Oral Vaccination Approaches for Anti-SHIV Immunity.
Oral Vaccination Approaches for Anti-SHIV Immunity.
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DOI：
10.3389/fimmu.2021.702705
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发表时间：
2021
影响因子：
7.3
通讯作者：
Aldovini A
中科院分区：
文献类型：
--
作者：
Velarde de la Cruz E;Wang L;Bose D;Gangadhara S;Wilson RL;Amara RR;Kozlowski PA;Aldovini A
我们修改了萨宾口服脊髓灰质炎病毒疫苗 (OPV) 载体，以允许分泌感兴趣的抗原，目的是改善由 DNA 和重组 OPV 组成的 SHIV 粘膜免疫中的抗 HIV Env 体液反应。 我们评估了两种方案对恒河猴全身和粘膜细胞介导的体液免疫的刺激，两种方案均涉及带有 SHIVBG505 DNA 构建体的初免，产生以脂质纳米颗粒配制的非感染性颗粒，在口腔中施用，以及两种不同的病毒载体加强剂，在口腔和肠道中施用。 第 1 组使用表达 SIV Gag/Pol 和 HIVBG505 Env 的 rMVA-SHIVBG505 进行加强。第 2 组使用 SHIVBG505-OPV 疫苗加强接种，其中包括表达 Gag CA、NC 和 p6 蛋白的非分泌型 SIVmac239CA-p6-OPV，以及分泌 HIV EnvBG505 C1-V2 片段（可被广泛中和抗体 PG16 识别）的 HIVBG505C1-V2-OPV。对 PBMC 以及淋巴结、直肠和阴道 MNC 中的抗 SHIV Gag 和 Env CD4+ 和 CD8+ T 细胞反应进行时程分析。两种方案均在所有区室中刺激显着的细胞介导的反应，其中SHIVBG505-OPV免疫比rMVA-SHIVBG505刺激更显着水平的反应。对这些反应的布尔分析揭示了所有组织中主要存在单功能反应和多功能反应。两组的抗体反应刺激均令人失望，血浆中抗 SHIV IgG 呈阴性，而唾液、直肠和阴道分泌物中的 IgA 仅限于少数动物。在用 SHIVBG505 重复直肠攻击后，两只第 1 组动物在攻击终止时仍未受到感染。组间感染后病毒载量没有观察到显着差异。急性期下降后，接种疫苗的动物和对照动物的 CD4+ T 细胞百分比恢复到正常水平。然而，与对照组相比，接种组的 PBMC 和直肠 MNC Th17/Treg 比率保留更显着，被认为是进展为 AIDS 的最强替代标志。我们的结论是，本研究中使用的疫苗平台不足以在测试的剂量和时间表下刺激显着的体液免疫，但足以刺激显着的粘膜和全身细胞介导的免疫，影响血液和直肠粘膜中关键 Th17 CD4+ T 细胞的保存。
We modified a Sabin Oral Poliovirus Vaccine (OPV) vector to permit secretion of the antigens of interest with the goal of improving anti-HIV Env humoral responses in a SHIV mucosal immunization composed of DNA and recombinant OPVs. We evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in Rhesus macaques by two regimens, both involving a prime with a SHIVBG505 DNA construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral cavity, and two different viral vector boostings, administered in the oral cavity and intestinally. Group 1 was boosted with rMVA-SHIVBG505, expressing SIV Gag/Pol and HIVBG505 Env. Group 2 was boosted with a SHIVBG505-OPV vaccine including a non-secreting SIVmac239CA-p6-OPV, expressing Gag CA, NC and p6 proteins, and a HIVBG505C1-V2-OPV, secreting the C1-V2 fragment of HIV EnvBG505, recognized by the broadly neutralizing antibody PG16. A time course analysis of anti-SHIV Gag and Env CD4+ and CD8+ T-cell responses in PBMC and in lymph node, rectal, and vaginal MNC was carried out. Both regimens stimulated significant cell-mediated responses in all compartments, with SHIVBG505-OPV immunization stimulating more significant levels of responses than rMVA- SHIVBG505. Boolean analysis of these responses revealed predominantly monofunctional responses with multifunctional responses also present in all tissues. Stimulation of antibody responses was disappointing in both groups with negative anti-SHIV IgG in plasma, and IgA in salivary, rectal and vaginal secretions being restricted to a few animals. After repeated rectal challenge with SHIVBG505, two Group 1 animals remained uninfected at challenge termination. No significant differences were observed in post-infection viral loads between groups. After the acute phase decline, CD4+ T cell percentages returned to normal levels in vaccinated as well as control animals. However, when compared to controls, vaccinate groups had more significant preservation of PBMC and rectal MNC Th17/Treg ratios, considered the strongest surrogate marker of progression to AIDS. We conclude that the vaccine platforms used in this study are insufficient to stimulate significant humoral immunity at the tested doses and schedule but sufficient to stimulate significant mucosal and systemic cell-mediated immunity, impacting the preservation of key Th17 CD4+ T cells in blood and rectal mucosa.
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影响因子：
3.7
作者：
Akapirat S;Karnasuta C;Vasan S;Rerks-Ngarm S;Pitisuttithum P;Madnote S;Savadsuk H;Rittiroongrad S;Puangkaew J;Phogat S;Tartaglia J;Sinangil F;de Souza MS;Excler JL;Kim JH;Robb ML;Michael NL;Ngauy V;O'Connell RJ;Karasavvas N;RV305 Study Group
通讯作者：
RV305 Study Group
影响因子：
3.3
作者：
Chung NP;Matthews K;Kim HJ;Ketas TJ;Golabek M;de Los Reyes K;Korzun J;Yasmeen A;Sanders RW;Klasse PJ;Wilson IA;Ward AB;Marozsan AJ;Moore JP;Cupo A
通讯作者：
Cupo A
影响因子：
--
作者：
Burrill CP;Strings VR;Schulte MB;Andino R
通讯作者：
Andino R
影响因子：
3.6
作者：
BEALE, AJ
通讯作者：
BEALE, AJ
影响因子：
5.4
作者：
Crotty, S;Miller, CJ;Andino, R
通讯作者：
Andino, R