key: cord-0827983-xuuqqufr
authors: Pozdnyakova, Valeriya; Weber, Brittany; Cheng, Susan; Ebinger, Joseph E.
title: Review of Immunologic Manifestations of COVID-19 Infection and Vaccination
date: 2022-03-29
journal: Cardiol Clin
DOI: 10.1016/j.ccl.2022.03.006
sha: 91a47e27dfdb45999bd06f883af2a35e522cb44a
doc_id: 827983
cord_uid: xuuqqufr

We herein summarize currently available and clinically relevant information regarding the human immune responses to SARS-CoV-2 infection and vaccination, in relation to COVID-19 outcomes with a focus on acute respiratory distress syndrome (ARDS) and myocarditis.

The 2003 SARS and 2012 MERS outbreaks had case fatality rates of 10% and 34%, respectively, while the majority of COVID-19 cases have remained relatively mild in comparison. 4 Specifically, the reported case fatality rate of COVID-19 peaked at 7.2% in April of 2020, declining to 2.2% by December 2020. 5 In the context of its lower mortality rate, SARS-CoV-2 is substantially more contagious than SARS-CoV and MERS-CoV. [6] [7] [8] This remarkable transmissibility, paired with its lower case fatality rate, has served as a double-edged sword given that milder illness affecting a majority of cases has hampered public compliance with masking and social distancing recommendations. 9,10 SARS-CoV-2 is spread through respiratory droplets and binds to the angiotensin-converting enzyme 2 (ACE2) receptor in nasal and bronchial epithelial cells and pneumocytes via viral Sprotein. 11, 12 The S-protein has two subunits, S1 and S2; S1 mediates binding to the host cell ACE2 receptor through the receptor binding domain (RBD) while S2 directs viral cell membrane fusion. By comparison, the RBD of SARS-CoV-2 binds ACE2 with 5-10 times greater affinity than the RBD of SARS-CoV. 6, 7 The recognition of the S-protein's importance in cellular entry has made it a key target for the immune response, as well as vaccine mediated protection.

Human expression of ACE2 occurs on epithelial cells in both the upper and lower respiratory tract, with nasal epithelial cells expressing slightly greater amounts, making it an ideal environment for SARS-CoV-2 to enter the body. 13 As such, early immune activation often begins in these locations. A study of ex vivo SARS-CoV-2 infected turbinate tissue identified a broad and robust innate immune response in nasal tissue, with increased upregulation of interferon stimulated genes (ISGs) and cytokine release, vital components in inhibiting viral infection of J o u r n a l P r e -p r o o f nucleated cells. 13, 14 Comparatively, this response to SARS-CoV-2 was larger than that initiated by the influenza virus, characterized by significant upregulation of genes that specifically enhanced antigen presentation and immune cell signaling, indicating a robust immune recognition and response to the virus in the nose. SARS-CoV-2 infected lung tissue, on the other hand, failed to upregulate INF types I, II, and III. Upregulation of ISGs in infected lung tissue was observed, but cellular immune pathways such as antigen presentation, immune cell maturation, TNF receptor signaling, and inflammasome pathways were not activated. 13 In effect, an early innate immune response is initiated in both the upper and lower respiratory tracts, however, the downstream effect is blunted in the pulmonary tissue.

