key: cord-0754641-g9u7u31n
authors: Peluso, Michael J.; Donatelli, Joanna; Henrich, Timothy J.
title: LONG-TERM IMMUNOLOGIC EFFECTS OF SARS-CoV-2 INFECTION: LEVERAGING TRANSLATIONAL RESEARCH METHODOLOGY TO ADDRESS EMERGING QUESTIONS
date: 2021-11-12
journal: Transl Res
DOI: 10.1016/j.trsl.2021.11.006
sha: 2a038982851d3350f66276c86b14dcd6b716d90d
doc_id: 754641
cord_uid: g9u7u31n

The current era of COVID-19 is characterized by emerging variants of concern (VOCs), waning vaccine- and natural infection-induced immunity, debate over the timing and necessity of vaccine boosting, and the emergence of post-acute sequelae of SARS-CoV-2 infection (PASC). As a result, there is an ongoing need for research to promote understanding of the immunology of both natural infection and prevention, especially as SARS-CoV-2 immunology is a rapidly changing field, with new questions arising as the pandemic continues to grow in complexity. The next phase of COVID-19 immunology research will need focus on clearer characterization of the immune processes defining acute illness, development of a better understanding of the immunologic processes driving protracted symptoms and prolonged recovery (i.e. PASC), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection. In this review, we address what is known about the long-term immune consequences of SARS-CoV-2 infection and propose how experience studying the translational immunology of other infections might inform the approach to some of the key questions that remain.

Most individuals with SARS-CoV-2 infection develop robust and persistent immunologic responses following natural infection, and as of the time of this review, many studies have characterized the humoral 1-23 and cellmediated 19, [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] immune responses during convalescence for periods of up to 1 year. While the magnitude of the immune response to natural infection is at least in part determined by the severity of the illness, 3, 6, 7, 15, 28, 30 the predictors of the duration of natural immunity are not fully understood and may be determined by a variety of clinical and measurement factors. 15, 18 Despite this complexity, there is general consensus that, in most cases, natural immunity persists for up to at least 8 months. Despite the observation that antibody levels may wane over time, several studies have now demonstrated persistence of virus-specific lymphocytes over 12 months following natural infection by various intracellular cytokine staining (ICS), activation induced marker (AIM), and EliSpot assays. These assays quantify T cell cytokine expression (ICS/EliSpot) or surface markers of T cell activation (AIM) following antigenic stimulation with various virus-specific peptide pools. For example, the percentage of virus-specific CD8 and CD4 T cells as measures by ICS or AIM range from approximately 0.01 to 10% during this extended time period across multiple studies, 25, 26, 28, 29, 31, 32 with the median or mean percentage typically <1%. Spot forming cells/units in ELISpot assays tend to range from 10 to >1,000 in response to SARS-CoV-2 peptides, including HLA-restricted pools. 27, 34 These responses wain slowly over time in all assays depending on initial disease severity and various clinical factors but can typically be detected across a range of virus gene regions (e.g. Spike, Nucleocapsid, Membrane).

These immunologic findings have been borne out by the clinical observation that reinfection with similar viral variants was relatively uncommon in the first year of the pandemic, with some exceptions. 35 During the first year of the pandemic, re-infection seemed exceedingly rare and fewer than 50 cases were reported in the literature, 35 although the true burden of re-infection is difficult to estimate given the scale of the pandemic, the high proportion of asymptomatic infections, and the variability in access to testing. While there was initially hope that those with prior SARS-CoV-2 infection would aid efforts toward herd immunity and could be at lower risk for re-infection, more recent studies have demonstrated that natural immunity within a population itself is likely insufficient to fully protect against reinfection, particularly with novel variants of concern. 36 The study of long-term natural immunity has been complicated by the relatively widespread rollout of highly efficacious vaccines with inconsistent uptake across demographic and geographic locales in addition to the recent authorization or approval of booster vaccine doses across the United States and Europe.

