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Long-term immunologic effects of SARS-CoV-2 infection: leveraging translational research methodology to address emerging questions

Published:November 12, 2021DOI:https://doi.org/10.1016/j.trsl.2021.11.006
      The current era of COVID-19 is characterized by emerging variants of concern, 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. 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 (ie, post-acute sequelae of SARS-CoV-2 infection), 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.

      Abbreviations:

      AIM assay (activation induced marker), COVID-19 (coronavirus disease 2019), ELISpot assay (Enzyme-linked immunospot), ICS (intracellular cytokine staining), IL (interleukin), MAIT cell (mucosa-association invariant T), PASC (post-acute sequelae of SARS-CoV-2 infection), RBD (receptor-binding domain), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), SOT (Solid organ transplant)

      OVERVIEW

      Many questions remain regarding the immunologic consequences of SARS-CoV-2 infection. While initial studies were crucial in demonstrating that most individuals develop long-term humoral and cell-mediated immunity to infection with the virus, the current era of COVID-19 is characterized by emerging variants of concern, 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 millions of individuals worldwide continue to become infected, there is an ongoing need for research to promote understanding of the immunology of both natural infection and prevention. 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.

      LONG-TERM PROTECTIVE IMMUNITY FOLLOWING INFECTION

      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
      • Seow J
      • Graham C
      • Merrick B
      • et al.
      Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans.
      • Long Q-X
      • Tang X-J
      • Shi Q-L
      • et al.
      Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
      • Gudbjartsson DF
      • Norddahl GL
      • Melsted P
      • et al.
      Humoral immune response to SARS-CoV-2 in Iceland.
      • Naaber P
      • Hunt K
      • Pesukova J
      • et al.
      Evaluation of SARS-CoV-2 IgG antibody response in PCR positive patients: Comparison of nine tests in relation to clinical data.
      • Chen Y
      • Zuiani A
      • Fischinger S
      • et al.
      Quick COVID-19 healers sustain anti-SARS-CoV-2 antibody production.
      • Chen X
      • Pan Z
      • Yue S
      • et al.
      Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19.
      • Kowitdamrong E
      • Puthanakit T
      • Jantarabenjakul W
      • et al.
      Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019.
      • Lei Q
      • Li Y
      • Hou H-Y
      • et al.
      Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections.
      • Zhao J
      • Yuan Q
      • Wang H
      • et al.
      Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019.
      • Ibarrondo FJ
      • Javier Ibarrondo F
      • Fulcher JA
      • et al.
      Rapid decay of anti–SARS-CoV-2 antibodies in persons with mild Covid-19.
      • Muecksch F
      • Wise H
      • Batchelor B
      • et al.
      Longitudinal serological analysis and neutralizing antibody levels in coronavirus disease 2019 convalescent patients.
      • Lau EHY
      • Tsang OTY
      • Hui DSC
      • et al.
      Neutralizing antibody titres in SARS-CoV-2 infections.
      • Iyer AS
      • Jones FK
      • Nodoushani A
      • et al.
      Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients.
      • Gaebler C
      • Wang Z
      • Lorenzi JCC
      • et al.
      Evolution of antibody immunity to SARS-CoV-2.
      • Peluso MJ
      • Takahashi S
      • Hakim J
      • et al.
      SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.
      • Chia WN
      • Zhu F
      • Ong SWX
      • et al.
      Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study.
      • L'Huillier AG
      • Meyer B
      • Andrey DO
      • et al.
      Antibody persistence in the first 6 months following SARS-CoV-2 infection among hospital workers: a prospective longitudinal study.
      • Di Germanio C
      • Simmons G
      • Kelly K
      • et al.
      SARS-CoV-2 antibody persistence in COVID-19 convalescent plasma donors: Dependency on assay format and applicability to serosurveillance.
      • Yao L
      • Wang G-L
      • Shen Y
      • et al.
      Persistence of antibody and cellular immune responses in COVID-19 patients over nine months after Infection.
      • Wisnivesky JP
      • Stone K
      • Bagiella E
      • et al.
      Long-term persistence of neutralizing antibodies to SARS-CoV-2 following infection.
      • Dispinseri S
      • Secchi M
      • Pirillo MF
      • et al.
      Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival.
      • Goto A
      • Go H
      • Miyakawa K
      • et al.
      Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.
      • Orth-Höller D
      • Eigentler A
      • Stiasny K
      • Weseslindtner L
      • Möst J.
      Kinetics of SARS-CoV-2 specific antibodies (IgM, IgA, IgG) in non-hospitalized patients four months following infection.
      and cell-mediated
      • Yao L
      • Wang G-L
      • Shen Y
      • et al.
      Persistence of antibody and cellular immune responses in COVID-19 patients over nine months after Infection.
      ,
      • Le Bert N
      • Clapham HE
      • Tan AT
      • et al.
      Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection.
      • Dan JM
      • Mateus J
      • Kato Y
      • et al.
      Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
      • Grifoni A
      • Weiskopf D
      • Ramirez SI
      • et al.
      Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.
      • Peng Y
      • Mentzer AJ
      • Liu G
      • et al.
      Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
      • Rydyznski Moderbacher C
      • Ramirez SI
      • Dan JM
      • et al.
      Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.
      • Sekine T
      • Perez-Potti A
      • Rivera-Ballesteros O
      • et al.
      Robust T Cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      • Bilich T
      • Nelde A
      • Heitmann JS
      • et al.
      T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals.
      • Jiang X-L
      • Wang G-L
      • Zhao X-N
      • et al.
      Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection.
      • Cho A
      • Muecksch F
      • Schaefer-Babajew D
      • et al.
      Anti-SARS-CoV-2 receptor binding domain antibody evolution after mRNA vaccination.
      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,
      • Gudbjartsson DF
      • Norddahl GL
      • Melsted P
      • et al.
      Humoral immune response to SARS-CoV-2 in Iceland.
      ,
      • Chen X
      • Pan Z
      • Yue S
      • et al.
      Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19.
      ,
      • Kowitdamrong E
      • Puthanakit T
      • Jantarabenjakul W
      • et al.
      Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019.
      ,
      • Peluso MJ
      • Takahashi S
      • Hakim J
      • et al.
      SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.
      ,
      • Rydyznski Moderbacher C
      • Ramirez SI
      • Dan JM
      • et al.
      Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.
      ,
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      the predictors of the duration of natural immunity are not fully understood and may be determined by a variety of clinical and measurement factors.
      • Peluso MJ
      • Takahashi S
      • Hakim J
      • et al.
      SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.
      ,
      • Di Germanio C
      • Simmons G
      • Kelly K
      • et al.
      SARS-CoV-2 antibody persistence in COVID-19 convalescent plasma donors: Dependency on assay format and applicability to serosurveillance.
      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%–10% during this extended time period across multiple studies,
      • Dan JM
      • Mateus J
      • Kato Y
      • et al.
      Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
      ,
      • Grifoni A
      • Weiskopf D
      • Ramirez SI
      • et al.
      Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.
      ,
      • Rydyznski Moderbacher C
      • Ramirez SI
      • Dan JM
      • et al.
      Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.
      ,
      • Sekine T
      • Perez-Potti A
      • Rivera-Ballesteros O
      • et al.
      Robust T Cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
      ,
      • Bilich T
      • Nelde A
      • Heitmann JS
      • et al.
      T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals.
      ,
      • Jiang X-L
      • Wang G-L
      • Zhao X-N
      • et al.
      Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection.
      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.
      • Peng Y
      • Mentzer AJ
      • Liu G
      • et al.
      Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
      ,
      • Le Bert N
      • Tan AT
      • Kunasegaran K
      • et al.
      SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.
      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 (eg, 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.
      • Stokel-Walker C.
      What we know about covid-19 reinfection so far.
      During the first year of the pandemic, re-infection seemed exceedingly rare and fewer than 50 cases were reported in the literature,
      • Stokel-Walker C.
      What we know about covid-19 reinfection so far.
      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.
      • Cavanaugh AM
      • Spicer KB
      • Thoroughman D
      • Glick C
      • Winter K
      Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination - kentucky, May-June 2021.
      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.