A possible explanation for this finding is the action of SARS-CoV-2 non-structural protein 1 (NSP1) which inactivates the translational activity of the human 40S ribosomal subunit, a key link in the chain in the activation of immune response following antigen detection. 8, 15 Failure to translate upregulation of ISGs could potentially explain the restricted innate response observed in the lung tissue. How nasal, but not lung, epithelial tissue overcomes the translation inhibiting effects of NSP1 is not yet understood. Other studies support this finding, demonstrating that in vitro SARS-CoV-2 infected primary human airway epithelial cultures are unable to produce type I or III IFN, yet addition of exogenous IFN was able to significantly reduce viral burden in the same cultures. 16 This suggests that SARS-CoV-2 inhibition of IFN production, not reduced susceptibility to INF's antiviral inducing mechanisms, may play an important role in the virus's ability to modulate and evade the immune response. patients who experienced a range of symptoms from mild to severe, both in the acute setting, as well as 4-7 months following recovery. 18 Patients with mild infection were well enough to convalesce at home and experienced minimal symptoms, while those with moderate disease were hospitalized, required oxygen, or had non-severe ARDS. Comparatively, severe infection was characterized by admission to the ICU, a P:F ratio of <200, or death from COVID-19. The researchers found that among patients with mild disease, the development of anti-S1 IgG antibodies was delayed nearly 2 weeks from symptom onset and that once formed, these antibodies demonstrated only modest neutralizing capacity. 18 Most patients in the moderate cohort also lacked detectable anti-S1 IgG for several weeks following symptom onset, however, once present, antibody levels were higher and consistent with robust neutralizing capacity.

Comparatively, patients with severe illness had detectable anti-S1 IgG within 2 weeks of symptoms, with some as soon as one week after initially feeling ill. 18 Further, antibodies from patients with severe illness had the strongest correlation between antibody levels and neutralizing viral response. This pattern, with a vigorous early antibody response, demonstrating stronger neutralization capacity among patients with severe COVID-19, has been duplicated by others and clearly demonstrates an association between severity of illness and early humoral immune response to native infection. 19 Given this pattern, there has been an appropriate focus on IgG and IgM production over the course of COVID-19 infection, however, antibody levels may not tell the whole story. As noted, higher binding antibody levels have been found among patients suffering from severe, rather than mild, COVID-19 disease. 20 Over the course of one to six months, anti-RBD IgG and IgM levels decrease, with an associated 5-fold reduction in plasma neutralizing activity. Importantly, memory B-cells, capable of rapidly producing RBD-specific antibodies, remain unchanged six months after infection, indicating the potential for the body to rapidly increase antibody levels upon repeat antigen exposure. 21 neutralizing antibodies may play an important role in early response to infection. 22 Less is known about differential IgA response by disease severity, a knowledge gap that, once filled, may help us better understand variations in host response to infection.

The cellular immune response to SARS-CoV-2 also correlates with severity of COVID-19 illness, however, in an opposite direction than that of humoral immunity. Analysis of blood samples from patients infected with SARS-CoV-2 found that those with mild disease had a robust SARS-CoV-2-specific INF--producing T-cell response against S1, M, and N viral proteins within the first two weeks of symptom onset while patients with moderate disease developed cellular responses to these epitopes at a slower rate, reaching equivocal numbers only 3 weeks post symptom onset. Patients with severe disease had still not started developing high numbers of SARS-CoV-2 specific T-cells by the end of the acute infection follow-up. 18 Fortunately, among those who recover, including recovery from severe disease, 97% maintained detectable SARS-CoV-2-specific memory T-cells out to at least 28 weeks, suggesting that even a delayed cellular response may produce longer lasting immunity across the spectrum of disease severity. 18 Interestingly, significant peripheral T-cell lymphopenia has been identified as a marker of severe COVID-19 infection. A recent systematic review of the T-cell response to SARS-CoV-2 infection found significantly lower CD3+, CD4+, and CD8+ cell counts in critically ill patients and those who ended up dying of COVID-19 as compared to survivors and moderately ill patients. 23 Further, in a multivariable adjusted analysis, CD8+ T-cell counts of <165 cells/µL were J o u r n a l P r e -p r o o f independently associated with COVID-19 related mortality. 24 Similarly, lower helper T-cell levels and higher CD4:CD8 ratios have also been identified as strong predictors of mortality. 25 Dysregulation of the T-regulatory cell (Treg)/Th17 balance has further been implicated in severity of infection, with increased Th17 and decreased Treg cells in patients with severe COVID-19. 26 Treg's play a critical role in dampening an overreactive immune response for the maintenance of immune homeostasis and self-tolerance during viral infections. Th17 cells produce IL-17 which can promote the production of downstream proinflammatory molecules, including IL-1, TNF, IL6 and neutrophil chemoattractants. In murine model of ARDS, IL-17 has previously been shown to augment lung parenchyma destruction by amplifying proinflammatory mediators and neutrophil recruitment. 27