Data regarding the breadth of SARS-CoV-2-specific T cell immune responses following natural infection and the potential for cross-reactivity with other human beta-coronaviruses are rapidly evolving and were reviewed by Grifoni and colleagues. 37 Thus far, over 1,400 unique CD8 and CD4 T cell epitopes have been identified, 37, 38 although only a handful of antigens comprise >85% of these. Interestingly, immunodominant regions of the spike protein for CD4 T cells are relatively limited, whereas distribution for CD8 cells are more homogeneous. 37 Nonetheless, a prior study estimates than an individual may recognize 17 different CD8 and 19 different CD4 immunologically important epitopes. 38 In addition, we and others have shown that SARS-CoV-2 specific CD4 T cell responses, and to a much lesser extent CD8 T cell responses, are significantly correlated with antibody responses including total levels and neutralization capacity. 30, 39, 40 CD4 and CD8 T cells also appear to play unique roles in clinical disease, or respond differently to natural infection, and it is important to impart that these cells play different roles in immune responses to infection and should not be thought of as a unified T cellular response. For example, we and others have demonstrated that the magnitude of virus-specific CD4 T cells appears to correlate with initial disease severity and with levels and neutralization capacity of antibody responses. 25, 30, 41, 42 These associations were not consistently observed with CD8 T cell responses in our study, which appear to be influenced by other clinical factors. For example, we previously reported that pre-existing lung disease is independently associated with higher long-term SARS-CoV-2-specific CD8+, but not CD4+, T cell responses. Regardless of the differences between CD4 and CD8 T cell responses, there is now data emerging that virus-specific T cell reactivity is not significantly disrupted by viral variants, such as Delta. 43, 44 There is also data emerging that some individuals may have cross-reactive T cell responses to other human beta-coronaviruses with detectable responses to those without a history of known infection. 25, 28, 41, 45, 46 Some of these responses may be a result of occult, asymptomatic prior SARS-CoV-2 infection that led to aborted or rapidly wainig antibody levels, 29, 47 but data exist suggesting that pre-existing memory responses from endemic, less-pathogenic coronaviruses or other pathogens occur in some individuals. 34, 48 Interestingly, pre-existing cross-reactive T cell responses may be better detected by assays that measure the capacity for T cells to proliferate in response to SARS-CoV-2 Spike protein stimulation ex vivo rather than by intracellular or cell surface markers of response. 49 Regardless, it is poorly understood to what extent or how long pre-existing cross-reactive immunity may protect from acute infection or modulate disease severity and the development and persistence of post-acute sequelae and further study is urgently needed.

Initial vaccine trials predmoniaty enrolled healthy adults, and those currently approved or pending approval for use in the United States and Europe (Pfizer/BioNTech BNT162b1, AstraZeneca ChadOx1, Moderna mRNA-1273, Janssen Ad26.COV2, Novavax NVX-CoV2373) lead to robust antibody binding and neutralization titers. 50 Antibody responses generally mirror protection from asymptomatic through severe disease, hospitalization and death. However, efficacy has been shown to wane over time leading various regulatory agencies in Europe and the United States to approve or authorize boosters or third doses for adults, 51-55 with or without underlying immunomodulatory conditions or belonging to risk groups. Despite waning antibody titers and increased cases of mild infection, vaccines continue to protect against severe disease and hospitalization for up to 6 months. [51] [52] [53] [54] [55] As of now, vaccines remain active against the predominant circulating strains of SARS-CoV-2, and variants that may be more resistant to vaccination, such as Mu, appear to have a replication disadvantage compared with the widely circulating delta variant. Whereas levels of nasopharyngeal shedding have been reported to be similar in persons who acquired infection after full vaccination compared with those who were previously unvaccinated, the duration of viral shedding and symptoms are significantly shorter, and infection may be more compartmentalized to non-shedding tissues. 56 To date, the immunologic response prior to SARS-CoV-2 vaccination has been characterized for over 12 months. 57, 58 The current surge of the delta variant of SARS-CoV-2 globally has revealed that vaccine-induced immunity might be insufficient to prevent infection and more severe disease in many cases. Furthermore, the duration for which vaccine-induced immunity can protect against severe disease and hospitalization remains unclear, although boosting is likely to significantly extend the duration of protection.