      BREADTH AND DEPTH OF T CELL IMMUNE RESPONSES AND CROSS-REACTIVITY OTHER CORONAVIRUSES

      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.
      • Grifoni A
      • Sidney J
      • Vita R
      • et al.
      SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19.
      Thus far, over 1400 unique CD8 and CD4 T cell epitopes have been identified,
      • Grifoni A
      • Sidney J
      • Vita R
      • et al.
      SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19.
      ,
      • Tarke A
      • Sidney J
      • Kidd CK
      • et al.
      Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.
      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.
      • Grifoni A
      • Sidney J
      • Vita R
      • et al.
      SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19.
      Nonetheless, a prior study estimates than an individual may recognize 17 different CD8 and 19 different CD4 immunologically important epitopes.
      • Tarke A
      • Sidney J
      • Kidd CK
      • et al.
      Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.
      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.
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      ,
      • Koblischke M
      • Traugott MT
      • Medits I
      • et al.
      Dynamics of CD4 T Cell and antibody responses in COVID-19 patients with different disease severity.
      ,
      • Boppana S
      • Qin K
      • Files JK
      • et al.
      SARS-CoV-2-specific circulating T follicular helper cells correlate with neutralizing antibodies and increase during early convalescence.
      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.
      • Dan JM
      • Mateus J
      • Kato Y
      • et al.
      Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
      ,
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      ,
      • Sette A
      • Crotty S.
      Adaptive immunity to SARS-CoV-2 and COVID-19.
      ,
      • Perez-Potti A
      • Lange J
      • Buggert M.
      Deciphering the ins and outs of SARS-CoV-2-specific T cells.
      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.
      • Tarke A
      • Sidney J
      • Methot N
      • et al.
      Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals.
      ,
      • Tarke A
      • Sidney J
      • Methot N
      • et al.
      Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees.
      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.
      • Dan JM
      • Mateus J
      • Kato Y
      • et al.
      Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
      ,
      • Rydyznski Moderbacher C
      • Ramirez SI
      • Dan JM
      • et al.
      Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.
      ,
      • Sette A
      • Crotty S.
      Adaptive immunity to SARS-CoV-2 and COVID-19.
      ,
      • Lipsitch M
      • Grad YH
      • Sette A
      • Crotty S.
      Cross-reactive memory T cells and herd immunity to SARS-CoV-2.
      ,
      • Karlsson AC
      • Humbert M
      • Buggert M.
      The known unknowns of T cell immunity to COVID-19.
      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,
      • Sekine T
      • Perez-Potti A
      • Rivera-Ballesteros O
      • et al.
      Robust T Cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
      ,
      • Nelde A
      • Bilich T
      • Heitmann JS
      • et al.
      SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition.
      but data exist suggesting that pre-existing memory responses from endemic, less-pathogenic coronaviruses or other pathogens occur in some individuals.
      • Le Bert N
      • Tan AT
      • Kunasegaran K
      • et al.
      SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.
      ,
      • Bacher P
      • Rosati E
      • Esser D
      • et al.
      Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.
      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.
      • Ogbe A
      • Kronsteiner B
      • Skelly DT
      • et al.
      T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.
      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.

      VACCINE INDUCED ANTIBODY AND T CELL RESPONSES

      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.
      • Klasse PJ
      • Nixon DF
      • Moore JP.
      Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans.
      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,
      • Abbasi J.
      SARS-CoV-2 variant antibodies wane 6 months after vaccination.
      • Jung J
      • Sung H
      • Kim S-H.
      Covid-19 breakthrough infections in vaccinated health care workers.
      • Levin EG
      • Lustig Y
      • Cohen C
      • et al.
      Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months.
      • Pilishvili T
      • Gierke R
      • Fleming-Dutra KE
      • et al.
      Effectiveness of mRNA Covid-19 vaccine among U.S. Health Care Personnel.
      • Thomas SJ
      • Moreira Jr, ED
      • Kitchin N
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.
      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.
      • Abbasi J.
      SARS-CoV-2 variant antibodies wane 6 months after vaccination.
      • Jung J
      • Sung H
      • Kim S-H.
      Covid-19 breakthrough infections in vaccinated health care workers.
      • Levin EG
      • Lustig Y
      • Cohen C
      • et al.
      Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months.
      • Pilishvili T
      • Gierke R
      • Fleming-Dutra KE
      • et al.
      Effectiveness of mRNA Covid-19 vaccine among U.S. Health Care Personnel.
      • Thomas SJ
      • Moreira Jr, ED
      • Kitchin N
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.
      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.
      • Ke R
      • Martinez PP
      • Smith RL
      • et al.
      Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution.
      Further research is warranted to more precisely determine the impact of vaccination on infectivity of breakthrough infection. Regardless, vaccine use has had a dramatic positive effect on reducing morbidity, mortality and community spread of SARS-CoV-2.
      Data on T cell responses from vaccine trials are more sparse, and systematic study of adaptive cellular responses varied across initial studies (as reviewed elsewhere
      • Klasse PJ
      • Nixon DF
      • Moore JP.
      Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans.
      ). A majority of approved or authorized vaccines, however, have demonstrated development of CD4, CD8 or total T cell responses as measured by spot forming colonies per 106 cells in EliSpot assays (40 to >2600 spot forming colonies). Data on the decay of T cell responses following vaccination over time are currently lacking, and it is not known what role vaccine-elicited virus-specific T cell responses play in preventing primary infection or modulating the course of acute and post-acute disease.
      To date, the immunologic response prior to SARS-CoV-2 vaccination has been characterized for over 12 months.
      • Doria-Rose N
      • Suthar MS
      • Makowski M
      • et al.
      Antibody Persistence through 6 months after the second dose of mRNA-1273 vaccine for Covid-19.
      ,
      • Terpos E
      • Trougakos IP
      • Karalis V
      • et al.
      Kinetics of anti-SARS-CoV-2 antibody responses 3 months post complete vaccination with BNT162b2; a prospective study in 283 health workers.
      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.

      IMMUNITY IN IMMUNOCOMPROMISED INDIVIDUALS

      It is now well established that antibody and T cell responses can be severely impaired following vaccination,
      • Stock PG
      • Henrich TJ
      • Segev DL
      • Werbel WA.
      Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid-organ transplant recipients.
      and to a lesser extent, natural infection,
      • Caballero-Marcos A
      • Salcedo M
      • Alonso-Fernández R
      • et al.
      Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients.
      • Favà A
      • Donadeu L
      • Sabé N
      • et al.
      SARS-CoV-2-specific serological and functional T cell immune responses during acute and early COVID-19 convalescence in solid organ transplant patients.
      • Azzi Y
      • Bartash R
      • Scalea J
      • Loarte-Campos P
      • Akalin E.
      COVID-19 and solid organ transplantation: a review article.
      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,
      • Herrera S
      • Colmenero J
      • Pascal M
      • et al.
      Cellular and humoral immune response after mRNA-1273 SARS-CoV-2 vaccine in liver and heart transplant recipients.
      • Miele M
      • Busà R
      • Russelli G
      • et al.
      Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients.
      • Boyarsky BJ
      • Werbel WA
      • Avery RK
      • et al.
      Antibody response to 2-Dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.
      • Ou MT
      • Boyarsky BJ
      • Motter JD
      • et al.
      Safety and reactogenicity of 2 Doses of SARS-CoV-2 vaccination in solid organ transplant recipients.
      • Boyarsky BJ
      • Werbel WA
      • Avery RK
      • et al.
      Immunogenicity of a single Dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
      • Sattler A
      • Schrezenmeier E
      • Weber UA
      • et al.
      Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.
      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.
      • Werbel WA
      • Boyarsky BJ
      • Ou MT
      • et al.
      Safety and immunogenicity of a third Dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.
      ,
      • Alejo JL
      • Mitchell J
      • Chiang TP-Y
      • et al.
      Antibody response to a fourth Dose of a SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.
      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,
      • Monin L
      • Laing AG
      • Muñoz-Ruiz M
      • et al.
      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.
      • Massarweh A
      • Eliakim-Raz N
      • Stemmer A
      • et al.
      Evaluation of seropositivity following BNT162b2 Messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer.
      • Greenberger LM
      • Saltzman LA
      • Senefeld JW
      • Johnson PW
      • DeGennaro LJ
      • Nichols GL.
      Anti-spike antibody response to SARS-CoV-2 booster vaccination in patients with B cell-derived hematologic malignancies.
      albeit to a lesser degree than those who have received SOT but may experience high rates of vaccine breakthrough.
      • Brosh-Nissimov T
      • Orenbuch-Harroch E
      • Chowers M
      • et al.
      BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.
      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.
      • Miele M
      • Busà R
      • Russelli G
      • et al.
      Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients.
      ,
      • Boyarsky BJ
      • Werbel WA
      • Avery RK
      • et al.
      Antibody response to 2-Dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.
      ,
      • Boyarsky BJ
      • Werbel WA
      • Avery RK
      • et al.
      Immunogenicity of a single Dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
      ,
      • Peluso MJ
      • Munter SE
      • Lynch KL
      • et al.
      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.
      • Haberman RH
      • Herati R
      • Simon D
      • et al.
      Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.
      • Simon D
      • Tascilar K
      • Fagni F
      • et al.
      SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.
      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.
      • Miele M
      • Busà R
      • Russelli G
      • et al.
      Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients.
      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 (eg, anti-CD20 for multiple sclerosis) have a paradoxical increase in SARS-CoV-2-specific CD8 T cell responses, despite significant impairment of humoral responses.
      • Peluso MJ
      • Munter SE
      • Lynch KL
      • et al.
      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.
      ,
      • Apostolidis SA
      • Kakara M
      • Painter MM
      • et al.
      Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.

