Collins Craig P, Longo Dan L, Murphy William J
Graduate Program in Immunology, University of California (UC) Davis, Davis, CA, United States.
Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States.
Front Immunol. 2024 Feb 26;15:1345499. doi: 10.3389/fimmu.2024.1345499. eCollection 2024.
Immune responses to both SARS-CoV-2 infection and its associated vaccines have been highly variable within the general population. The increasing evidence of long-lasting symptoms after resolution of infection, called post-acute sequelae of COVID-19 (PASC) or "Long COVID," suggests that immune-mediated mechanisms are at play. Closely related endemic common human coronaviruses (hCoV) can induce pre-existing and potentially cross-reactive immunity, which can then affect primary SARS-CoV-2 infection, as well as vaccination responses. The influence of pre-existing immunity from these hCoVs, as well as responses generated from original CoV2 strains or vaccines on the development of new high-affinity responses to CoV2 antigenic viral variants, needs to be better understood given the need for continuous vaccine adaptation and application in the population. Due in part to thymic involution, normal aging is associated with reduced naïve T cell compartments and impaired primary antigen responsiveness, resulting in a reliance on the pre-existing cross-reactive memory cell pool which may be of lower affinity, restricted in diversity, or of shorter duration. These effects can also be mediated by the presence of down-regulatory anti-idiotype responses which also increase in aging. Given the tremendous heterogeneity of clinical data, utilization of preclinical models offers the greatest ability to assess immune responses under a controlled setting. These models should now involve prior antigen/viral exposure combined with incorporation of modifying factors such as age on immune responses and effects. This will also allow for mechanistic dissection and understanding of the different immune pathways involved in both SARS-CoV-2 pathogen and potential vaccine responses over time and how pre-existing memory responses, including potential anti-idiotype responses, can affect efficacy as well as potential off-target effects in different tissues as well as modeling PASC.
在普通人群中，对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染及其相关疫苗的免疫反应差异很大。感染消退后出现长期症状的证据越来越多，即冠状病毒病的急性后遗症（PASC）或“长新冠”，这表明免疫介导机制在起作用。密切相关的地方性常见人类冠状病毒（hCoV）可诱导预先存在且可能具有交叉反应性的免疫力，进而影响原发性SARS-CoV-2感染以及疫苗接种反应。鉴于需要在人群中持续调整和应用疫苗，需要更好地了解这些hCoV预先存在的免疫力以及原始新冠病毒毒株或疫苗产生的反应对针对新冠病毒抗原性变体产生新的高亲和力反应的影响。部分由于胸腺退化，正常衰老与幼稚T细胞区室减少和原发性抗原反应性受损有关，导致依赖于预先存在的交叉反应性记忆细胞库，而该细胞库可能亲和力较低、多样性受限或持续时间较短。这些影响也可由下调的抗独特型反应介导，这种反应也会随着年龄增长而增加。鉴于临床数据的巨大异质性，临床前模型的利用提供了在受控环境下评估免疫反应的最大能力。这些模型现在应包括先前的抗原/病毒暴露，并结合年龄等修饰因素对免疫反应及其影响。这也将有助于从机制上剖析和理解随时间推移参与SARS-CoV-2病原体和潜在疫苗反应的不同免疫途径，以及预先存在的记忆反应（包括潜在的抗独特型反应）如何影响疗效以及在不同组织中的潜在脱靶效应，以及对PASC进行建模。