It is now well established that antibody and T cell responses can be severely impaired following vaccination, 59 and to a lesser extent, natural infection, [60] [61] [62] in immunocompromised individuals, including solid organ transplant (SOT) recipients, cancer patients, and others receiving immunomodulatory medications for various conditions. For example, there is growing evidence that SOT recipients do not develop detectable antibody levels or measurable neutralizing capacity following two-dose vaccination, [63] [64] [65] [66] [67] [68] and current clinical experience demonstrates higher rates of post-vaccine infection and hospitalizations in this population. An additional third or even routh dose appears to increase antibody responses, however. 69, 70 Patients with cancer, especially those with hematological malignancies on cytoreductive or anti-B cell therapies and certain rheumatologic diseases also exhibit reduced antibody responses to vaccination, 71-73 albeit to a lesser degree than those who have received SOT but may experience high rates of vaccine breakthrough. 74 Various medications that have anti-proliferative mechanisms of actions (such as mycophenolic acid derivatives) may be associated with more impaired antibody, B and T cell responses. As above, anti-B cell agents and systemic corticosteroids impact antibody responses and memory B cell responses and combinations of immunomodulatory agents are likely to have more profound and lasting negative impacts on these immune responses. 64, 65, 67, [75] [76] [77] T cell responses are also impaired in the setting of immunosuppressive medications and diseases, but data are now emerging that these responses are somewhat discordant with antibody responses following vaccination. For example, nearly half of kidney transplant recipients in one study that did not develop antibody responses following vaccination had detectable SARS-CoV-2-specific T cell responses. 64 Whether or not these T cell responses are protective, as discussed above, is not known and requires further study. However, recent data show that persons that receive anti B cell therapy (e.g. anti-CD20 for multiple sclerosis) have a paradoxical increase in SARS-CoV-2-specific CD8 T cell responses, despite significant impairment of humoral responses. 75, [78] [79] [80] [81] [82] The increase in CD8 T cell responses may reflect an immune compensatory mechanism, 78,83,84 but it is still not clear what role virus-specific CD8 T cells have in protection from infection or modulation of disease severity. It is also interesting to note that despite the potential for increased CD8 T cell responses, individuals with impaired humoral responses have increased risk of more severe infection. 78, 85 Immunity in other immunocompromised individuals, such as those living with HIV infection, is more variable.

Recent work has suggested a lower magnitude humoral and cell-mediated immune responses [86] [87] [88] or shorter duration of the antibody response in comparison to the general population, 89 although both observations require further study. Recent studies suggest that the immune response following vaccination is equal amongst PLWH and the general population 90 and in comparison to those with other immunocompromising conditions, 91 but further work is needed to confirm these findings given the global concern for sustained immunity to SARS-CoV-2 and the known poorer responses to immunization for other infections among PLWH. [92] [93] [94] [95] [96] [97] This includes suboptimal responses to vaccination to prevent against yellow fever, 93,94 , Hepatitis B, 96 , influenza, 95 polio, diphtheria, and tetanus. 97 . It is likely that inadequate CD4+ T cell immune reconstitution, chronic inflammation, and T cell exhaustion underlie these observations, 93 and careful studies will be needed to understand how HIV and COVID-19 vaccination durability overlap.