      Sabatino JJ, Mittl K, Rowles W, et al. Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity. medRxiv2021. doi:10.1101/2021.09.10.21262933

      • Sormani MP
      • Inglese M
      • Schiavetti I
      • et al.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      • Disanto G
      • Sacco R
      • Bernasconi E
      • et al.
      Association of disease-modifying treatment and anti-CD20 infusion timing with humoral response to 2 SARS-CoV-2 vaccines in patients with multiple sclerosis.
      • Moor MB
      • Suter-Riniker F
      • Horn MP
      • et al.
      Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study.
      The increase in CD8 T cell responses may reflect an immune compensatory mechanism,
      • Apostolidis SA
      • Kakara M
      • Painter MM
      • et al.
      Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
      ,
      • Schmidt T
      • Klemis V
      • Schub D
      • et al.
      Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients.
      ,
      • Hall VG
      • Ferreira VH
      • Ierullo M
      • et al.
      Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients.
      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.
      • Apostolidis SA
      • Kakara M
      • Painter MM
      • et al.
      Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
      ,
      • Esmaeili S
      • Abbasi MH
      • Abolmaali M
      • et al.
      Rituximab and risk of COVID-19 infection and its severity in patients with MS and NMOSD.
      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
      • Spinelli MA
      • Lynch KL
      • Yun C
      • et al.
      SARS-CoV-2 seroprevalence, and IgG concentration and pseudovirus neutralising antibody titres after infection, compared by HIV status: a matched case-control observational study.
      • Mondi A
      • Cimini E
      • Colavita F
      • et al.
      COVID-19 in people living with HIV: Clinical implications of dynamics of the immune response to SARS-CoV-2.
      • Papalini C
      • Paciosi F
      • Schiaroli E
      • et al.
      Seroprevalence of anti-SARS-CoV2 antibodies in Umbrian persons living with HIV.
      or shorter duration of the antibody response in comparison to the general population,

      Liu Y, Xiao Y, Wu S, et al. People Living with HIV Easily lose their Immune Response to SARS-CoV-2: Result From A Cohort of COVID-19 Cases in Wuhan, China. 2021. doi:10.21203/rs.3.rs-543375/v1

      although both observations require further study. Recent studies suggest that the immune response following vaccination is equal amongst PLWH and the general population
      • Woldemeskel BA
      • Karaba AH
      • Garliss CC
      • et al.
      The BNT162b2 mRNA vaccine elicits robust humoral and cellular immune responses in people living with HIV.
      and in comparison to those with other immunocompromising conditions,
      • Ruddy JA
      • Boyarsky BJ
      • Bailey JR
      • et al.
      Safety and antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in persons with HIV.
      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.
      • Buechler MB
      • Newman LP
      • Chohan BH
      • Njoroge A
      • Wamalwa D
      • Farquhar C.
      T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya.
      • Avelino-Silva VI
      • Miyaji KT
      • Hunt PW
      • et al.
      CD4/CD8 Ratio and KT ratio predict yellow fever vaccine immunogenicity in HIV-infected patients.
      • Colin de Verdiere N
      • Durier C
      • Samri A
      • et al.
      Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.
      • Parmigiani A
      • Alcaide ML
      • Freguja R
      • et al.
      Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation.
      • van den Berg R
      • van Hoogstraten I
      • van Agtmael M.
      Non-responsiveness to hepatitis B vaccination in HIV seropositive patients; possible causes and solutions.
      • Kroon FP
      • van Dissel JT
      • Labadie J
      • van Loon AM
      • van Furth R.
      Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus.
      This includes suboptimal responses to vaccination to prevent against yellow fever,
      • Avelino-Silva VI
      • Miyaji KT
      • Hunt PW
      • et al.
      CD4/CD8 Ratio and KT ratio predict yellow fever vaccine immunogenicity in HIV-infected patients.
      ,
      • Colin de Verdiere N
      • Durier C
      • Samri A
      • et al.
      Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.
      Hepatitis B,
      • van den Berg R
      • van Hoogstraten I
      • van Agtmael M.
      Non-responsiveness to hepatitis B vaccination in HIV seropositive patients; possible causes and solutions.
      , influenza,
      • Parmigiani A
      • Alcaide ML
      • Freguja R
      • et al.
      Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation.
      polio, diphtheria, and tetanus.
      • Kroon FP
      • van Dissel JT
      • Labadie J
      • van Loon AM
      • van Furth R.
      Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus.
      It is likely that inadequate CD4+ T cell immune reconstitution, chronic inflammation, and T cell exhaustion underlie these observations,
      • Avelino-Silva VI
      • Miyaji KT
      • Hunt PW
      • et al.
      CD4/CD8 Ratio and KT ratio predict yellow fever vaccine immunogenicity in HIV-infected patients.
      and careful studies will be needed to understand how HIV and COVID-19 vaccination durability overlap.

      HUMAN INFLAMMATORY RESPONSES IN COVID-19

      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.
      • Zheng M
      • Gao Y
      • Wang G
      • et al.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      • Zheng H-Y
      • Zhang M
      • Yang C-X
      • et al.
      Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.
      • Ye Q
      • Wang B
      • Mao J.
      The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
      • Terpos E
      • Ntanasis-Stathopoulos I
      • Elalamy I
      • et al.
      Hematological findings and complications of COVID-19.
      • Qin C
      • Zhou L
      • Hu Z
      • et al.
      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      • Li CK-F
      • Wu H
      • Yan H
      • et al.
      T cell responses to whole SARS coronavirus in humans.
      Especially among those hospitalized with COVID-19, inflammation during the acute and early post-acute phase of infection has been associated with poor outcomes.
      • Lavillegrand J-R
      • Garnier M
      • Spaeth A
      • et al.
      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.
      • Sharifpour M
      • Rangaraju S
      • Liu M
      • et al.
      C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19.

      Tobias Herold MD, Arnreich C, Hellmuth JC, Matthias Klein MD, Tobias Weinberger MD. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. https://www.allergy.org.au/images/stories/about/attach-IL-6_as_a_marker_of_outcome_in_COVID-19.pdf

      • Del Valle DM
      • Kim-Schulze S
      • Huang H-H
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      • Lucas C
      • Wong P
      • Klein J
      • et al.
      Longitudinal analyses reveal immunological misfiring in severe COVID-19.
      • Laing AG
      • Lorenc A
      • del Molino del Barrio I
      • et al.
      A dynamic COVID-19 immune signature includes associations with poor prognosis.
      • Han H
      • Ma Q
      • Li C
      • et al.
      Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors.
      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.
      • Zheng M
      • Gao Y
      • Wang G
      • et al.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      • Zheng H-Y
      • Zhang M
      • Yang C-X
      • et al.
      Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.
      • Ye Q
      • Wang B
      • Mao J.
      The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
      • Terpos E
      • Ntanasis-Stathopoulos I
      • Elalamy I
      • et al.
      Hematological findings and complications of COVID-19.
      • Qin C
      • Zhou L
      • Hu Z
      • et al.
      Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
      • Li CK-F
      • Wu H
      • Yan H
      • et al.
      T cell responses to whole SARS coronavirus in humans.
      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.
      • Liu Y
      • Du X
      • Chen J
      • et al.
      Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19.
      ,
      • Lagunas-Rangel FA.
      Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis.
      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 (eg, ORF 1ab) peptide sequences develop within the weeks following infection.
      • Sekine T
      • Perez-Potti A
      • Rivera-Ballesteros O
      • et al.
      Robust T Cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
      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.
      • Zheng M
      • Gao Y
      • Wang G
      • et al.
      Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
      ,
      • Zheng H-Y
      • Zhang M
      • Yang C-X
      • et al.
      Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.
      ,
      • Wang F
      • Nie J
      • Wang H
      • et al.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      ,
      • Shi Y
      • Wang Y
      • Shao C
      • et al.
      COVID-19 infection: the perspectives on immune responses.
      Emerging data suggest that inflammation related to acute SARS-CoV-2 infection can persist for weeks or even months.
      • Bonny TS
      • Patel EU
      • Zhu X
      • et al.
      Cytokine and chemokine levels in coronavirus disease 2019 convalescent plasma.
      ,
      • Ong SWX
      • Fong S-W
      • Young BE
      • et al.
      Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients.
      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.
      • Bonny TS
      • Patel EU
      • Zhu X
      • et al.
      Cytokine and chemokine levels in coronavirus disease 2019 convalescent plasma.
      These markers include interferon (IFN)-gamma, certain interleukin (IL) proteins (eg, 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.
      • Ong SWX
      • Fong S-W
      • Young BE
      • et al.
      Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients.
      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,
      • Tenorio AR
      • Zheng Y
      • Bosch RJ
      • et al.
      Soluble markers of inflammation and coagulation but not T-cell activation predict non–AIDS-defining morbid events during suppressive antiretroviral treatment.
      ,
      • Serrano-Villar S
      • Sainz T
      • Lee SA
      • et al.
      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.
      this is less well understood for acute infections like SARS-CoV-2 which is not thought to persist over the long-term.

