and gE2. The epitopes of interest include those on gC2 that bind complement component C3b to inhibit complement activation, gE2 that bind the IgG Fc domain to block Fc-mediated activities including complement activation and antibody-dependent cellular cytotoxicity, and gD2 that bind to cell receptors for virus entry and mediate cell-to-cell spread. We will correlate antibody binding to these important epitopes with protection against clinical outcomes including genital lesions and latent infection. The epitope mapping studies will enable us to assess the contribution of each of the glycoprotein immunogens to protection. Aim 2 uses mRNA immunogens to develop a genital herpes therapeutic vaccine. We hypothesize that T cell responses will be particularly important for a successful therapeutic vaccine. In Preliminary studies, we infected guinea pigs intravaginally with HSV-2 and once recovered, we immunized with glycoproteins E and I (gE2/gI2) mRNA-LNP. gE2/gI2 mRNA-LNP reduced the number of days with recurrent genital lesions by 47%, an excellent start towards our primary endpoint of >70% reduction in recurrent genital lesions. To achieve our goal of >70%, we will incorporate other antigens, including additional glycoproteins, immediate early, capsid and tegument immunogens and assess CD4 and CD8 T cell responses in male and female mice. We will advance the best candidates for efficacy studies in guinea pigs. We will focus initially on glycoprotein immunogens because of the remarkable success of a therapeutic vaccine for a closely related virus, varicella zoster virus, that uses glycoprotein E as the antigen. We will include the trivalent gC2/gD2/gE2 vaccine in the therapeutic studies to determine whether one vaccine formulation will be effective for prevention and treatment. If successful, the studies in Aims 1 and 2 will have a positive impact on billions of people by preventing and treating genital herpes.
摘要

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Guinea Pig and Mouse Models for Genital Herpes Infection.
  • DOI:
    10.1002/cpz1.332
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hook LM;Friedman HM;Awasthi S
  • 通讯作者:
    Awasthi S
An mRNA vaccine to prevent genital herpes.
Receptor Binding-Induced Conformational Changes in Herpes Simplex Virus Glycoprotein D Permit Interaction with the gH/gL Complex to Activate Fusion.
  • DOI:
    10.3390/v15040895
  • 发表时间:
    2023-03-30
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Atanasiu D;Saw WT;Cairns TM;Friedman HM;Eisenberg RJ;Cohen GH
  • 通讯作者:
    Cohen GH
Localization of the Interaction Site of Herpes Simplex Virus Glycoprotein D (gD) on the Membrane Fusion Regulator, gH/gL
  • DOI:
    10.1128/jvi.00983-20
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Cairns, Tina M.;Atanasiu, Doina;Cohen, Gary H.
  • 通讯作者:
    Cohen, Gary H.
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Harvey Michael Friedman其他文献

Harvey Michael Friedman的其他文献

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{{ truncateString('Harvey Michael Friedman', 18)}}的其他基金

A vaccine for genital herpes that achieves sterilizing immunity
实现绝育免疫力的生殖器疱疹疫苗
  • 批准号:
    10375434
  • 财政年份:
    2019
  • 资助金额:
    $ 81.25万
  • 项目类别:
A vaccine for genital herpes that achieves sterilizing immunity
实现绝育免疫力的生殖器疱疹疫苗
  • 批准号:
    9915856
  • 财政年份:
    2019
  • 资助金额:
    $ 81.25万
  • 项目类别:
Combined Adult and Pediatric Infectious Disease Postdoctoral Training Grant
成人和儿童传染病博士后培训补助金
  • 批准号:
    9327865
  • 财政年份:
    2016
  • 资助金额:
    $ 81.25万
  • 项目类别:
Combined Adult and Pediatric Infectious Disease Postdoctoral Training Grant
成人和儿童传染病博士后培训补助金
  • 批准号:
    10670416
  • 财政年份:
    2016
  • 资助金额:
    $ 81.25万
  • 项目类别:
Mentoring/ Career Development Core
指导/职业发展核心
  • 批准号:
    9128440
  • 财政年份:
    2016
  • 资助金额:
    $ 81.25万
  • 项目类别:
HSV-2 immune evasion as a virulence factor
HSV-2 免疫逃避作为毒力因子
  • 批准号:
    9212090
  • 财政年份:
    2014
  • 资助金额:
    $ 81.25万
  • 项目类别:
HSV-2 immune evasion as a virulence factor
HSV-2 免疫逃避作为毒力因子
  • 批准号:
    8695604
  • 财政年份:
    2014
  • 资助金额:
    $ 81.25万
  • 项目类别:
Mentoring/ Career Development Core
指导/职业发展核心
  • 批准号:
    9042685
  • 财政年份:
    2014
  • 资助金额:
    $ 81.25万
  • 项目类别:
International
国际的
  • 批准号:
    7684977
  • 财政年份:
    2009
  • 资助金额:
    $ 81.25万
  • 项目类别:
PROTEASE INHIBITOR-SPARING REGIMENS FOR THE INITIAL TREATMENT OF HIV SUBJECTS
用于 HIV 受试者初始治疗的蛋白酶抑制剂保留方案
  • 批准号:
    7199032
  • 财政年份:
    2004
  • 资助金额:
    $ 81.25万
  • 项目类别:

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