COVID-19 can lead to profound inflammatory responses in acute infection and to increased levels of various cytokines, such as TNF-α, IL-6, and IP10, which are associated with more severe disease and organ damage. [98] [99] [100] [101] [102] [103] Especially among those hospitalized with COVID-19, inflammation during the acute and early post-acute phase of infection has been associated with poor outcomes. [104] [105] [106] [107] [108] [109] [110] In addition, many individuals present with profound lymphopenia, including a marked decrease in circulating NK, CD8 and CD4 T cells, including helper & regulatory T cells. [98] [99] [100] [101] [102] [103] Lower numbers of circulating monocytes, eosinophils and basophils have also been observed. In contrast, leukocyte counts tend to be higher in patients with severe clinical manifestations. 111, 112 Despite lymphopenia in more severe SARS-CoV-2 infection, increased frequency of T cells responding to various antigens such as, Spike, Nucleocapsid, membrane, and accessory (functional) protein (e.g. ORF 1ab) peptide sequences develop within the weeks following infection. 29 Although lymphocyte counts return and virus-specific adaptive immunity develop early during clinical recovery, increased markers of T cell exhaustion and reduced functional diversity of T cell subsets have been reported in the early convalescent period. 98, 99, 113, 114 Emerging data suggest that inflammation related to acute SARS-CoV-2 infection can persist for weeks or even months. 115, 116 One study found that convalescent plasma donors with prior COVID-19 demonstrated elevations in certain markers of inflammation compared to historical controls, even though they presumably felt well enough to donate plasma. 115 These markers include interferon (IFN)-gamma, certain interleukin (IL) proteins (e.g. IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-5, IL-33), and monocyte chemoattractant protein (MCP)-1 and suggest ongoing immune activation. Another study of a large cohort of individuals hospitalized with asymptomatic, mild, and severe disease showed that individuals who recovered from COVID-19 had elevated levels of proinflammatory and angiogenic markers at 6 months in comparison to healthy controls. 116 There is an ongoing need for work exploring the clinical implications of persistent inflammation following SARS-CoV-2; while such elevations are clearly significant in chronic infections like HIV, 117, 118 this is less well understood for acute infections like SARS-CoV-2 which is not thought to persist over the long-term.

Recently, there has been recognition that a significant proportion of individuals recovering from SARS-CoV-2 infection experience new or persistent symptoms that did not pre-date their infection. [119] [120] [121] [122] Investigation into post-acute sequelae of SARS-CoV-2 infection (PASC) is only just beginning, and the pathophysiology of the condition is thus far entirely unknown. While well-designed epidemiologic studies are beginning to identify certain risk factors for PASC, including female sex, older age, severity of initial infection, number of symptoms during acute illness, and sociodemographic factors, the condition remains poorly understood. [119] [120] [121] [122] One major question is whether PASC is an immunologic phenomenon, either from long-term sequelae following an immunologic insult that occurs early in the course of the infection (i.e., a "hit and run" mechanism) or related to an ongoing immunologic or other perturbation, potentially in the setting of ongoing viral persistent in tissue. So far, the clues have been limited. A handful of studies have identified higher levels of binding or neutralizing antibodies in those with PASC, 122, 123 suggesting that persistent symptoms could be a manifestation of more severe illness (which is known to be associated with higher antibody levels and correlated with higher risk of developing PASC) or possibly persistent immune stimulation. 14 Other studies have found that the humoral response appears lower among those with persistent symptoms. [124] [125] [126] For example, ongoing viral shedding in the gut is associated with lower RBD-specific antibodies 124 , suggesting suboptimal immune responses may result in persistent viral antigen. Furthermore, a handful of studies have correlated PASC with lower SARS-CoV-2 specific antibody responses 126 , and have shown that those with lower titres during early recovery might be more likely to have persistent symptoms. Cellular immune studies are limited and have thus far not revealed obvious differences, although our recent work has suggested lower 126 or differential decay in the magnitude of SARS-CoV-2 specific CD8+ T cell responses among those with PASC. 30 Studies that have evaluated persistent inflammation have suggested potential elevations in biomarkers, 116, 127 although no clear immunologic pathways have yet to be consistently implicated. We recently demonstrated that during early recovery (i.e. one to two months after initial infection), those who went on to develop PASC generally had higher levels of biomarkers including significant elevations in circulating TNF-alpha and IP-10, and a trend towards higher IL-6 levels. During late recovery (4 months following infection), levels of TNF-alpha and IP-10 levels decayed and converged with levels in participants without PASC, whereas IL-6 elevations became more pronounced. These differences tended to be more pronounced among those with a greater number of PASC symptoms suggesting that PASC is associated with increased immune activation over time, which may underlie some symptoms which persist for more than 3 months following SARS-CoV-2 infection. IL-6 elevations may result from immune cell activation and signaling, degradation of gut mucosal integrity and translocation of bacterial and other infectious agents, B cell activation, among many other processes. 117, 128, 129 Further characterization of such biological pathways and the processes that might drive them could lead to the identification of therapeutic targets for those experiencing PASC. In a prior study, we did not observe differences in markers of aberrant blood clotting, such as D-Dimer in those with and without persistent symptoms, despite disorders of hemostasis contributing to some individuals with severe COVID- 19. 30 However, further study is certainly warranted given sample size limitations and the lack of a standard working definition of PASC.