      IMMUNOLOGIC AND INFLAMMATORY MANIFESTATIONS OF POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION (PASC)

      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.
      • Nalbandian A
      • Sehgal K
      • Gupta A
      • et al.
      Post-acute COVID-19 syndrome.
      • Al-Aly Z
      • Xie Y
      • Bowe B
      High-dimensional characterization of post-acute sequelae of COVID-19.
      • Ayoubkhani D
      • Blomberg B
      • Mohn KG-I
      • Brokstad KA
      • et al.
      Long COVID in a prospective cohort of home-isolated patients.
      Investigation into 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.
      • Nalbandian A
      • Sehgal K
      • Gupta A
      • et al.
      Post-acute COVID-19 syndrome.
      • Al-Aly Z
      • Xie Y
      • Bowe B
      High-dimensional characterization of post-acute sequelae of COVID-19.
      • Ayoubkhani D
      • Blomberg B
      • Mohn KG-I
      • Brokstad KA
      • et al.
      Long COVID in a prospective cohort of home-isolated patients.
      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 (ie, 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,
      • Blomberg B
      • Mohn KG-I
      • Brokstad KA
      • et al.
      Long COVID in a prospective cohort of home-isolated patients.
      ,
      • Horton DB
      • Barrett ES
      • Roy J
      • et al.
      Determinants and dynamics of SARS-CoV-2 infection in a diverse population: 6-month evaluation of a prospective cohort study.
      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.
      • Gaebler C
      • Wang Z
      • Lorenzi JCC
      • et al.
      Evolution of antibody immunity to SARS-CoV-2.
      Other studies have found that the humoral response appears lower among those with persistent symptoms.
      • Hu F
      • Chen F
      • Ou Z
      • et al.
      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.
      • Augustin M
      • Schommers P
      • Stecher M
      • et al.
      Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study.
      • Talla A
      • Vasaikar SV
      • Lemos MP
      • et al.
      Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence.
      For example, ongoing viral shedding in the gut is associated with lower RBD-specific antibodies,
      • Hu F
      • Chen F
      • Ou Z
      • et al.
      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.
      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,
      • Talla A
      • Vasaikar SV
      • Lemos MP
      • et al.
      Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence.
      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
      • Talla A
      • Vasaikar SV
      • Lemos MP
      • et al.
      Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence.
      or differential decay in the magnitude of SARS-CoV-2 specific CD8+ T cell responses among those with PASC.
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      While intriguing, the precise implications of this finding is not known, and could either represent a more exhausted pool of viral-specific cells that develop over time or other immune dysregulation or detrimental systemic inflammation leading to decay in the frequency of these CD8 T cells. Understanding the relationship between immune responses during early recovery and the persistence of PASC symptoms could guide diagnostic or therapeutic decision making for millions of individuals recovering from COVID-19.
      Studies that have evaluated persistent inflammation have suggested potential elevations in biomarkers,
      • Ong SWX
      • Fong S-W
      • Young BE
      • et al.
      Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients.
      ,
      • Peluso MJ
      • Lu S
      • Tang AF
      • et al.
      Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.
      although no clear immunologic pathways have yet to be consistently implicated. We recently demonstrated that during early recovery (ie, 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.
      • Tenorio AR
      • Zheng Y
      • Bosch RJ
      • et al.
      Soluble markers of inflammation and coagulation but not T-cell activation predict non–AIDS-defining morbid events during suppressive antiretroviral treatment.
      ,
      • Hunt PW
      • Sinclair E
      • Rodriguez B
      • et al.
      Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.
      ,
      • Gianella S
      • Chaillon A
      • Mutlu EA
      • et al.
      Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals.
      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.
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      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,
      • Sacchi MC
      • Tamiazzo S
      • Stobbione P
      • et al.
      SARS-CoV-2 infection as a trigger of autoimmune response.
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      • Song E
      • Bartley CM
      • Chow RD
      • et al.
      Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.
      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.
      • Seeßle J
      • Waterboer T
      • Hippchen T
      • et al.
      Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
      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.
      • Peluso MJ
      • Thomas IJ
      • Munter SE
      • Deeks SG
      • Henrich TJ.
      Lack of antinuclear antibodies in convalescent COVID-19 patients with persistent symptoms.
      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.

      TISSUE PERSISTENCE OF SARS-COV-2 INFECTION: A POTENTIAL MECHANISM FOR PASC?

      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.
      • Avanzato VA
      • Matson MJ
      • Seifert SN
      • et al.
      Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer.
      ,
      • Choi B
      • Choudhary MC
      • Regan J
      • et al.
      Persistence and evolution of SARS-CoV-2 in an immunocompromised host.
      However, RNA shedding usually resolves within a month in immunocompetent patients,
      • Zheng S
      • Fan J
      • Yu F
      • et al.
      Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.
      and we recently observed no persistent RNA shedding in convalescent COVID-19 patients who exhibit PASC approximately 4 months after initial infection.
      • Peluso MJ
      • Deitchman AN
      • Torres L
      • et al.
      Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
      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.
      • Gaebler C
      • Wang Z
      • Lorenzi JCC
      • et al.
      Evolution of antibody immunity to SARS-CoV-2.
      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.
      • O'Donnell JS
      • Chappell KJ.
      Chronic SARS-CoV-2, a cause of post-acute COVID-19 sequelae (Long-COVID)?.
      There is also data emerging that COVID-19 may lead to intestinal damage and microbial translocation.
      • Oliva A
      • Miele MC
      • Di Timoteo F
      • et al.
      Persistent systemic microbial translocation and intestinal damage during coronavirus disease-19.
      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.
      • Hunt PW
      • Sinclair E
      • Rodriguez B
      • et al.
      Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.
      Furthermore, elevations in IL-6 and other inflammatory markers in the setting of chronic HIV infection are associated with worse clinical outcomes,
      • ÁH Borges
      • JL O'Connor
      • Phillips AN
      • et al.
      Interleukin 6 is a stronger predictor of clinical events than high-sensitivity c-reactive protein or D-dimer during HIV infection.
      • Hsu DC
      • Ma YF
      • Hur S
      • et al.
      Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy.
      • Wada NI
      • Bream JH
      • Martínez-Maza O
      • et al.
      Inflammatory biomarkers and mortality risk among HIV-suppressed men: a multisite prospective cohort study.
      and the longer-term clinical impact of persistent IL-6 elevations identified in our PASC cohort requires further investigation.
      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.

      LEVERAGING THE STUDY OF OTHER CHRONIC INFECTIONS TO UNDERSTAND POST-ACUTE SEQUELAE OF SARS-COV-2 INFECTION

      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,
      • Freeman ML
      • Mudd JC
      • Shive CL
      • et al.
      CD8 T-Cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection.
      • Freeman ML
      • Lederman MM
      • Gianella S.
      Partners in crime: the role of CMV in immune dysregulation and clinical outcome during HIV infection.
      • Ljungman P
      • Boeckh M
      • Hirsch HH
      • et al.
      Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials.
      • Simanek AM
      • Dowd JB
      • Pawelec G
      • Melzer D
      • Dutta A
      • Aiello AE.
      Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.
      • Wang H
      • Peng G
      • Bai J
      • et al.
      Cytomegalovirus infection and relative risk of cardiovascular disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): a meta-analysis of prospective studies up to 2016.
      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.
      • Hamming I
      • Timens W
      • Bulthuis MLC
      • Lely AT
      • Navis GJ
      • van Goor H.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      • Salamanna F
      • Maglio M
      • Landini MP
      • Fini M.
      Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2.
      • Vaduganathan M
      • Vardeny O
      • Michel T
      • McMurray JJV
      • Pfeffer MA
      • Solomon SD.
      Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.
      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.
      • Wu G
      • Zuck P
      • Goh SL
      • et al.
      Gag p24 is a marker of HIV expression in tissues and correlates with immune response.
      • McManus WR
      • Bale MJ
      • Spindler J
      • et al.
      HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy.
      • Nguyen S
      • Deleage C
      • Darko S
      • et al.
      Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells.
      • Patro SC
      • Brandt LD
      • Bale MJ
      • et al.
      Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors.
      • Lee E
      • von Stockenstrom S
      • Morcilla V
      • et al.
      Impact of antiretroviral therapy duration on HIV-1 infection of T Cells within anatomic sites.
      • Henrich TJ
      • Hatano H
      • Bacon O
      • et al.
      HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.
      • Khoury G
      • Fromentin R
      • Solomon A
      • et al.
      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.
      • Telwatte S
      • Kim P
      • Chen T-H
      • et al.
      Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents.
      • Telwatte S
      • Lee S
      • Somsouk M
      • et al.
      Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency.
      • Yukl SA
      • Sinclair E
      • Somsouk M
      • et al.
      A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells.
      • Hatano H
      • Somsouk M
      • Sinclair E
      • et al.
      Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers.
      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.
      • Nguyen S
      • Deleage C
      • Darko S
      • et al.
      Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells.
      ,
      • Busman-Sahay K
      • Starke CE
      • Nekorchuk MD
      • Estes JD.
      Eliminating HIV reservoirs for a cure: the issue is in the tissue.
      • Moysi E
      • Del Rio Estrada PM
      • Torres-Ruiz F
      • Reyes-Terán G
      • Koup RA
      • In Petrovas C.
      Situ characterization of human lymphoid tissue immune cells by multispectral confocal imaging and quantitative image analysis; implications for HIV reservoir characterization.
      • Vasquez JJ
      • Hussien R
      • Aguilar-Rodriguez B
      • et al.
      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.
      • McBrien JB
      • Mavigner M
      • Franchitti L
      • et al.
      Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells.
      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 (eg, lung-associated lymph nodes in adults or tonsillar tissue in children) and mucosa-association invariant T 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.

