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

项目概要/摘要 在COVID-19大流行的这个时候，随着疫苗的推出，最紧迫的问题之一是 艾滋病毒感染者（PLWH）及其提供者面临的问题是，艾滋病毒是否调节免疫反应， 以及随后SARS-CoV-2疫苗的有效性。不幸的是，所有三种药物的3期试验 美国--授权的疫苗没有报告艾滋病毒特异性数据和/或没有包括足够的PLWH来检查 艾滋病毒感染对疫苗效力影响。 PLWH可能会经历较不持久的SARS-CoV-2特异性中和抗体（NAb）反应 对SARS-CoV-2疫苗的反应，就像对其他感染疫苗的反应一样。这种缺乏持久性 NAb反应可能是由HIV感染的炎症状态介导的，尽管有足够的抗HIV抗体， 抑制性抗逆转录病毒疗法（ART）、T细胞耗竭和/或较低的CD 4/CD 8比率。我们的前期工作 在UCSF新型冠状病毒感染的长期影响（LIINC）COVID-19恢复研究中， 在HIV阴性患者中， 从自然SARS-CoV-2感染中恢复的人。然而，替代病毒中和滴度和 在mRNA疫苗接种后，与没有HIV的成人相比，PLWH中的IgG浓度较低， 这引起了人们对艾滋病毒携带者对疫苗接种的体液反应减弱的担忧。是否安装PLWH 对COVID-19疫苗的体液和细胞介导的免疫应答不如没有艾滋病毒的人持久， 大部分未知，包括这些差异的机制，尽管这些信息可以告知临床 策略，包括疫苗接种后的额外加强剂或安全措施。 该提案将回答有关艾滋病毒携带者疫苗接种反应的两个重要问题。要求1 将为SARS-CoV-2中和抗体如何对SARS病毒产生反应提供新的、迫切需要的见解。 培养的B.1.617.2（δ）变体、IgG浓度、抗体强度和持久性可能因HIV 基于mRNA的SARS-CoV-2疫苗接种后随时间推移的状态，包括加强免疫后。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，艾滋病毒感染者与未感染艾滋病毒者之间的差异。哈纳辛 UCSF CFAR的研究基础设施，LIINC研究，以及PLWH的大量老龄化人口 由Ward 86诊所提供服务，这项分析将利用正在进行的队列研究来解决PLWH是否会增加 减弱了COVID-19疫苗的免疫反应。这些数据将告知临床和公共卫生 应对措施，包括在COVID-19期间需要额外的疫苗剂量或PLWH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.