Evaluation of the Impact of HIV Status on the Immune Response to mRNA COVID-19 Vaccines

项目摘要/摘要 在新冠肺炎大流行的这个时候，随着疫苗的推出，最紧迫的问题之一 艾滋病毒携带者(PLWH)及其提供者面临的问题是，艾滋病毒是否调节免疫反应 以及SARS-CoV-2疫苗随后的有效性。不幸的是，这三个项目的第三阶段试验 美国授权的疫苗没有报告艾滋病毒特定数据和/或没有包括足够的PLWH来检查 HIV感染对疫苗效力的影响。 PLWH可能会经历不那么持久的SARS-CoV-2特异性中和抗体(NAB)反应 对SARS-CoV-2疫苗的反应，就像对其他感染的疫苗的反应一样。这种耐用性的缺乏 NAB反应可能是由HIV感染的炎症状态介导的，尽管足够的炎症状态仍然存在 抑制性抗逆转录病毒治疗(ART)、T细胞耗竭和/或降低CD4/CD8比率。我们的前期工作 在加州大学旧金山分校感染新型冠状病毒(LIINC)对新冠肺炎恢复影响的长期研究中 HIV阴性者的抗体应答减弱，但CD4和CD8 T细胞应答稳定 自然感染SARS-CoV-2后康复的个人。然而，代理病毒中和效价和 在接种了mRNA疫苗后，PLWH患者的免疫球蛋白水平低于未接种HIV病毒的成年人。 这引起了人们的担忧，即PLWH对疫苗接种的体液反应可能会减弱。PLWH是否挂载 新冠肺炎疫苗的体液和细胞免疫应答不如未接种的疫苗持久 很大程度上是未知的，包括这些差异的机制，尽管这些信息可以告知临床 战略，包括接种疫苗后的额外助剂或安全措施。 这项提案将回答关于公共卫生部门对疫苗接种反应的两个重要问题。目标1 将为SARS-CoV-2中和抗体如何反应提供新的、迫切需要的见解 培养的B.1.617.2(Delta)变异体、免疫球蛋白浓度、抗体强度和持久性可能因HIV而不同 在基于mRNA的SARS-CoV-2疫苗接种后一段时间内的状况，包括以下加强剂。目标2将 检测基于mRNA的SARS-CoV-2产生的T细胞记忆反应和生发中心发育 在接种疫苗后一年内，PLWH与未接种艾滋病毒的人之间的疫苗接种情况进行比较。驾驭， 加州大学旧金山分校CFAR的研究基础设施，LIINC研究，以及PLWH的大量老龄化人口 在Ward 86诊所的服务下，这项分析将利用正在进行的队列来解决PLWH是否增加 减弱对新冠肺炎疫苗的免疫反应。这些数据将为临床和公共卫生提供信息 反应，包括需要额外的疫苗剂量或在新冠肺炎期间为PLWH制定安全策略。

PROJECT SUMMARY/ ABSTRACT At this point in the COVID-19 pandemic, with vaccine roll-out ongoing, one of the most urgent questions facing people living with HIV (PLWH) and their providers is whether HIV modulates the immune response to and subsequent effectiveness of the SARS-CoV-2 vaccines. Unfortunately, phase 3 trials for all three of the U.S.-authorized vaccines did not report HIV specific data and/or did not include enough PLWH to examine the impact of HIV infection on vaccine efficacy. PLWH might plausibly experience a less durable SARS-CoV-2 specific neutralizing antibody (NAb) response to a SARS-CoV-2 vaccine, as has been seen in response to vaccines for other infections. This lack of durable NAb responses may be mediated by inflammatory state of HIV infection that persists despite adequate suppressive antiretroviral therapy (ART), T cell exhaustion, and/or lower CD4/CD8 ratios. Our preliminary work in the UCSF Long-term Impact of Infection with Novel Coronavirus (LIINC) COVID-19 recovery study has demonstrated waning antibody responses but stable CD4+ and CD8+ T cell responses among HIV-negative individuals recovering from natural SARS-CoV-2 infection. However, surrogate virus neutralization titers and IgG concentrations were lower among PLWH compared to adults without HIV following mRNA vaccination, raising concerns that PLWH might have a diminished humoral response to vaccination. Whether PLWH mount less durable humoral and cell-mediated immune responses to COVID-19 vaccines than those without HIV is largely unknown, including the mechanisms of these differences, although this information could inform clinical strategies, including additional boosters or safety measures after vaccination. This proposal will answer two vital questions about the response to vaccination among PLWH. Aim 1 will provide novel, urgently needed insights into how the SARS-CoV-2 neutralizing antibody response to a cultured B.1.617.2 (delta) variant, IgG concentration, and antibody magnitude and durability could differ by HIV status over time following mRNA-based SARS-CoV-2 vaccination, including following boosters. Aim 2 will examine T cell memory responses and germinal center development generated by mRNA-based SARS-CoV-2 vaccination among PLWH compared to those without HIV out to a year following vaccination. Harnessing, the research infrastructure of the UCSF CFAR, the LIINC study, and a large, aging population of PLWH served by the Ward 86 clinic, this analysis will leverage an ongoing cohort to address whether PLWH mount attenuated immune responses to COVID-19 vaccines. Such data will inform clinical and public health responses, including the need for additional vaccine doses or safety strategies for PLWH during COVID-19.