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

项目概要/摘要 目前，在 COVID-19 大流行期间，随着疫苗的推出，最紧迫的问题之一 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会调节免疫反应 以及 SARS-CoV-2 疫苗随后的有效性。不幸的是，所有这三个药物的第三阶段试验 美国授权的疫苗没有报告艾滋病毒具体数据和/或没有包括足够的艾滋病毒感染者和艾滋病病毒感染者 HIV 感染对疫苗功效的影响。 PLWH 可能会经历不太持久的 SARS-CoV-2 特异性中和抗体 (NAb) 反应 正如人们对其他感染疫苗的反应一样，SARS-CoV-2 疫苗也出现了这种情况。这种缺乏耐用性 Nab 反应可能是由 HIV 感染的炎症状态介导的，尽管有足够的剂量，这种炎症状态仍然持续存在。 抑制性抗逆转录病毒治疗 (ART)、T 细胞耗竭和/或较低的 CD4/CD8 比率。我们的前期工作 在 UCSF 感染新型冠状病毒 (LIINC) COVID-19 恢复的长期影响研究中 HIV 阴性人群中抗体反应减弱，但 CD4 和 CD8 T 细胞反应稳定 从自然 SARS-CoV-2 感染中恢复的个体。然而，替代病毒中和滴度和 与 mRNA 疫苗接种后未感染 HIV 的成年人相比，PLWH 中的 IgG 浓度较低， 引起人们的担忧，即艾滋病病毒感染者可能对疫苗接种的体液反应减弱。是否感染者安装 与未感染 HIV 的疫苗相比，对 COVID-19 疫苗的体液和细胞介导免疫反应的持久性较差 尽管这些信息可以为临床提供信息，但很大程度上未知，包括这些差异的机制 策略，包括疫苗接种后额外的加强剂或安全措施。 该提案将回答有关感染者疫苗接种反应的两个重要问题。目标1 将提供新的、迫切需要的见解，了解 SARS-CoV-2 中和抗体如何响应 培养的 B.1.617.2 (delta) 变体、IgG 浓度以及抗体强度和持久性可能因 HIV 而异 基于 mRNA 的 SARS-CoV-2 疫苗接种（包括加强疫苗接种）后一段时间内的状态。目标2将 检查基于 mRNA 的 SARS-CoV-2 产生的 T 细胞记忆反应和生发中心发育 与接种后一年内未感染艾滋病毒的人群相比，艾滋病病毒感染者的疫苗接种情况。驾驭， UCSF CFAR 的研究基础设施、LIINC 研究以及大量老龄化的 PLWH 人群 由 Ward 86 诊所提供服务，该分析将利用正在进行的队列来解决 PLWH 是否增加 对 COVID-19 疫苗的免疫反应减弱。这些数据将为临床和公共卫生提供信息 应对措施，包括在 COVID-19 期间需要额外疫苗剂量或针对 PLWH 的安全策略。

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.