      CONCLUSION

      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 (ie, PASC), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection.

      UNCITED LINKS

      Table I
      Table ITranslational science questions related to long-term immunologic consequences of COVID-19
      Humoral and Cellular Immunology
      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?
      Mucosal Immunity
      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 (eg, mucosal and organized lymphoid tissues, lower respiratory tract, etc.)
      What is the role of secretary and circulating IgA antibodies?
      Post-Acute Sequelae of SARS-CoV-2 Infection
      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 (ie, 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 replication-competent 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?
      Quantifying Tissue SARS-CoV-2 Burden and Sequelae
      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?

      ACKNOWLEDGMENTS

      T. J. H is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant number 3R01AI141003–03S1 to T. J. H.). M. J. P. is supported by the National Institutes of Health ( T32 AI60530–12 ) and by the UCSF Resource Allocation Program. T. J. H. receives grant support from Merck and Co. M. J. P. and J. D. report no conflicts of interest.
      Conflicts of Interest: All authors have read the journal's policy on conflicts of interest and the authorship agreement.

      REFERENCES

        • Seow J
        • Graham C
        • Merrick B
        • et al.
        Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans.
        Nat Microbiol. 2020; 5: 1598-1607
        • Long Q-X
        • Tang X-J
        • Shi Q-L
        • et al.
        Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
        Nat Med. 2020; 26: 1200-1204
        • Gudbjartsson DF
        • Norddahl GL
        • Melsted P
        • et al.
        Humoral immune response to SARS-CoV-2 in Iceland.
        N Engl J Med. 2020; 383: 1724-1734
        • Naaber P
        • Hunt K
        • Pesukova J
        • et al.
        Evaluation of SARS-CoV-2 IgG antibody response in PCR positive patients: Comparison of nine tests in relation to clinical data.
        PLoS One. 2020; 15e0237548
        • Chen Y
        • Zuiani A
        • Fischinger S
        • et al.
        Quick COVID-19 healers sustain anti-SARS-CoV-2 antibody production.
        Cell. 2020; 183 (.e16): 1496-1507
        • Chen X
        • Pan Z
        • Yue S
        • et al.
        Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19.
        Signal Transduct Target Ther. 2020; 5: 180
        • Kowitdamrong E
        • Puthanakit T
        • Jantarabenjakul W
        • et al.
        Antibody responses to SARS-CoV-2 in patients with differing severities of coronavirus disease 2019.
        PLoS One. 2020; 15e0240502
        • Lei Q
        • Li Y
        • Hou H-Y
        • et al.
        Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections.
        Allergy. 2020; https://doi.org/10.1111/all.14622
        • Zhao J
        • Yuan Q
        • Wang H
        • et al.
        Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease 2019.
        Clin Infect Dis. 2020; 71: 2027-2034
        • Ibarrondo FJ
        • Javier Ibarrondo F
        • Fulcher JA
        • et al.
        Rapid decay of anti–SARS-CoV-2 antibodies in persons with mild Covid-19.
        N Engl J Med. 2020; 383: 1085-1087https://doi.org/10.1056/nejmc2025179
        • Muecksch F
        • Wise H
        • Batchelor B
        • et al.
        Longitudinal serological analysis and neutralizing antibody levels in coronavirus disease 2019 convalescent patients.
        J Infect Dis. 2021; 223: 389-398https://doi.org/10.1093/infdis/jiaa659
        • Lau EHY
        • Tsang OTY
        • Hui DSC
        • et al.
        Neutralizing antibody titres in SARS-CoV-2 infections.
        Nat Commun. 2021; 12https://doi.org/10.1038/s41467-020-20247-4
        • Iyer AS
        • Jones FK
        • Nodoushani A
        • et al.
        Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients.
        Sci Immunol. 2020; 5: eabe0367https://doi.org/10.1126/sciimmunol.abe0367
        • Gaebler C
        • Wang Z
        • Lorenzi JCC
        • et al.
        Evolution of antibody immunity to SARS-CoV-2.
        Nature. 2021; https://doi.org/10.1038/s41586-021-03207-w
        • Peluso MJ
        • Takahashi S
        • Hakim J
        • et al.
        SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.
        Sci Adv. 2021; 7https://doi.org/10.1126/sciadv.abh3409
        • Chia WN
        • Zhu F
        • Ong SWX
        • et al.
        Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study.
        Lancet Microbe. 2021; 2: e240-e249
        • L'Huillier AG
        • Meyer B
        • Andrey DO
        • et al.
        Antibody persistence in the first 6 months following SARS-CoV-2 infection among hospital workers: a prospective longitudinal study.
        Clin Microbiol Infect. 2021; https://doi.org/10.1016/j.cmi.2021.01.005
        • Di Germanio C
        • Simmons G
        • Kelly K
        • et al.
        SARS-CoV-2 antibody persistence in COVID-19 convalescent plasma donors: Dependency on assay format and applicability to serosurveillance.
        Transfusion. 2021; (trf.16555)https://doi.org/10.1111/trf.16555
        • Yao L
        • Wang G-L
        • Shen Y
        • et al.
        Persistence of antibody and cellular immune responses in COVID-19 patients over nine months after Infection.
        J Infect Dis. 2021; https://doi.org/10.1093/infdis/jiab255
        • Wisnivesky JP
        • Stone K
        • Bagiella E
        • et al.
        Long-term persistence of neutralizing antibodies to SARS-CoV-2 following infection.
        J Gen Intern Med. 2021; https://doi.org/10.1007/s11606-021-07057-0
        • Dispinseri S
        • Secchi M
        • Pirillo MF
        • et al.
        Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival.
        Nat Commun. 2021; 12: 2670
        • Goto A
        • Go H
        • Miyakawa K
        • et al.
        Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.
        Front Microbiol. 2021; 12661187
        • Orth-Höller D
        • Eigentler A
        • Stiasny K
        • Weseslindtner L
        • Möst J.
        Kinetics of SARS-CoV-2 specific antibodies (IgM, IgA, IgG) in non-hospitalized patients four months following infection.
        J Infect. 2021; 82: 282-327
        • Le Bert N
        • Clapham HE
        • Tan AT
        • et al.
        Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection.
        J Exp Med. 2021; 218https://doi.org/10.1084/jem.20202617
        • Dan JM
        • Mateus J
        • Kato Y
        • et al.
        Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
        Science. 2021; 371https://doi.org/10.1126/science.abf4063
        • Grifoni A
        • Weiskopf D
        • Ramirez SI
        • et al.
        Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.
        Cell. 2020; 181 (.e15): 1489-1501
        • Peng Y
        • Mentzer AJ
        • Liu G
        • et al.
        Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
        Nat Immunol. 2020; 21: 1336-1345
        • Rydyznski Moderbacher C
        • Ramirez SI
        • Dan JM
        • et al.
        Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity.
        Cell. 2020; 183 (e19): 996-1012
        • Sekine T
        • Perez-Potti A
        • Rivera-Ballesteros O
        • et al.
        Robust T Cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
        Cell. 2020; 183 (e14): 158-168
        • Peluso MJ
        • Deitchman AN
        • Torres L
        • et al.
        Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms.
        Cell Rep. 2021; 109518
        • Bilich T
        • Nelde A
        • Heitmann JS
        • et al.
        T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals.
        Sci Transl Med. 2021; 13https://doi.org/10.1126/scitranslmed.abf7517
        • Jiang X-L
        • Wang G-L
        • Zhao X-N
        • et al.
        Lasting antibody and T cell responses to SARS-CoV-2 in COVID-19 patients three months after infection.
        Nat Commun. 2021; 12: 897
        • Cho A
        • Muecksch F
        • Schaefer-Babajew D
        • et al.
        Anti-SARS-CoV-2 receptor binding domain antibody evolution after mRNA vaccination.
        Nature. 2021; https://doi.org/10.1038/s41586-021-04060-7
        • Le Bert N
        • Tan AT
        • Kunasegaran K
        • et al.
        SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.
        Nature. 2020; 584: 457-462
        • Stokel-Walker C.
        What we know about covid-19 reinfection so far.
        BMJ. 2021; 372: n99
        • Cavanaugh AM
        • Spicer KB
        • Thoroughman D
        • Glick C
        • Winter K
        Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination - kentucky, May-June 2021.
        MMWR Morb Mortal Wkly Rep. 2021; 70: 1081-1083
        • Grifoni A
        • Sidney J
        • Vita R
        • et al.
        SARS-CoV-2 human T cell epitopes: Adaptive immune response against COVID-19.
        Cell Host Microbe. 2021; 29: 1076-1092
        • Tarke A
        • Sidney J
        • Kidd CK
        • et al.
        Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases.
        bioRxiv. 2020; https://doi.org/10.1101/2020.12.08.416750
        • Koblischke M
        • Traugott MT
        • Medits I
        • et al.
        Dynamics of CD4 T Cell and antibody responses in COVID-19 patients with different disease severity.
        Front Med. 2020; 7592629
        • Boppana S
        • Qin K
        • Files JK
        • et al.
        SARS-CoV-2-specific circulating T follicular helper cells correlate with neutralizing antibodies and increase during early convalescence.
        PLoS Pathog. 2021; 17e1009761
        • Sette A
        • Crotty S.
        Adaptive immunity to SARS-CoV-2 and COVID-19.
        Cell. 2021; 184: 861-880
        • Perez-Potti A
        • Lange J
        • Buggert M.
        Deciphering the ins and outs of SARS-CoV-2-specific T cells.
        Nat Immunol. 2021; 22: 8-9
        • Tarke A
        • Sidney J
        • Methot N
        • et al.
        Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals.
        Cell Rep Med. 2021; 2100355
        • Tarke A
        • Sidney J
        • Methot N
        • et al.
        Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees.
        bioRxiv. 2021; https://doi.org/10.1101/2021.02.27.433180
        • Lipsitch M
        • Grad YH
        • Sette A
        • Crotty S.
        Cross-reactive memory T cells and herd immunity to SARS-CoV-2.
        Nat Rev Immunol. 2020; 20: 709-713
        • Karlsson AC
        • Humbert M
        • Buggert M.
        The known unknowns of T cell immunity to COVID-19.
        Sci Immunol. 2020; 5https://doi.org/10.1126/sciimmunol.abe8063
        • Nelde A
        • Bilich T
        • Heitmann JS
        • et al.
        SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition.
        Nat Immunol. 2021; 22: 74-85
        • Bacher P
        • Rosati E
        • Esser D
        • et al.
        Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.
        Immunity. 2020; 53 (.e5): 1258-1271
        • Ogbe A
        • Kronsteiner B
        • Skelly DT
        • et al.
        T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.
        Nat Commun. 2021; 12: 2055
        • Klasse PJ
        • Nixon DF
        • Moore JP.
        Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans.
        Sci Adv. 2021; 7https://doi.org/10.1126/sciadv.abe8065
        • Abbasi J.
        SARS-CoV-2 variant antibodies wane 6 months after vaccination.
        JAMA. 2021; 326: 901
        • Jung J
        • Sung H
        • Kim S-H.
        Covid-19 breakthrough infections in vaccinated health care workers.
        N Engl J Med. 2021; 385https://doi.org/10.1056/NEJMc2113497
        • Levin EG
        • Lustig Y
        • Cohen C
        • et al.
        Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months.
        N Engl J Med. 2021; https://doi.org/10.1056/NEJMoa2114583
        • Pilishvili T
        • Gierke R
        • Fleming-Dutra KE
        • et al.
        Effectiveness of mRNA Covid-19 vaccine among U.S. Health Care Personnel.
        N Engl J Med. 2021; https://doi.org/10.1056/NEJMoa2106599
        • Thomas SJ
        • Moreira Jr, ED
        • Kitchin N
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.
        N Engl J Med. 2021; https://doi.org/10.1056/NEJMoa2110345
        • Ke R
        • Martinez PP
        • Smith RL
        • et al.
        Longitudinal analysis of SARS-CoV-2 vaccine breakthrough infections reveal limited infectious virus shedding and restricted tissue distribution.
        medRxiv. 2021; https://doi.org/10.1101/2021.08.30.21262701
        • Doria-Rose N
        • Suthar MS
        • Makowski M
        • et al.
        Antibody Persistence through 6 months after the second dose of mRNA-1273 vaccine for Covid-19.
        N Engl J Med. 2021; 384: 2259-2261
        • Terpos E
        • Trougakos IP
        • Karalis V
        • et al.
        Kinetics of anti-SARS-CoV-2 antibody responses 3 months post complete vaccination with BNT162b2; a prospective study in 283 health workers.
        Cells. 2021; 10: 1942
        • Stock PG
        • Henrich TJ
        • Segev DL
        • Werbel WA.
        Interpreting and addressing suboptimal immune responses after COVID-19 vaccination in solid-organ transplant recipients.
        J Clin Invest. 2021; 131https://doi.org/10.1172/JCI151178
        • Caballero-Marcos A
        • Salcedo M
        • Alonso-Fernández R
        • et al.
        Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients.
        Am J Transplant. 2021; 21: 2876-2884
        • Favà A
        • Donadeu L
        • Sabé N
        • et al.
        SARS-CoV-2-specific serological and functional T cell immune responses during acute and early COVID-19 convalescence in solid organ transplant patients.
        Am J Transplant. 2021; 21: 2749-2761
        • Azzi Y
        • Bartash R
        • Scalea J
        • Loarte-Campos P
        • Akalin E.
        COVID-19 and solid organ transplantation: a review article.
        Transplantation. 2021; 105: 37-55
        • Herrera S
        • Colmenero J
        • Pascal M
        • et al.
        Cellular and humoral immune response after mRNA-1273 SARS-CoV-2 vaccine in liver and heart transplant recipients.
        Am J Transplant. 2021; https://doi.org/10.1111/ajt.16768
        • Miele M
        • Busà R
        • Russelli G
        • et al.
        Impaired anti-SARS-CoV-2 humoral and cellular immune response induced by Pfizer-BioNTech BNT162b2 mRNA vaccine in solid organ transplanted patients.
        Am J Transplant. 2021; 21: 2919-2921
        • Boyarsky BJ
        • Werbel WA
        • Avery RK
        • et al.
        Antibody response to 2-Dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.
        JAMA. 2021; 325: 2204-2206
        • Ou MT
        • Boyarsky BJ
        • Motter JD
        • et al.
        Safety and reactogenicity of 2 Doses of SARS-CoV-2 vaccination in solid organ transplant recipients.
        Transplantation. 2021; 105: 2170-2174
        • Boyarsky BJ
        • Werbel WA
        • Avery RK
        • et al.
        Immunogenicity of a single Dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients.
        JAMA. 2021; 325: 1784-1786
        • Sattler A
        • Schrezenmeier E
        • Weber UA
        • et al.
        Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.
        J Clin Invest. 2021; 131https://doi.org/10.1172/JCI150175
        • Werbel WA
        • Boyarsky BJ
        • Ou MT
        • et al.
        Safety and immunogenicity of a third Dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.
        Ann Intern Med. 2021; 174: 1330-1332
        • Alejo JL
        • Mitchell J
        • Chiang TP-Y
        • et al.
        Antibody response to a fourth Dose of a SARS-CoV-2 vaccine in solid organ transplant recipients: a case series.
        Transplantation. 2021; https://doi.org/10.1097/TP.0000000000003934
        • Monin L
        • Laing AG
        • Muñoz-Ruiz M
        • et al.
        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.
        Lancet Oncol. 2021; 22: 765-778
        • Massarweh A
        • Eliakim-Raz N
        • Stemmer A
        • et al.
        Evaluation of seropositivity following BNT162b2 Messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer.
        JAMA Oncol. 2021; 7: 1133-1140
        • Greenberger LM
        • Saltzman LA
        • Senefeld JW
        • Johnson PW
        • DeGennaro LJ
        • Nichols GL.
        Anti-spike antibody response to SARS-CoV-2 booster vaccination in patients with B cell-derived hematologic malignancies.
        Cancer Cell. 2021; https://doi.org/10.1016/j.ccell.2021.09.001
        • Brosh-Nissimov T
        • Orenbuch-Harroch E
        • Chowers M
        • et al.
        BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.
        Clin Microbiol Infect. 2021; https://doi.org/10.1016/j.cmi.2021.06.036
        • Peluso MJ
        • Munter SE
        • Lynch KL
        • et al.
        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.
        Open Forum Infect Dis. 2021; 8: ofab393
        • Haberman RH
        • Herati R
        • Simon D
        • et al.
        Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.
        Ann Rheum Dis. 2021; 80: 1339-1344
        • Simon D
        • Tascilar K
        • Fagni F
        • et al.
        SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.
        Ann Rheum Dis. 2021; 80: 1312-1316
        • Apostolidis SA
        • Kakara M
        • Painter MM
        • et al.
        Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy.
        Nat Med. 2021; https://doi.org/10.1038/s41591-021-01507-2
      1. Sabatino JJ, Mittl K, Rowles W, et al. Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity. medRxiv2021. doi:10.1101/2021.09.10.21262933

        • Sormani MP
        • Inglese M
        • Schiavetti I
        • et al.
        Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
        EBioMedicine. 2021; 103581
        • Disanto G
        • Sacco R
        • Bernasconi E
        • et al.
        Association of disease-modifying treatment and anti-CD20 infusion timing with humoral response to 2 SARS-CoV-2 vaccines in patients with multiple sclerosis.
        JAMA Neurol. 2021; https://doi.org/10.1001/jamaneurol.2021.3609
        • Moor MB
        • Suter-Riniker F
        • Horn MP
        • et al.
        Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study.
        Lancet Rheumatol. 2021; https://doi.org/10.1016/S2665-9913(21)00251-4
        • Schmidt T
        • Klemis V
        • Schub D
        • et al.
        Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients.
        Am J Transplant. 2021; https://doi.org/10.1111/ajt.16818
        • Hall VG
        • Ferreira VH
        • Ierullo M
        • et al.
        Humoral and cellular immune response and safety of two-dose SARS-CoV-2 mRNA-1273 vaccine in solid organ transplant recipients.
        Am J Transplant. 2021; https://doi.org/10.1111/ajt.16766
        • Esmaeili S
        • Abbasi MH
        • Abolmaali M
        • et al.
        Rituximab and risk of COVID-19 infection and its severity in patients with MS and NMOSD.
        BMC Neurol. 2021; 21: 183
        • Spinelli MA
        • Lynch KL
        • Yun C
        • et al.
        SARS-CoV-2 seroprevalence, and IgG concentration and pseudovirus neutralising antibody titres after infection, compared by HIV status: a matched case-control observational study.
        Lancet HIV. 2021; 8: e334-e341https://doi.org/10.1016/s2352-3018(21)00072-2
        • Mondi A
        • Cimini E
        • Colavita F
        • et al.
        COVID-19 in people living with HIV: Clinical implications of dynamics of the immune response to SARS-CoV-2.
        J Med Virol. 2021; 93: 1796-1804
        • Papalini C
        • Paciosi F
        • Schiaroli E
        • et al.
        Seroprevalence of anti-SARS-CoV2 antibodies in Umbrian persons living with HIV.
        Mediterr J Hematol Infect Dis. 2020; 12https://doi.org/10.4084/MJHID.2020.080
      2. Liu Y, Xiao Y, Wu S, et al. People Living with HIV Easily lose their Immune Response to SARS-CoV-2: Result From A Cohort of COVID-19 Cases in Wuhan, China. 2021. doi:10.21203/rs.3.rs-543375/v1

        • Woldemeskel BA
        • Karaba AH
        • Garliss CC
        • et al.
        The BNT162b2 mRNA vaccine elicits robust humoral and cellular immune responses in people living with HIV.
        Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab648
        • Ruddy JA
        • Boyarsky BJ
        • Bailey JR
        • et al.
        Safety and antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in persons with HIV.
        AIDS. 2021; https://doi.org/10.1097/QAD.0000000000003017
        • Buechler MB
        • Newman LP
        • Chohan BH
        • Njoroge A
        • Wamalwa D
        • Farquhar C.
        T cell anergy and activation are associated with suboptimal humoral responses to measles revaccination in HIV-infected children on anti-retroviral therapy in Nairobi, Kenya.
        Clin Exp Immunol. 2015; 181: 451-456
        • Avelino-Silva VI
        • Miyaji KT
        • Hunt PW
        • et al.
        CD4/CD8 Ratio and KT ratio predict yellow fever vaccine immunogenicity in HIV-infected patients.
        PLoS Negl Trop Dis. 2016; 10e0005219
        • Colin de Verdiere N
        • Durier C
        • Samri A
        • et al.
        Immunogenicity and safety of yellow fever vaccine in HIV-1-infected patients.
        AIDS. 2018; 32: 2291-2299
        • Parmigiani A
        • Alcaide ML
        • Freguja R
        • et al.
        Impaired antibody response to influenza vaccine in HIV-infected and uninfected aging women is associated with immune activation and inflammation.
        PLoS One. 2013; 8: e79816
        • van den Berg R
        • van Hoogstraten I
        • van Agtmael M.
        Non-responsiveness to hepatitis B vaccination in HIV seropositive patients; possible causes and solutions.
        AIDS Rev. 2009; 11: 157-164
        • Kroon FP
        • van Dissel JT
        • Labadie J
        • van Loon AM
        • van Furth R.
        Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus.
        Clin Infect Dis. 1995; 21: 1197-1203
        • Zheng M
        • Gao Y
        • Wang G
        • et al.
        Functional exhaustion of antiviral lymphocytes in COVID-19 patients.
        Cell Mol Immunol. 2020; 17: 533-535
        • Zheng H-Y
        • Zhang M
        • Yang C-X
        • et al.
        Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.
        Cell Mol Immunol. 2020; 17: 541-543
        • Ye Q
        • Wang B
        • Mao J.
        The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.
        J Infect. 2020; 80: 607-613
        • Terpos E
        • Ntanasis-Stathopoulos I
        • Elalamy I
        • et al.
        Hematological findings and complications of COVID-19.
        Am J Hematol. 2020; 95: 834-847
        • Qin C
        • Zhou L
        • Hu Z
        • et al.
        Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.
        Clin Infect Dis. 2020; 71: 762-768
        • Li CK-F
        • Wu H
        • Yan H
        • et al.
        T cell responses to whole SARS coronavirus in humans.
        J Immunol. 2008; 181: 5490-5500
        • Lavillegrand J-R
        • Garnier M
        • Spaeth A
        • et al.
        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.
        Ann Intensive Care. 2021; 11: 9
        • Sharifpour M
        • Rangaraju S
        • Liu M
        • et al.
        C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19.
        PLoS One. 2020; 15e0242400
      3. Tobias Herold MD, Arnreich C, Hellmuth JC, Matthias Klein MD, Tobias Weinberger MD. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. https://www.allergy.org.au/images/stories/about/attach-IL-6_as_a_marker_of_outcome_in_COVID-19.pdf

        • Del Valle DM
        • Kim-Schulze S
        • Huang H-H
        • et al.
        An inflammatory cytokine signature predicts COVID-19 severity and survival.
        Nat Med. 2020; 26: 1636-1643
        • Lucas C
        • Wong P
        • Klein J
        • et al.
        Longitudinal analyses reveal immunological misfiring in severe COVID-19.
        Nature. 2020; 584: 463-469
        • Laing AG
        • Lorenc A
        • del Molino del Barrio I
        • et al.
        A dynamic COVID-19 immune signature includes associations with poor prognosis.
        Nat Med. 2020; 26: 1623-1635
        • Han H
        • Ma Q
        • Li C
        • et al.
        Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors.
        Emerg Microbes Infect. 2020; 9: 1123-1130
        • Liu Y
        • Du X
        • Chen J
        • et al.
        Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19.
        J Infect. 2020; 81: e6-e12
        • Lagunas-Rangel FA.
        Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis.
        J Med Virol. 2020; 92: 1733-1734
        • Wang F
        • Nie J
        • Wang H
        • et al.
        Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
        J Infect Dis. 2020; 221: 1762-1769
        • Shi Y
        • Wang Y
        • Shao C
        • et al.
        COVID-19 infection: the perspectives on immune responses.
        Cell Death Differ. 2020; 27: 1451-1454
        • Bonny TS
        • Patel EU
        • Zhu X
        • et al.
        Cytokine and chemokine levels in coronavirus disease 2019 convalescent plasma.
        Open Forum Infect Dis. 2021; 8: ofaa574
        • Ong SWX
        • Fong S-W
        • Young BE
        • et al.
        Persistent symptoms and association with inflammatory cytokine signatures in recovered coronavirus disease 2019 patients.
        Open Forum Infect Dis. 2021; 8: ofab156
        • Tenorio AR
        • Zheng Y
        • Bosch RJ
        • et al.
        Soluble markers of inflammation and coagulation but not T-cell activation predict non–AIDS-defining morbid events during suppressive antiretroviral treatment.
        J Infect Dis. 2014; 210: 1248-1259
        • Serrano-Villar S
        • Sainz T
        • Lee SA
        • et al.
        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.
        PLoS Pathog. 2014; 10e1004078
        • Nalbandian A
        • Sehgal K
        • Gupta A
        • et al.
        Post-acute COVID-19 syndrome.
        Nat Med. 2021; https://doi.org/10.1038/s41591-021-01283-z
        • Al-Aly Z
        • Xie Y
        • Bowe B
        High-dimensional characterization of post-acute sequelae of COVID-19.
        Nature. 2021; 594: 259-264
        • Ayoubkhani D
        Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK - Office for National Statistics. 2021; (Accessed April 7, 2021)
        • Blomberg B
        • Mohn KG-I
        • Brokstad KA
        • et al.
        Long COVID in a prospective cohort of home-isolated patients.
        Nat Med. 2021; https://doi.org/10.1038/s41591-021-01433-3
        • Horton DB
        • Barrett ES
        • Roy J
        • et al.
        Determinants and dynamics of SARS-CoV-2 infection in a diverse population: 6-month evaluation of a prospective cohort study.
        J Infect Dis. 2021; https://doi.org/10.1093/infdis/jiab411
        • Hu F
        • Chen F
        • Ou Z
        • et al.
        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.
        Cell Mol Immunol. 2020; 17: 1119-1125
        • Augustin M
        • Schommers P
        • Stecher M
        • et al.
        Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study.
        Lancet Reg Health Eur. 2021; 6100122
        • Talla A
        • Vasaikar SV
        • Lemos MP
        • et al.
        Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence.
        bioRxiv. 2021; https://doi.org/10.1101/2021.05.26.442666
        • Peluso MJ
        • Lu S
        • Tang AF
        • et al.
        Markers of Immune Activation and Inflammation in Individuals With Postacute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.
        J Infect Dis. 2021; https://doi.org/10.1093/infdis/jiab490
        • Hunt PW
        • Sinclair E
        • Rodriguez B
        • et al.
        Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection.
        J Infect Dis. 2014; 210: 1228-1238
        • Gianella S
        • Chaillon A
        • Mutlu EA
        • et al.
        Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals.
        AIDS. 2017; 31: 2059-2067
        • Sacchi MC
        • Tamiazzo S
        • Stobbione P
        • et al.
        SARS-CoV-2 infection as a trigger of autoimmune response.
        Clin Transl Sci. 2021; 14: 898-907
        • Guilmot A
        • Maldonado Slootjes S
        • Sellimi A
        • et al.
        Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
        J Neurol. 2021; 268: 751-757
        • Song E
        • Bartley CM
        • Chow RD
        • et al.
        Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.
        Cell Rep Med. 2021; 2100288
        • Seeßle J
        • Waterboer T
        • Hippchen T
        • et al.
        Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study.
        Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab611
        • Peluso MJ
        • Thomas IJ
        • Munter SE
        • Deeks SG
        • Henrich TJ.
        Lack of antinuclear antibodies in convalescent COVID-19 patients with persistent symptoms.
        Clin Infect Dis. 2021; https://doi.org/10.1093/cid/ciab890
        • Avanzato VA
        • Matson MJ
        • Seifert SN
        • et al.
        Case study: prolonged infectious SARS-CoV-2 shedding from an asymptomatic immunocompromised individual with cancer.
        Cell. 2020; 183 (e9): 1901-1912
        • Choi B
        • Choudhary MC
        • Regan J
        • et al.
        Persistence and evolution of SARS-CoV-2 in an immunocompromised host.
        N Engl J Med. 2020; 383: 2291-2293
        • Zheng S
        • Fan J
        • Yu F
        • et al.
        Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.
        BMJ. 2020; 369: m1443
        • O'Donnell JS
        • Chappell KJ.
        Chronic SARS-CoV-2, a cause of post-acute COVID-19 sequelae (Long-COVID)?.
        Front Microbiol. 2021; 12724654
        • Oliva A
        • Miele MC
        • Di Timoteo F
        • et al.
        Persistent systemic microbial translocation and intestinal damage during coronavirus disease-19.
        Front Immunol. 2021; 12708149
        • ÁH Borges
        • JL O'Connor
        • Phillips AN
        • et al.
        Interleukin 6 is a stronger predictor of clinical events than high-sensitivity c-reactive protein or D-dimer during HIV infection.
        J Infect Dis. 2016; 214: 408-416
        • Hsu DC
        • Ma YF
        • Hur S
        • et al.
        Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy.
        AIDS. 2016; 30: 2065-2074
        • Wada NI
        • Bream JH
        • Martínez-Maza O
        • et al.
        Inflammatory biomarkers and mortality risk among HIV-suppressed men: a multisite prospective cohort study.
        Clin Infect Dis. 2016; 63: 984-990
        • Freeman ML
        • Mudd JC
        • Shive CL
        • et al.
        CD8 T-Cell expansion and inflammation linked to CMV coinfection in ART-treated HIV infection.
        Clin Infect Dis. 2016; 62: 392-396
        • Freeman ML
        • Lederman MM
        • Gianella S.
        Partners in crime: the role of CMV in immune dysregulation and clinical outcome during HIV infection.
        Curr HIV/AIDS Rep. 2016; 13: 10-19
        • Ljungman P
        • Boeckh M
        • Hirsch HH
        • et al.
        Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials.
        Clin Infect Dis. 2017; 64: 87-91
        • Simanek AM
        • Dowd JB
        • Pawelec G
        • Melzer D
        • Dutta A
        • Aiello AE.
        Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States.
        PLoS One. 2011; 6: e16103
        • Wang H
        • Peng G
        • Bai J
        • et al.
        Cytomegalovirus infection and relative risk of cardiovascular disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): a meta-analysis of prospective studies up to 2016.
        J Am Heart Assoc. 2017; 6https://doi.org/10.1161/JAHA.116.005025
        • Hamming I
        • Timens W
        • Bulthuis MLC
        • Lely AT
        • Navis GJ
        • van Goor H.
        Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
        J Pathol. 2004; 203: 631-637
        • Salamanna F
        • Maglio M
        • Landini MP
        • Fini M.
        Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2.
        Front Med. 2020; 7594495
        • Vaduganathan M
        • Vardeny O
        • Michel T
        • McMurray JJV
        • Pfeffer MA
        • Solomon SD.
        Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.
        N Engl J Med. 2020; 382: 1653-1659
        • Wu G
        • Zuck P
        • Goh SL
        • et al.
        Gag p24 is a marker of HIV expression in tissues and correlates with immune response.
        J Infect Dis. 2021; https://doi.org/10.1093/infdis/jiab121
        • McManus WR
        • Bale MJ
        • Spindler J
        • et al.
        HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy.
        J Clin Invest. 2019; 129: 4629-4642
        • Nguyen S
        • Deleage C
        • Darko S
        • et al.
        Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells.
        Sci Transl Med. 2019; 11https://doi.org/10.1126/scitranslmed.aax4077
        • Patro SC
        • Brandt LD
        • Bale MJ
        • et al.
        Combined HIV-1 sequence and integration site analysis informs viral dynamics and allows reconstruction of replicating viral ancestors.
        Proc Natl Acad Sci U S A. 2019; 116: 25891-25899
        • Lee E
        • von Stockenstrom S
        • Morcilla V
        • et al.
        Impact of antiretroviral therapy duration on HIV-1 infection of T Cells within anatomic sites.
        J Virol. 2020; 94https://doi.org/10.1128/JVI.01270-19
        • Henrich TJ
        • Hatano H
        • Bacon O
        • et al.
        HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.
        PLoS Med. 2017; 14e1002417
        • Khoury G
        • Fromentin R
        • Solomon A
        • et al.
        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.
        J Infect Dis. 2017; 215: 911-919
        • Telwatte S
        • Kim P
        • Chen T-H
        • et al.
        Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents.
        AIDS. 2020; 34: 2013-2024
        • Telwatte S
        • Lee S
        • Somsouk M
        • et al.
        Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency.
        PLoS Pathog. 2018; 14e1007357
        • Yukl SA
        • Sinclair E
        • Somsouk M
        • et al.
        A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells.
        AIDS. 2014; 28: 439-442
        • Hatano H
        • Somsouk M
        • Sinclair E
        • et al.
        Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers.
        AIDS. 2013; 27: 2255-2260
        • Busman-Sahay K
        • Starke CE
        • Nekorchuk MD
        • Estes JD.
        Eliminating HIV reservoirs for a cure: the issue is in the tissue.
        Curr Opin HIV AIDS. 2021; 16: 200-208
        • Moysi E
        • Del Rio Estrada PM
        • Torres-Ruiz F
        • Reyes-Terán G
        • Koup RA
        • In Petrovas C.
        Situ characterization of human lymphoid tissue immune cells by multispectral confocal imaging and quantitative image analysis; implications for HIV reservoir characterization.
        Front Immunol. 2021; 12683396
        • Vasquez JJ
        • Hussien R
        • Aguilar-Rodriguez B
        • et al.
        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.
        J Histochem Cytochem. 2018; 66: 427-446
        • McBrien JB
        • Mavigner M
        • Franchitti L
        • et al.
        Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells.
        Nature. 2020; 578: 154-159