Aberrant autoimmune responses are present during acute COVID-19 and have been proposed as a potential underlying etiology of PASC, [130] [131] [132] and recent study showed that over 40% of patients in a longitudinal study have positive antinuclear antibody (ANA) titers >1:160 12 months following infection. 133 A majority of the cohort reported PASC symptoms and the number of symptoms reported were higher in those with a positive ANA. In our long-term COVID-19 cohort, however, we were unable to detect positive ANAs in any of 49 participants approximately 4 months after initial infection and 3 of 69 participants 8 months after acute infection, which is similar to the percentage of people in the general population without known autoimmune disease that have detectable ANAs. Our cohort included individuals with and without PASC, including those with >20 symptoms 8 months after initial infection and perturbation of activities of daily life. 134 As a result, further studies of potential autoimmune mechanisms behind PASC are needed in order to understand these disparate findings.

Finally, the alterations of both inflammation and immune responses in the setting of convalescent COVID-19 may also influence future risk of various conditions such as cardiovascular, pulmonary and neurological diseases. Unfortunately, time will be needed to understand the longer impact of SARS-CoV-2 infection more fully beyond persistent symptoms.

It is well established that immunocompromised individuals are capable of shedding SARS-CoV-2 RNA from oral/nasopharyngeal tissues months after acute infection, and novel variants may have arisen in such individuals under the setting of partial immune pressure. 135, 136 However, RNA shedding usually resolves within a month in immunocompetent patients, 137 and we recently observed no persistent RNA shedding in convalescent COVID-19 patients who exhibit PASC approximately 4 months after initial infection. 30 Despite this, there has been limited but intriguing data suggesting that SARS-CoV-2 proteins can be identified in gut tissue months after initial infection. 14 If SARS-CoV-2 remains transcriptionally and/or translationally active in various tissue reservoirs following clearance from naso-pharyngeal tissues, this could represent a potential mechanism underlying the development and maintenance of PASC. 138 There is also data emerging that COVID-19 may lead to intestinal damage and microbial translocation. 139 . In chronic infections, such as Human Immunodeficiency Virus (HIV), persistence of virus in gut-associated mucosal tissue leads to gut barrier dysfunction and bacterial/fungal translocation that may lead to elevated markers of immune activation (including IL-6) and inflammation, even in those on suppressive antiretroviral therapy. 128 Although the mechanisms of PASC are not known, the current thinking is that PASC is a multifactorial process that manifests in diverse clinical and demographic phenotypes. In addition, there is yet to be a standard working definition of PASC and objective phenotypes have yet to be determined. As a result, studying the pathophysiological basis of PASC is going to be challenging and require large numbers of study participants with well curated control groups.

The infectious disease research community has developed tools over the last two decades that can be leveraged to support research into duration of immunity and immunologic consequences following SARS-COV-2 infection. Decades of research in chronic viral infections, such as HIV as mentioned above, all show that tissue persistence and ongoing inflammation and immune activation can lead to increased morbidity across multiple organ systems. In addition, other chronic viral infections, such as CMV, may lead to long-term inflammation in those with various immune suppressing conditions such as HIV and organ transplantation and increases risk of cardiovascular disease through chronic immune dysregulation, [143] [144] [145] [146] [147] and tools have been developed to study tissue-based disease that can be applied to the long-term pathogenesis of COVID-19.