In effect, COVID-19 severity of illness demonstrates a dichotomous immune response, with early humoral activation and delayed cellular immune response associated with more severe disease, while early T-cell activation predominates in milder cases (Figure 1) . 28 Pfizer and Moderna vaccines carry mRNA, encapsulated in a lipid nanoparticle, that encode a modified version of the SARS-CoV-2 S-protein. 33 This modified mRNA has intentional mutations so translated, the S-protein is in it's prefusion conformation, critical for preservation of neutralization-sensitive epitopes and therefore effective vaccine-induced immunity. In contrast, Janssen's vaccine delivers DNA that codes for the SARS-CoV-2 S-protein on a recombinant adenovirus vector. The DNA is transcribed, producing S-protein, stimulating strong humoral and cellular immune responses. 34, 35 Study of the mRNA vaccine platforms demonstrate successful production of neutralizing antibodies, active SARS-CoV-2 specific CD4+ and CD8+ T-cells, and robust levels of cytokines such as IFN. 36 A study of the Pfizer vaccine demonstrated a strong SARS-CoV-2 spike-specific memory B-cell response, peaking one week after second dose, which gradually declined over time but maintained strong ACE2/RBD binding inhibiting activity for at least six months. 37 Such circulating vaccine induced spike-specific memory B-cells were restimulated in vitro and demonstrated ability to differentiate into anti-spike IgG or IgM-secreting cells.

The Pfizer, Moderna, and Janssen vaccines have each shown to be safe and effective at reducing severe COVID-19 illness by 88%, 93%, and 71%, respectively, following two doses of the mRNA or one dose of the adenovirus vector vaccine. 29 The Washington State Department of Health has been compiling and releasing data on COVID-19 cases, hospitalizations, and deaths by vaccination status since February 2021. They report that, among 12-34 year-olds, unvaccinated individuals were 5-times more likely to be hospitalized with COVID-19 compared to their fully vaccinated age matched counterparts. For those over the age of 65, the risk of COVID-19 hospitalization is 7-fold higher among the unvaccinated, with a risk of death 13-times J o u r n a l P r e -p r o o f greater than fully vaccinated individuals in the same age group. 38 Comparably, significant adverse events associated with vaccine were exceedingly rare (between 0.2%-0.3%). 39 Patients do report symptoms following vaccination, most frequently injection site pain and fatigue or malaise, however, these are overwhelmingly mild and short lasting, with >80% resolving within 2 days. 40 Dual antigen exposure from both vaccine and infection may also augment host immune response. Early work comparing serial IgG levels between previously infected and COVID-19 naïve individuals found that IgG levels were similar after 1 mRNA vaccine dose in those with a history of COVID-19 to those following 2 doses in participants without prior infection. 41 Expanding on this work, researchers found that while COVID-19 naïve individuals developed lower overall IgG levels, the two groups had comparable neutralizing antibodies and S-specific B-cell levels 8 months after vaccination. Interestingly, the COVID-19 naïve subjects also exhibited higher SARS-CoV-2-specific cytokine production, CD4+ T-cell activation, and proliferation than those who recovered from COVID-19. 42 While the exact mechanism behind the elevated T-cell response following vaccination in COVID-19 individuals remains uncertain, this finding is reassuring, particularly in the setting of the previously noted association of a robust cellular response to infection and the development of only mild symptoms.

As the pandemic has stretched over multiple years, appropriate concern has been directed to the potential of wanning immunity following initial vaccination. Marot et al. found that neutralizing antibodies against SARS-CoV-2 declined 38.5% among healthcare workers as soon as 2 months after primary COVID-19 infection and 3 months after second mRNA vaccine dose. 43 Such declines varied by age and sex, with those over age 65 experiencing a larger decrease in antibody levels following vaccination compared to those between the ages of 18-44. Further, vaccine mediated antibodies among men in this older cohort were found to decrease 46% more J o u r n a l P r e -p r o o f than similarly aged women. 44 Such declines in antibody levels have lead the Centers for Disease Control and Prevention, to recommend vaccine boosters and continued use of masks in high-risk areas to limit viral transmission.

There has also been concern that mutations in the S-protein, such as those appreciated in the Omicron variant, may allow the virus to evade neutralization by vaccine-elicited antibodies. To assess this possibility, researchers evaluated the neutralizing capacity of sera collected from individuals recently (<3 months) and remotely (6-12 months) vaccinated with any of the 3 major vaccines available in the United States against wild-type, Delta, and Omicron SARS-CoV-2

variants. 45 They further tested the sera of subjects recently boosted with either mRNA vaccine.

While neutralization of the Omicron variant was not appreciated among those who received only the initial vaccine regimen, neutralization was appreciated using sera from those who received a booster dose. Taken together, and particularly in the setting of recurrent COVID-19 surges, boosters remain a recommended mechanism to increase protection from severe COVID-19

illness. 45

While the immune response to COVID-19 facilitates viral clearance and imparts at least some protection against future infections, an excessively robust response has been implicated as a potential driver of severe disease. Specifically, high levels of cytokines including increases in circulating T-cell chemoattractants, natural killer (NK) cells, macrophages, and classic neutrophils, with an absence of IFN types I and III are found in individuals suffering from severe COVID-19. 46 Such response, paired with elevated IL-6 and IL1RA cytokines suggest a link between COVID-19 and cytokine release syndrome, characterized by vigorous activation of vast numbers of white blood cells resulting in exuberant release of proinflammatory cytokines that in turn activate more white blood cells in a cascading fashion. 23, 46, 47 High concentrations of IL-6, a J o u r n a l P r e -p r o o f proinflammatory cytokine, have also been correlated with lymphopenia, increased severity of disease and mortality. 23, 48 Together, local and systemic inflammation, particularly when paired with risk for secondary bacterial infections, increase the risk of progression of disease to ARDS. 49 A review of 72 publications reported that 30% of patients admitted to the ICU with COVID-19 went on to develop lung edema, dyspnea, hypoxemia, or ARDS and 65% of those who developed ARDS died. 49, 50 Infection is one of the main inducers of lung edema in ARDS, traditionally known to be caused by neutrophil activation in other illnesses such as influenza.

However, given the high rate of ARDS noted, it is uncertain whether SARS-CoV-2 has a unique pathophysiologic immune response that may further predispose to lung injury. 49 Among the more feared complications of COVID-19 infection are the development of myocarditis and pericarditis. Importantly, while cardiac involvement from COVID-19 infection does occur, clinically significant myocarditis remains a rare complication, with cases typically mild and self-limited. 51 Multiple potential immunologic mechanisms have been proposed as drivers of infection and vaccine associated myocarditis. Specifically following infection, the two-leading hypothesis for the mechanism of myocarditis include direct viral infection of cardiac myocytes and a maladaptive immune response, as described above. Interestingly, histological analysis of biopsy tissue from SARS-CoV-2 infected myocarditis patients did not display the classic lymphocytic pattern associated with viral myocarditis. This has led many to believe that overactivation of the immune response, particularly in the setting of severe COVID-19, likely contributes to cardiac dysfunction through thromboinflammation and endothelial dysfunction. 57 Work has also specifically implicated CD68+ T-cells found in high numbers in the myocardium of COVID-19 hearts, in the development of myocarditis following infection. 58 Vaccine associated myocarditis is thought to result from parallel, though importantly different mechanisms. The previously noted nucleoside modifications to the mRNA vaccines are designed in part to reduce the innate immune system's response to foreign RNA molecules. At least some vaccine associated myocarditis cases may represent breakthrough of this innate immune response, a mechanism associated with certain genetic predispositions. 59 Another proposed mechanism evokes molecular mimicry of the S-protein transcribed from the delivered mRNA resulting in crossreactivity with alpha-myosin. 60 Eosinophilic hypersensitivity has further been implicated as a mechanism particularly given the predilection for second or third dose and been described with the smallpox vaccine, as well. 61 Finally, sex hormones may play a role in the noted male predominance of COVID-19 and vaccine associated myocarditis. Specifically, estrogen may work to mitigate proinflammatory T-cells, while testosterone may block the function of certain damage. 57

The immune response to the novel SARS-CoV-2 virus is pivotal in both regaining health and potentially attenuating development of severe disease. Early robust humoral response coupled with delayed cellular immune response is associated with severe disease. Further, dysregulated immune response, including cytokine release syndrome, can lead to worse outcomes particularly via development of ARDS. Finally, while rare, infection and vaccine associated myocarditis can occur, though typically in mild and self-limited forms. Importantly, our understanding of the immune mechanisms underlying health and disease in COVID-19 have been essential to the rapid development of safe and effective vaccines, which remain among our best tools for combating this pandemic.

J o u r n a l P r e -p r o o f 

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

The immune response to SARS-CoV-2 and COVID-19 immunopathology -Current perspectives

The Global Case-Fatality Rate of COVID-19 Has Been Declining Since

Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

Structural basis of receptor recognition by SARS-CoV-2

Modes of transmission of SARS-CoV-2 and evidence for preventive behavioral interventions

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Human Nasal and Lung Tissues Infected Ex Vivo with SARS-CoV-2 Provide Insights into Differential Tissue-Specific and Virus-Specific Innate Immune Responses in the Upper and Lower Respiratory Tract

Interferon-inducible effector mechanisms in cell-autonomous immunity

Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells

Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination

IgA-Ab response to spike glycoprotein of SARS-CoV-2 in patients with COVID-19: A longitudinal study

Patterns of IgG and IgM antibody response in COVID-19 patients

Evolution of antibody immunity to SARS-CoV-2

IgA dominates the early neutralizing antibody response to SARS-CoV-2

T cell response to SARS-CoV-2 infection in humans: A systematic review

IL-6 and CD8+ T cell counts combined are an early predictor of in-hospital mortality of patients with COVID-19

Prediction of the clinical outcome of COVID-19 patients using T lymphocyte subsets with 340 cases from Wuhan, China: a retrospective cohort study and a web visualization tool. medRxiv

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity

Comparative Effectiveness of Moderna

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

COVID-19 Vaccine Tracker

Administration UFaD. COVID-19 Vaccines

SARS-CoV-2 mRNA Vaccines: Immunological Mechanism and Beyond. Vaccines (Basel)

Vaccines based on replication incompetent Ad26 viral vectors: Standardized template with key considerations for a risk/benefit assessment

Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination

COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses

Evidence of SARS-CoV-2-Specific Memory B Cells Six Months After Vaccination With the BNT162b2 mRNA Vaccine

Washington State Department of Health Public Health Outbreak Coordination I, and Surveillance; Disease Control and Health Statistics. COVID-19 Cases, Hospitalizations, and Deaths by Vaccination Status

Analysis of COVID-19 Vaccine Type and Adverse Effects Following Vaccination

Symptomology following mRNA vaccination against SARS-CoV-2

Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2

Cellular and humoral functional responses after BNT162b2 mRNA vaccination differ longitudinally between naive and subjects recovered from COVID-19

Covid-19 Vaccine over 6 Months

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Acute lung injury in patients with COVID-19 infection

Association Between COVID-19 and Myocarditis Using Hospital-Based Administrative Data -United States

Myocarditis and Pericarditis After Vaccination for COVID-19

Myocarditis after BNT162b2 Vaccination in Israeli Adolescents

Prevalence of Clinical and Subclinical Myocarditis in Competitive Athletes With Recent SARS-CoV-2 Infection: Results From the Big Ten COVID-19 Cardiac Registry

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization

The Novel Platform of mRNA COVID-19 Vaccines and Myocarditis: Clues into the Potential Underlying Mechanism

Myocarditis With COVID-19 mRNA Vaccines

COVID-19 myocarditis: quantitative analysis of the inflammatory infiltrate and a proposed mechanism

Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?

Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases