The immunology and immunopathology of COVID-19

Abstract

Considerable research effort has been made worldwide to decipher the immune response triggered upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, identify the drivers of severe and fatal COVID-19, and understand what leads to the prolongation of symptoms after disease resolution. We review the results of almost 2 years of COVID-19 immunology research and discuss definitive findings and remaining questions regarding our understanding of COVID-19 pathophysiology. We discuss emerging understanding of differences in immune responses seen in those with and without Long Covid syndrome, also known as post-acute sequelae of SARS-CoV-2. We hope that the knowledge gained from this COVID-19 research will be applied in studies of inflammatory processes involved in critical and chronic illnesses, which remain a major unmet need.

In December 2019, the Chinese Center for Disease Control and Prevention reported a cluster of pneumonia cases with unknown cause. The first complete sequence of the novel beta coronavirus genome was then identified in January 2020 (1). Initially called 2019-nCoV (for 2019 novel coronavirus), the virus was renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease caused by the virus as coronavirus disease 2019 (COVID-19). COVID-19 manifests with symptoms ranging from fully asymptomatic to severe disease and death (Table 1). The most common manifestations are fever, cough, and shortness of breath; additional common symptoms include fatigue, myalgias, nausea, vomiting, diarrhea, headache, weakness, rhinorrhea, anosmia, and ageusia (2, 3). A wide range of complications can lead to severe illness and death, including pneumonia, acute respiratory distress syndrome, liver injury, cardiac injury, thrombosis including stroke, renal disease, neurologic disease, and sepsis (2–7).

Table 1.

Common manifestations and potential complications of COVID-19.

	Acute and severe Covid		Long Covid
Organ system	Common symptoms	Potential complications	Common symptoms
Respiratory	Cough  Dyspnea, Rhinorrhea (runny nose)	Pneumonia Acute respiratory distress syndrome (ARDS) Respiratory failure	Dyspnea, cough, interstitial lung disease
Systemic	Fever Fatigue	Sepsis, kidney injury Liver injury	Fever, fatigue post-exertional malaise
Nervous System	Headache Confusion Anosmia (loss of smell) Ageusia (loss of taste)	Stroke Seizure Guillain-Barre syndrome	Memory deficit, loss of concentration, sleep difficulty, mood disorder, paresthesia, myelopathy, neuropathy, anosmia, ageusia, blurry vision, tinnitus, headache
Cardiovascular	Chest pain Shortness of breath	Myocardial infarction Myocarditis Cardiogenic shock Stress-induced cardiomyopathy Clotting abnormalities	Chest pain, palpitations, hypertension, angina, myocarditis, pericarditis, cardiac arrhythmias, postural orthostatic syndrome
Gastrointestinal	Nausea Vomiting Diarrhea Anorexia (loss of appetite)	Acute pancreatitis Acute appendicitis Intestinal obstruction Bowel ischemia Hemoperitoneum Abdominal compartment syndrome	Diarrhea, vomiting, nausea, loss of appetite, hepatitis
Skin	Rash	N/A	Hair loss
Musculoskeletal	Myalgias (muscle aches)	N/A	Myalgia, arthralgia, weakness
Endocrine	Hyperglycemia	Diabetes	Hot/cold sensation, thyroid abnormalities, diabetes, hormonal abnormalities

N/A, not applicable.

As the virus evolves and new variants emerge, there have been concerns that such variants could increase pathogenesis by escaping from immunity generated through previous infection or vaccination or by inducing more severe disease. Some variants of concern (VOC), such as 1.351 (Beta), P.1 (Gamma), and the recently described B.1.1.529 (Omicron), have mutations that render them less susceptible to vaccine-mediated and infection-acquired immunity. It is less apparent whether some variants induce more severe disease upon primary infection than others, though strains such as B.1.1.7 (Alpha) and B.1.617.2 (Delta) are known to spread more efficiently, making it difficult to distinguish increased infection rates from increased severity. As new variants emerge, it will be important to direct continued research efforts into identifying how such variants escape from either innate or adaptive immune responses. Here, we review progress in our understanding of the immunology and immunopathology of COVID-19.

Innate immunity to SARS-CoV-2

Coronaviruses are enveloped viruses with a positive-sense RNA-strand genome of ~30,000 bases. SARS-CoV-2 is a member of the Betacoronavirus genus, which also includes severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). The innate immune system uses various pattern recognition receptors (PRRs) to detect the presence of viruses. RNA viruses such as coronaviruses are detected through two separate strategies (8). In one strategy, specialized immune cells such as plasmacytoid dendritic cells (pDCs) detect the incoming viral genomic RNA in the endosome through Toll-like receptor 7 (TLR7). Other cell types express endosomal TLR3 (variety of cells) and TLR8 (myeloid cells) that can also recognize endocytosed double-stranded RNA (dsRNA) or single-stranded RNA (ssRNA), respectively. Alveolar macrophages survey the lumen of the respiratory tract and provide the first line of defense. The other strategy involves viral recognition within infected cells. During viral replication dsRNA intermediates can be recognized by cytosolic RNA sensors such as RIG-I and MDA5, or RIG-I–like receptors (RLRs). Upon engagement of TLRs and RLRs, signaling downstream activates the IRF3/IRF7-dependent transcription of type I and type III interferons (IFNs) as well as nuclear factor κB (NF-κB)–dependent proinflammatory cytokines and chemokines.

SARS-CoV-2 is adept at evading innate recognition, signaling, IFN induction, and IFN-stimulated genes (ISGs) through the expression of a number of viral proteins that block these pathways (9). Consequently, lower levels of IFN-I or IFN-III are detected in the lungs or peripheral blood of SARS-CoV-2–infected individuals compared with other respiratory viruses (10–12). IFN-III (IFN-λ1 and IFN-λ3) and ISGs are expressed in the upper airways of patients with reduced disease risk or severity, whereas expression of IFN-λ2 and type I IFNs—but not ISGs—can be elevated in the upper airways of those who develop severe COVID-19 (13). Patients with genetic mutations or autoantibodies that interfere with IFN pathways suffer from life-threatening COVID-19 disease as discussed below. During the late phase of disease, prolonged IFN secretion correlates with worse disease outcomes (14, 15), possibly through the induction of chemokines that recruit inflammatory cellular infiltrates (16). In addition, COVID-19 is accompanied by a significant decline in the number of immune sentinel cells including pDCs and conventional DCs (cDCs) in the blood (14) and lungs (17).

Innate immune responses induced by PRR signaling activate effector cells to mediate viral clearance. NK cells, for example, contribute to detecting and eliminating virally infected cells. However, in patients with severe COVID-19, NK cells are depleted from the blood and become dysfunctional as a result of transforming growth factor–β (TGF-β), which impairs their antiviral function (18). Alveolar macrophages, which play an important sentinel role in the lungs by sensing and triggering potent antiviral immunity, are severely depleted in the lungs of patients with severe disease (19, 20). In contrast to the impaired early antiviral defense mediated by IFN-I and IFN-III, proinflammatory cytokines and chemokines are significantly elevated (16). In addition, T cells are profoundly depleted from the blood circulation of patients with severe disease compared with patients with moderate disease, which suggests that induction of adaptive effector T cells able to clear virally infected cells is likely impaired in severe patients (14, 21–24). Pathological immune responses that contribute to severe COVID-19 are discussed below.

Adaptive immunity to SARS-CoV-2

Given the key role of adaptive immunity in protection from viral infection and disease, the study of humoral antibody (Ab) and cell-mediated immunity has been aggressively pursued by the scientific community with the aim of defining correlates of protection, developing immune-based therapies, and optimizing vaccine design and administration (25–27).

Abs can neutralize SARS-CoV-2 by blocking binding of the viral spike (S) protein to the ACE2 receptor and can promote effector function by binding to the complement and Fc receptors (28). Structure-guided serological studies demonstrated that the bulk of neutralizing Abs bind to distinct epitopes in the receptor binding domain (RBD) of the S protein and primarily to sites 1a and 1b, which represent the receptor-binding motif (RBM). Additionally, a minor fraction of neutralizing Abs bind to the N-terminal domain (NTD) (29–31). Furthermore, some RBM-specific Abs can mimic ACE2 and directly trigger and consequently disable the fusion protein, a property that was initially discovered in SARS-CoV. Neutralizing epitopes outside RBD and NTD are generally subdominant but may be more conserved as in the case of the stem-helix region (32). The quantity and quality of the Ab response is related to the amount of antigen and the duration of the germinal center reaction where the response matures (33). Ab responses of increasing magnitudes are detected in infected, preimmune, and vaccinated individuals, most likely reflecting differences in antigenic load and exposure (29, 34). In immunosuppressed patients and those undergoing dialysis, Ab response is generally poor and has been shown to contribute to the chronic persistence of the virus favoring the selection of variants (35).

CD4⁺ and CD8⁺ T cells elicited by SARS-CoV-2 infection are directed against a range of antigens including structural and nonstructural proteins and are significantly associated with milder disease (36). Ab-mediated depletion of CD8⁺ T cells in convalescent macaques partially abrogates protection against rechallenge with SARS-CoV-2, suggesting a role for CD8⁺ T cells in the face of waning Ab responses (37). In view of its relevance for the induction of neutralizing Abs, the CD4⁺ T cell response to the S protein has been studied in great detail in convalescent individuals and vaccinees with prediction algorithms, peptide or protein stimulation, and isolation of T cell clones (38–40). These studies revealed multiple T cell epitopes in the RBD—including an immunodominant site, which is highly conserved among Sarbecoviruses and VOCs. As discussed below, one of the limitations imposed by severe COVID-19 is the profound T cell lymphopenia that affects the host’s ability to mount a robust immune response.

Abs and memory T cells elicited by common cold coronaviruses are recalled by SARS-CoV-2 infection or vaccination, but their role in protection or pathology remains to be established (41, 42). Further, it was suggested that preexisting memory CD4⁺ T cells specific to an early transcribed replication transcription complex found in abortive infection may confer cross-protection against SARS-CoV-2 (43). In addition, cross-reactive Abs elicited by seasonal coronaviruses may influence the course of the disease as well as de novo immune responses to SARS-CoV-2 (44, 45).

Seminal studies on RSV have paved the way for the use of stabilized prefusion proteins as vaccines to facilitate the production of neutralizing Abs (46). Similarly, a prefusion stabilized S protein in the Moderna and Pfizer/BioNTech mRNA vaccines and in the Ad26-based Johnson & Johnson vaccine was used to optimize the production of neutralizing Abs while limiting the production of non-neutralizing Abs specific for the postfusion conformation, which are elicited by natural infection (47). Emerging SARS-CoV-2 VOCs can, however, evade the neutralizing Ab response elicited by infection or by current vaccines based on the Wuhan strain (Wuhan-Hu-1) (48–50). Mutations found in VOCs primarily cluster in the RBM, resulting in increased binding to ACE2 and escape from neutralizing Abs. Furthermore, mutations and deletions in NTD change the domain structure and may account for differences in neutralizing titers observed against different VOCs (31). The Omicron variant in particular carries 15 mutations in the RBD, which substantially erode the neutralizing activity induced by previous infection or vaccination.

The interrogation of memory B cells has provided a plethora of monoclonal Abs that have been instrumental in dissecting the mechanisms of protection and informing vaccine design. Notably, several potent neutralizing mAbs have been rapidly developed and found to be effective as therapeutics when administered to patients who may be at risk during early infection (27). One limitation of this approach can be found in the variability of the S protein, particularly of the RBM, which has reduced or abolished the efficacy of several approved mAbs—even when used in combination—against the highly mutated Omicron variant (51). The current strategy is to focus on Abs that are less susceptible to variants because they mimic ACE2 or recognize conserved epitopes such as S309/sotrovimab, which binds to RBD site IV outside of the RBM and retains virus-neutralizing activity and effector functions against VOCs, including Omicron (51).

Immunopathology of severe COVID-19

SARS-CoV-2 shares 73% homology with SARS-CoV, and similar to SARS-CoV the pathogenesis of SARS-CoV-2-induced pneumonia likely occurs in two phases (52): First, the viral phase is characterized by viral replication resulting in direct virus-mediated tissue damage. The extent of this damage determines the pathogenesis of the secondary phase, which is characterized by the recruitment of effector immune cells causing a local and systemic inflammatory response that can persist even after viral clearance. The development of pulmonary disease is associated with excess vascular permeability leading to microthrombi deposition and vascular permeability (53), in addition to a range of systemic symptoms including (i) olfactory dysfunction, which occurs in approximately half of people diagnosed with COVID-19 but has not been described for SARS-CoV (54); (ii) gastrointestinal (GI) symptoms (55); and (iii) cardiac, hepatobiliary, and renal dysfunction (53). The pathogenesis of extra-pulmonary manifestations is likely multifactorial as a result of direct viral injury to the tissue cells, vessels, or neurons, as well as cytokine release, auto-Ab-induced tissue damage, vascular damage, or gut dysbiosis in the case of GI symptoms. Although several risk factors for severe COVID-19 have been identified, the pathophysiological underpinnings that contribute to disease severity are not fully understood. Below, we discuss two broad hypotheses that have emerged to explain severe COVID-19 pathophysiology and examine how the identified risk factors contribute to these pathophysiological drivers (Fig. 1).

Fig. 1. COVID-19 pathogenesis.

Inability to mount a timely and effective antiviral response because of delayed IFN response, altered antigen presentation function, or altered tissue resident macrophage pool, common in older individuals, promotes viral persistence and prolonged tissue damage that trigger the prolonged blood release and recruitment of damaging inflammatory myeloid cells to the infected site. Enhanced myelopoiesis and vascular damage common in older individuals and in patients with chronic inflammatory diseases further contribute to the enhanced release of inflammatory myeloid cells from the bone marrow to the blood circulation and their recruitment to the site of infection leading to profound tissue damage, vascular lesions, and blood clots common in patients with severe disease.

Inability to mount a timely antiviral response

The inability to mount a timely and effective immune response against SARS-CoV-2 is multi-factorial and is discussed as follows:

Viral load:

The exact contribution of viral loads in disease course has been difficult to establish likely because of discrepancies in measurements between studies and sampling biases as well as viral dynamics, and it is still unclear how much this contributes to disease outcome.

Defects in type I IFN response:

The timely production of type I IFN by host cells is critical for limiting viral replication and promoting antiviral immunity. Loss of function variants in loci that control TLR3- and IRF7-dependent type I IFN immunity have been identified in a small number of severe patients (56). Notably, these patients were adults who had never been hospitalized for severe viral illness before COVID-19. AutoAbs against IFN-α and IFN-ω (57–59) have been identified in patients with severe disease and have been shown to contribute to delayed viral clearance (59). Neutralizing IFN-α and IFN-ω autoAbs have recently been found to increase with age (60) suggesting that type I IFN autoAbs can precede the disease and serve as a biomarker of disease severity.

Imbalanced adaptive immunity:

The reduction of DC numbers and profound T cell lymphopenia driven by T cell sequestration in tissues or T cell apoptosis as a result of proinflammatory cytokines is common in severe patients (22, 23) and may contribute to defective T cell–mediated viral clearance. Defects in type 1 immune responses (23) and excess type 2 immunity have both been shown to correlate with severe COVID-19 (14), suggesting that a maladapted adaptive immune response to the virus may also lead to delayed viral clearance and disease progression. Substantial plasmablast expansion reaching up to 30% of circulating B cells—sometimes associated with extrafollicular responses—has also been reported in severe patients (61). The massive plasmablast expansion may reflect polyreactivity given the low levels of somatic mutations in Ab clones observed in patients and may have less potent viral control while contributing to tissue damage as suggested below.

Inability to control SARS-CoV-2–driven inflammatory responses

Autopsies of deceased COVID-19 patients have revealed very little active viral infection and substantial accumulation of activated immune cells, suggesting that organ failure is unlikely to result from extensive viral-induced tissue damage but is instead caused by an over-activated immune system or vascular damage. Below, we discuss the potential causes of these excessive inflammatory responses.

Altered myeloid responses:

Excess circulating immature monocytes, neutrophils, and myeloid progenitors—referred to as emergency myelopoiesis—are almost pathognomonic of severe disease and are triggered during the first phase of infection, likely because of delayed viral clearance especially in conditions with preexisting altered myelopoiesis (62, 63). Circulating myeloid cells produce excessive amounts of inflammatory molecules that promote vascular permeability and organ damage (Fig. 1). By contrast, lung tissue–resident macrophages known to play a key role in tissue homeostasis and repair are often depleted in severe patients (19, 20). The exact nature of their depletion is unclear, however, and may be a result of direct viral injury or cell death induced by excess inflammation.

Pathogenic antibodies:

AutoAbs have been identified in severe COVID-19 including a high proportion of Abs targeting nuclear antigen (58, 59), phospholipids (64), T cell antigens, B cell antigens, chemokines, and cytokines (57–59). Anti-phospholipid Abs cause clots in mouse models (64) whereas immunoglobulin G (IgG) from patients with anti-CD38 or anti-CD3ε autoAbs exhibit increased Ab-dependent cellular phagocytosis by macrophages, which may contribute to the profound lymphopenia observed in some patients (59). AutoAbs have also been detected in the cerebrospinal fluid of patients with neurological symptoms (65).

In addition, afucosylated anti–SARS-CoV-2 IgG1 with enhanced affinity for the activating FcγRIIIa accumulates mainly in male patients with severe COVID-19 (66). These Abs fuel the production of inflammatory cytokines and NK cell degranulation, which may contribute to tissue damage; furthermore, they are absent in asymptomatic patients and seropositive children (66). The mechanisms that lead to the production of afucosylated Abs and whether these Abs can be induced upon vaccination still remains to be understood.

Vascular damage:

Hypercoagulation, endothelial damage, and arterial and venous embolism are very common in severe COVID-19 (55). Although the exact mechanisms of hypercoagulability remain unclear, it may be a result of direct viral damage to the vasculature or severe inflammatory responses, which can alter the vascular endothelium and induce the activation of platelets, monocytes, and macrophages which in turn promote the release of tissue factor, von Willebrand factor, and factor VIII, leading to the production of thrombin and fibrin clot formation (53).

Predisposing risk factors

Age is by far the strongest risk factor for critical pneumonia with the risk of life-threatening disease sharply increasing from 65 years of age onward. Surprisingly, infants and young toddlers commonly at risk for influenza infections are usually protected from severe disease (67). Male patients are at much higher risk of developing severe COVID-19, which may be a result of enhanced innate immunity and impaired T cell activation compared with females (68) and/or higher levels of afucosylated anti–SARS-CoV-2 Abs (66). Diabetes, hypertension, obesity, and chronic kidney diseases are also important risk factors for severe COVID-19. These conditions can include chronic inflammatory lesions, which may enhance and perpetuate the inflammatory cycle. Metabolic syndrome—often associated with insulin resistance in diabetic and obese patients—also leads to vascular damage and impaired tissue repair. It is likely that the rapidity and quality of immune responses during the first phase of infection is particularly critical in these patients as delayed viral clearance is more likely to lead to overt recruitment and activation of immune cells, vascular damage, and impaired tissue repair.

Immune-directed therapy for COVID-19

Consistent with the major role of the immune response in driving pathogenesis, a wide range of immunomodulatory agents have been tested for the treatment of COVID-19, and several have demonstrated efficacy. Evidence-based treatment guidelines are regularly updated by the National Institutes of Health and contain references to all the primary literature guiding these recommendations (69). Such guidelines will continue to evolve as new drugs are developed and new clinical trials enable new indications. The recent approval of the direct-acting antivirals ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir, and molnupiravir for nonhospitalized patients with mild-to-moderate COVID-19 who are at high risk of disease progression is an excellent example of such a recent modification. Patients who are not hospitalized but are at high risk of disease progression can benefit from anti–SARS-CoV-2mAbproducts (either bamlanivimab plus etesevimab, or sasirivimab plus imdevimab or sotrovimab) (69). For hospitalized patients who require supplemental oxygen, remdesivir (a direct-acting antiviral) and dexamethasone (a broad-spectrum corticosteroid) are recommended (69). The success of dexamethasone in improving outcomes of patients with advanced disease highlights the critical role of inflammatory responses in mediating pathogenesis and marks a considerable departure from the treatment of influenza, in which such steroid treatments are harmful. Indeed, several more targeted agents have also proven beneficial, particularly agents counteracting the IL-6 pathway including tociluzimab and sarilumab (69). Inhibitors of the JAK–STAT signaling pathway such as baricitinib and tofactinib have also shown promise (69). Drugs that target the IL-1 pathway such as anakinra and canakinumab have also been tested, though there is a lack of sufficiently strong evidence of benefits to recommend their use (69). Critically, IL-6- and JAK–STAT-blocking agents must be used within a brief window in recently hospitalized patients with rapidly declining courses. Presumably, this is when interruption of the “cytokine storm” can change the outcome of the disease. When such anti-inflammatory drugs are used in less ill populations or too late, there is a trend toward harm, making it imperative to identify those patients with inflammation that warrants intervention. This opens the door for future diagnostics to better match a specific patient with a specific drug.

Immunology of Long Covid

It is now clear that COVID-19 can lead to long-term disease—often referred to as Long Covid syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC)—in a significant proportion of survivors. Although there is no universal consensus in the definition of PASC, the American Centers for Disease Control and Prevention defines it as a wide range of new, returning, or ongoing health problems that people experience 4 or more weeks after first being infected with SARS-CoV-2. By contrast, the World Health Organization defines it as a condition that occurs in people with confirmed or probable SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis (Fig. 2). A systematic review of 57 peer-reviewed studies with 250,351 survivors of COVID-19 who met their inclusion criteria for PASC showed that the median age of patients was 54.4 years, 56% were male, and 79% were hospitalized during acute COVID-19 (70). At 6 months, 54% of survivors suffered at least one PASC symptom. However, nonhospitalized COVID-19 survivors who developed PASC were primarily middle-aged women. In a survey of 445 nonhospitalized Danish COVID-19 patients, persistent symptoms—most commonly fatigue and difficulty with memory and concentration—were reported by 36% of symptomatic participants with a follow up of >4 weeks. Risk factors for persistent symptoms included female sex (44% and 24% for women and men respectively, odds ratio 2.7) and Body Mass Index (odds ratio 1.1) (71).

Fig. 2. Immunology of PASC.

A fraction of COVID-19 patients with either severe or mild COVID-19 develop a variety of new, recurring, or ongoing symptoms and clinical findings 4 or more weeks after infection. Analyses of immune responses in people with PASC reveal key inflammatory cytokines and cellular activation phenotypes that are significantly elevated over nonPASC convalescent controls. Further studies are needed to identify the drivers of PASC pathophysiology.

The immunobiology of PASC is currently under investigation. Leading hypotheses include (i) persistent virus or viral antigens and RNA in tissues that drive chronic inflammation, (ii) the triggering of autoimmunity after acute viral infection (72), (iii) dysbiosis of microbiome or virome, and (iv) unrepaired tissue damage (Fig. 2). SARS-CoV-2 viral proteins and/or RNA have been detected throughout respiratory, cardiac, renal, and reproductive systems, aswell as in the brain, muscles, eyes (73), GI tract (73–75), and lymph nodes (73, 75) months after infection. Aberrant innate immune stimulation is associated with PASC during the early and late phases of disease. Studies have shown that some inflammatory cytokines—including IL-6, TNF-α, and IL-1β—are elevated in PASC patients (76, 77). IFN-β and IFN-λ1 remain elevated 8 months after infection in PASC patients compared with recovered controls. Furthermore, combinations of IFN-β, PTX3, IFN-γ, IFN-λ2/3, and IL-6 were associated with PASC with 78.5 to 81.6% accuracy (78). A deep, multiomic, longitudinal investigation of 309 COVID-19 patients (71% hospitalized) from initial diagnosis to 2 to 3 months after identified four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein–Barr virus viremia, and autoAbs (79). AutoAbs were anticorrelated with anti–SARS-CoV-2 Abs. These data collectively suggest that the persistence of viral components may result in chronically elevated IFNs and cytokines. Moreover, certain autoAbs may provide permissive conditions for such viral persistence. However, there is no causal link between viral proteins and RNA and these elevated cytokines.

Adaptive immune responses to SARS-CoV-2 have been examined in PASC versus nonPASC convalescent individuals. Studies of individuals with confirmed COVID-19 with or without PASC found no difference in anti-S Ab levels during the 8 months of study and no differences in the initial PCR Ct value for viral RNA (80, 81). Other studies found that anti-N, -M, and -S CD8 T effector memory (T_EM) cells and T_EM cells that reexpress CD45RA (T_EMRA) in PASC patients were reduced compared with those of convalescent individuals, whereas anti-N T follicular helper cells (T_FH) and anti-N IgG levels were elevated in blood circulation (82). These studies suggest a possible persistence of viral antigens driving immune stimulation.

As discussed above, autoAbs have been detected in acute COVID-19 and evidence is emerging that autoAbs at the time of diagnosis were correlated with PASC (79). A study of 31 patients suffering from different PASC symptoms—including neurological and cardiovascular symptoms—revealed that in all 31 patients, 2 to 7 different GPCR-functional autoAbs (fAAbs) were present, acting as receptor agonists. Some of those GPCR-fAABs activated their target receptors, causing a positive chronotropic effect in neonatal rat cardiomyocytes, whereas others caused a negative chronotropic effect (83). AutoAbs to GPCR have been associated with numerous diseases of the cardiovascular, pulmonary, and the central nervous system in addition to autoimmune conditions (84) and may play a pathological role in mediating PASC symptoms.

Emergent results suggest that COVID-19 vaccines may have an effect on PASC symptoms in a subset of individuals. A prospective case control study using self-reported data found that two doses of vaccines before SARS-CoV-2 infection (n = 906) reduced the risk of prolonged symptoms after 28 days compared with unvaccinated matched controls (n = 906) (85). Analysis of existing data on a 1296-patient cohort with PASC emulated a 1:1 matched (vaccinated: unvaccinated) trial to determine the effect of vaccination in PASC patients, and found that vaccination ~38 days postinfection significantly reduced the risk of prolonged symptoms 120 days postinfection (86). Even after infection, vaccination within the first 12 weeks was associated with a reduced risk of developing Long Covid on the basis of a retrospective analysis of the medical history of 240,648 SARS-CoV-2–infected persons (87).How exactly the vaccine prevents or treats PASC is currently unclear. It is possible that the anti-S Abs and T cells elicited by the vaccines promote clearance of residual antigens or viral particles, eliminating the cause of chronic inflammation. It is also possible that vaccine-induced cytokines act on autoreactive lymphocytes and shut down the production of pathogenic cytokines or reprogram pathogenic lymphocytes. Evaluation of immune responses in PASC patients to vaccines is needed to reveal the underlying mechanism of protection.

Concluding remarks and future directions

The COVID-19 pandemic has wrought massive disruption and resulted in the loss of countless lives; however, there have been silver linings. The particularly rapid development of highly efficacious vaccines is foremost among these and has established a playbook for the response to future pandemics. One comforting prospect is the degree to which advances in our understanding and treatment of COVID-19 have been aided by an unprecedented degree of scientific cooperation. Free sharing of data has allowed us to rapidly glean critical insights into the role of the immune system in contributing to both protection and pathogenesis in COVID-19. Such insights will undoubtedly help us prepare for the next pandemic, just as decades of previous immunological research led to our current COVID-19 vaccines. However, many challenges remain, and our progress in ending this pandemic is threatened by inequitable distribution of vaccines and the rise of variants that are less susceptible to vaccination and prior-infection–mediated immunity. As infections continue to occur, there remains a need for new therapeutics and hence a need for a better understanding of the pathophysiology of COVID-19. In addition to treating acute infections, there is a dire need to better understand and develop treatments for individuals with PASC. Another threat is the amount of misinformation and erroneous theories about the pandemic, vaccines, and therapeutic efforts that have been circulating in social media, some unfortunately introduced by scientists. More than ever, interdisciplinary and integrative approaches to scientific collaboration and fighting misinformation are necessary to tackle these and other challenges that lie ahead.