Although SARS-CoV-2 is predominately thought of as a respiratory illness, viral receptors, suchy as ACE2, can be found throughout various tissues in the body, including endovascular tissue and many organ systems. [148] [149] [150] Given data hinting at potential viral persistence in gut tissues, many of the potential drivers of PASC could require tissue investigation for meaningful in-depth mechanistic studies.

First, there is an urgent need to understand the long-term immunological and inflammatory impact of SARS-CoV-2 infection in mucosal, gastrointestinal and respiratory tissues. Whereas procedures such as bronchoalveolar lavage can be relatively easy in patients requiring mechanical ventilation for diagnostics or therapeutics, invasive or semi-invasive sampling in the setting of convalescent disease presents greater challenges. Although challenging, the HIV research community has developed a wide range of translational research tools to study viral persistence and immune and inflammatory responses in various mucosal, lymphoid and other tissues which can be applied to the study of COVID-19 and PASC. For example, gut tissue biopsies and lymph node sampling are routinely performed in the clinical and translational HIV research settings, and the study of these tissues have revealed much information on how HIV persists in the setting of suppressive antiretroviral therapy over time and how immune responses (or lack thereof) interact with infected cells. [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] In addition, in situ study of viral infection within an anatomic histological context has proved critical in elucidating the burden of infection and impact on immune and inflammatory responses. 153, [162] [163] [164] [165] . In addition to the gastrointestinal studies as discussed above, studies of COVID-19 are now emerging examining the role of T and B cell memory responses in various tissues (e.g. lung-associated lymph nodes in adults or tonsillar tissue in children) and mucosa-association invariant T (MAIT) cells in lower airways. It is likely that analysis of human nasopharyngeal, respiratory, lymph node, gut and vascular endothelium will be necessary to fully understand the long-term immune and inflammatory implications of COVID-19. Given the challenges of studying tissues that are not routinely accessible to clinical sampling, such as the brain, heart, liver, spleen, deeper lymph node chains, to name just a few, non-invasive technologies to determine the burden of SARS-CoV-2 infection and short-and long-term immune and inflammatory sequelae are urgently needed.

SARS-CoV-2 immunology is a rapidly changing field, with new questions arising as the pandemic continues to grow in complexity. The next phase of COVID-19 immunology research will focus on clearer characterization of the immune processes defining acute illness, development of a better understanding of the immunologic processes driving protracted symptoms and prolonged recovery (i.e. PASC), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection.

What is the role of T cells in preventing or mitigating the severity of acute infection or re-infection in those with prior SARS-CoV-2 infection or vaccination?

At what point following infection or vaccination is protection from hospitalization and severe illness lost? At what point is protection from reinfection lost?

How does post-infection immunity compare with post-vaccine immunity? How does this immunity compare across emerging variants of concern?

What is the functional half-life of SARS-CoV-2-specific T cells and amnestic potential following infection or vaccination?

How do novel SARS-CoV-2 therapeutics, including antivirals and immunomodulatory agents, affect long-term immunity following natural infection?

Are the compensatory T cell responses observed in immunocompromised patients with imparied humoral immunity following vaccination protective?

What are the key factors in determining the presence and duration of protective mucosal immunity?

How does immune memory differ between what has been observed in peripheral blood with various tissues (e.g. mucosal and organized lymphoid tissues, lower respiratory tract, etc.)

What is the role of secretary and circulating IgA antibodies?

Are there immune mechanisms active during acute infection that predict the development of post-acute sequelae of SARS-CoV-2 infection (PASC)?

Are there immune mechanisms that are initiated during the recovery phase (i.e., after acute infection has resolved) that are associated with PASC?

If immune mechanisms are found to underlie PASC, can we distinguish persistent immune perturbations from the sequelae of so-called "hit-and-run" mechanisms?

Does SARS-CoV-2 antigen persist beyond the period of mucosal viral shedding, either in the form of replicationcompetent or non-replication-competent virus? If so, at what body sites?

Do inadequate or excessive immune responses (including autoimmune) contribute to PASC?

If immune mechanisms drive PASC, are there interventions which can prevent or treat PASC symptoms?

Will PASC lead to increased risk of cardiovascular or neurologic diseases over time?

What tissue-based measurements will be informative in determining whether SARS-CoV-2 genetic material or protein persist in tissues? What measurements will be acceptable in those who have entered the convalescent phase?

Are there non-invasive methods of measuring whole-body immune responses or inflammation in the setting of SARS-CoV-2 infection?

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans

Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

Humoral Immune Response to SARS-CoV-2 in Iceland

Evaluation of SARS-CoV-2 IgG antibody response in PCR positive patients: Comparison of nine tests in relation to clinical data

Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production

Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19

Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019

Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections

Antibody Responses to SARS-CoV-2 in Patients With Novel Coronavirus Disease

Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19

Longitudinal Serological Analysis and Neutralizing Antibody Levels in Coronavirus Disease 2019 Convalescent Patients

Neutralizing antibody titres in SARS-CoV-2 infections

Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients

Evolution of antibody immunity to SARS-CoV-2

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay

Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study

Antibody persistence in the first 6 months following SARS-CoV-2 infection among hospital workers: a prospective longitudinal study

SARS-CoV-2 antibody persistence in COVID-19 convalescent plasma donors: Dependency on assay format and applicability to serosurveillance

Persistence of Antibody and Cellular Immune Responses in COVID-19 patients over Nine Months after Infection

Long-term Persistence of Neutralizing Antibodies to SARS-CoV-2 Following Infection

Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors

Kinetics of SARS-CoV-2 specific antibodies (IgM, IgA, IgG) in non-hospitalized patients four months following infection

Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals

Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity

Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19

Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms

T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals

Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection

Anti-SARS-CoV-2 receptor binding domain antibody evolution after mRNA vaccination

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls

What we know about covid-19 reinfection so far

Reduced Risk of Reinfection with SARS-CoV-2 After COVID-19 Vaccination -Kentucky

SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19

Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. bioRxiv

Dynamics of CD4 T Cell and Antibody Responses in COVID-19 Patients With Different Disease Severity

SARS-CoV-2-specific circulating T follicular helper cells correlate with neutralizing antibodies and increase during early convalescence

Adaptive immunity to SARS-CoV-2 and COVID-19

Deciphering the ins and outs of SARS-CoV-2-specific T cells

Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals

Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees. bioRxiv

Cross-reactive memory T cells and herd immunity to SARS-CoV-2

The known unknowns of T cell immunity to COVID-19

SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition

Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses

Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans

SARS-CoV-2 Variant Antibodies Wane 6 Months After Vaccination

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months

Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months

Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution. medRxiv

Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19

Kinetics of Anti-SARS-CoV-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers

Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid-organ transplant recipients

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

SARS-CoV-2-specific serological and functional T cell immune responses during acute and early COVID-19 convalescence in solid organ transplant patients

COVID-19 and Solid Organ Transplantation: A Review Article

Cellular and humoral immune response after mRNA-1273 SARS-CoV-2 vaccine in liver and heart transplant recipients

Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients

Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients

Safety and Reactogenicity of 2 Doses of SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients

Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients

Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series

Antibody Response to a Fourth Dose of a SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study

Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer

Anti-spike antibody response to SARS-CoV-2 booster vaccination in patients with B cell-derived hematologic malignancies. Cancer Cell

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel

Discordant Virus-Specific Antibody Levels, Antibody Neutralization Capacity, and T-cell Responses Following 3 Doses of SARS-CoV-2 Vaccination in a Patient With Connective Tissue Disease

Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases

Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy

Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity. medRxiv

Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies

Association of Disease-Modifying Treatment and Anti-CD20 Infusion Timing With Humoral Response to 2 SARS-CoV-2 Vaccines in Patients With Multiple Sclerosis

Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigatorinitiated, single-centre, open-label study

Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients

Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients

Rituximab and risk of COVID-19 infection and its severity in patients with MS and NMOSD

SARS-CoV-2 seroprevalence, and IgG concentration and pseudovirus neutralising antibody titres after infection, compared by HIV status: a matched case-control observational study

COVID-19 in people living with HIV: Clinical implications of dynamics of the immune response to SARS-CoV-2

Seroprevalence of anti-SARS-CoV2 Antibodies in Umbrian Persons Living with HIV

People Living with HIV Easily lose their Immune Response to SARS-CoV-2: Result From A Cohort of COVID-19 Cases in Wuhan, China

The BNT162b2 mRNA Vaccine Elicits Robust Humoral and Cellular Immune Responses in People Living with HIV. Clin Infect Dis

Safety and antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in persons with HIV

T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in

CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients

Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients

Impaired antibody response to influenza vaccine in HIVinfected and uninfected aging women is associated with immune activation and inflammation

Non-responsiveness to hepatitis B vaccination in HIV seropositive patients; possible causes and solutions

Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus

Functional exhaustion of antiviral lymphocytes in COVID-19 patients

Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

The pathogenesis and treatment of the `Cytokine Storm' in COVID-19

Hematological findings and complications of COVID-19

Dysregulation of Immune Response in Patients With Coronavirus

T cell responses to whole SARS coronavirus in humans

Elevated plasma IL-6 and CRP levels are associated with adverse clinical outcomes and death in critically ill SARS-CoV-2 patients: inflammatory response of SARS-CoV-2 patients

C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19

Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients

An inflammatory cytokine signature predicts COVID-19 severity and survival

Longitudinal analyses reveal immunological misfiring in severe COVID-19

A dynamic COVID-19 immune signature includes associations with poor prognosis

Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors

Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19

Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis

Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia

COVID-19 infection: the perspectives on immune responses

Cytokine and Chemokine Levels in Coronavirus Disease 2019 Convalescent Plasma

Persistent Symptoms and Association With Inflammatory Cytokine Signatures in Recovered Coronavirus Disease

Soluble markers of inflammation and coagulation but not T-cell activation predict non--AIDS-defining morbid events during suppressive antiretroviral treatment

HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality

Post-acute COVID-19 syndrome

High-dimensional characterization of post-acute sequelae of COVID-19

Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK -Office for National Statistics

Long COVID in a prospective cohort of home-isolated patients

Determinants and dynamics of SARS-CoV-2 infection in a diverse population: 6-month evaluation of a prospective cohort study

A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract

Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study

Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence. bioRxiv

Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection

Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals

SARS-CoV-2 infection as a trigger of autoimmune response

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study

Lack of Antinuclear Antibodies in Convalescent COVID-19 Patients with Persistent Symptoms

Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with

Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host

Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China

Chronic SARS-CoV-2, a Cause of Post-acute COVID-19 Sequelae (Long-COVID)? Front Microbiol

Persistent Systemic Microbial Translocation and Intestinal Damage During Coronavirus Disease-19

Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection

Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy

Inflammatory Biomarkers and Mortality Risk Among HIV-Suppressed Men: A Multisite Prospective Cohort Study

CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection

Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection

Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials

Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States

Cytomegalovirus Infection and Relative Risk of Cardiovascular Disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): A Meta-Analysis of Prospective Studies Up to 2016

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Gag p24 is a Marker of HIV Expression in Tissues and Correlates with Immune Response

HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy

Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells

Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors

Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites

HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

Human Immunodeficiency Virus Persistence and T-Cell Activation in Blood, Rectal, and Lymph Node Tissue in Human Immunodeficiency Virus-Infected Individuals Receiving Suppressive Antiretroviral Therapy

Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents

Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency

A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells

Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers

Eliminating HIV reservoirs for a cure: the issue is in the tissue

In Situ Characterization of Human Lymphoid Tissue Immune Cells by Multispectral Confocal Imaging and Quantitative Image Analysis; Implications for HIV Reservoir Characterization

Elucidating the Burden of HIV in Tissues Using Multiplexed Immunofluorescence and In Situ Hybridization: Methods for the Single-Cell Phenotypic Characterization of Cells Harboring HIV In Situ

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells