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Immunology of COVID-19
The extraordinary global spread of SARS-CoV-2 through naïve populations provides compelling evidence of both the strengths and limitations of the human immune response: on the one hand, recognizing and eliminating a novel viral pathogen, while on the other, causing potentially lethal immunopathological conditions ( Fig. 3.1 ). The pandemic also provided a striking opportunity to understand SARS-CoV-2 pathogenesis through a lens offered by multiple clinical trials. COVID-19 disease seems best considered in two phases: a brief early phase with high-level viral replication and limited immune responses, and a later phase in which these are reversed. A minority of infected persons progress to life-threatening illness in the later phase of infection, with striking consistency across diverse populations. Except for age, the risk for progression in most individuals cannot yet be attributed to a single critical social, economic, environmental, or genetic factor. For immunologists, the key emerging research questions regard how early responses to SARS-CoV-2 affect subsequent risks for severe disease and the underlying protective and pathogenic mechanisms. To this end, this chapter will discuss innate and adaptive immune responses to SARS-CoV-2 infection, the role of immune dysregulation and its contribution to severe pathological processes, and the potential role of endotypes to guide future studies of immunotherapy.
The immune processes involved with beneficial and damaging responses to SARS-CoV-2 infection in humans is outlined with high level supportive and mitigating interventions.
Innate Immune Responses
Early responses to many infections are driven by activation of cellular pattern recognition receptors (PRRs). Genetic sequences for these receptors are fixed: unlike immunoglobulin or T-cell receptor genes, they do not undergo rearrangement in somatic cells. PRRs located on cell membranes, such as Toll-like receptors (TLRs), are generally triggered by microbial ligands, whereas those in the cytoplasm may be triggered by indicators of molecular damage (damage-associated molecular patterns [DAMPs]) or by RNA or DNA with specific characteristics. As a single-stranded RNA virus, SARS-CoV-2 may be recognized by TLRs 7 or 8 (recognizing single-stranded RNA), retinoic acid–inducible gene I (RIG-Ia) (recognizing uncapped viral RNA), or melanoma differentiation–associated protein 5 (MDA5), an RIG-I–like PRR recognizing long double-stranded cytosolic RNA. PRR triggering results in a signaling cascade that includes production of interferons (IFNs), so named in the 1950s for their ability to interfere with virus propagation ( Fig. 3.2 ). Many IFN-stimulated genes (ISGs) encode proteins with direct antiviral effects ( Fig. 3.3 ). The breadth of ISG responses hampers the emergence of viral avoidance mechanisms, although viruses nonetheless devote substantial genomic space in an attempt to do so. This competition between viruses and host cells is one of the strongest drivers of protein adaptation in mammalian evolution. Emerging evidence indicates that the enhanced transmissibility of new SARS-CoV-2 variants is due in part to enhanced evasion of innate responses.
The IFN-driven innate response to viral infections has three important functions: creating an intracellular milieu that limits viral replication, recruiting immune cells to the site of infection, and priming an adaptive immune response through the expression of costimulatory molecules. However, the very breadth of the innate response can also pose significant costs to the host. This is best illustrated by clinical experience with various forms of recombinant IFN-α, which, for more than a decade, was combined with ribavirin for treatment of chronic hepatitis C virus infection. Together, these drugs could cure about half of patients; factors increasing the likelihood of cure included low pretreatment levels of IFN-induced protein 10 (IP-10). , However, IFN treatments were poorly tolerated, with black box warnings of fatal or life-threatening neuropsychiatric, hematological, autoimmune, ischemic, and infectious disorders. In routine clinical use, less than 25% of patients were able to complete a full course of treatment. The IFN regimens have largely fallen out of use now that alternatives (direct-acting antiviral drugs) are available.
IFN appears essential for protection against SARS-CoV-2, based on reports of life-threatening disease in persons with inborn errors or autoantibodies affecting pathways for type I IFNs (α and β). , Early IFN responses appear insufficient for optimal control of viral replication even in the absence of recognized immune defects. The clearest evidence for this comes from a small trial in which 60 newly diagnosed COVID-19 outpatients were administered a single dose of pegylated IFN-λ (PEG–IFN-λ) or placebo. IFN recipients were more likely to have undetectable virus by day 7 (odds ratio [OR], 4.12; P = .029). The benefit was greatest in those with high viral loads at baseline. Receptors for IFN-λ (a type III IFN) are expressed on epithelial cells but not on lymphocytes, potentially preserving efficacy while increasing safety and tolerability. Further trials comparing subtypes of the IFN-α, β, or λ families are underway to test this hypothesis.
A trial conducted in Hong Kong examined the addition of IFN-β plus ribavirin to lopinavir/ritonavir in 127 patients. Although subjects in this trial were inpatients, its patient population was similar to that of the IFN-λ trial, in that only 13% required supplemental oxygen at baseline. IFN treatment yielded a shorter median time to negative polymerase chain reaction (PCR) (7 vs. 12 days; P = .0010), and a shorter time to resolution of symptoms (4 vs. 8 days; P < .0001). In contrast, the World Health Organization Solidarity Trial examined IFN-β treatment in 243 hospitalized patients, most of whom already required oxygen therapy. In this population with more advanced disease, IFN treatment tended to increase mortality risk compared with controls (relative risk [RR], 1.16; P = .11). Similarly, a retrospective study published early in the pandemic suggested that the likelihood of survival was increased by early IFN-α treatment (within 5 days of hospitalization), whereas survival was reduced if IFN was started later. Several studies have confirmed that IFN levels correlate generally with COVID-19 disease severity; that is, IFN levels are highest in persons with severe disease. One study suggests that mutations outside of the spike coding region contributed to the evolutionary success of SARS-CoV-2 variants (most notably alpha) through the enhanced suppression of innate responses. However, it seems that for later variants, evasion of antibody responses (induced by vaccination or prior infection with early lineage strains) may better account for evolutionary success (discussed below).
Together, these studies support a hypothesis that innate responses during early SARS-CoV-2 infection are insufficient for viral control, and that the subsequent amplification of these responses contributes to immunopathological processes.
Adaptive Immune Responses
The humoral and cellular arms of the adaptive immune system are integrally linked with innate immune mechanisms in the overall response to viral infection. Distinct mechanisms of each system are engaged differently depending on virus type, the timing of a response, and the cell types involved ( Table 3.1 ). Unlike innate responses, which recognize patterns shared by many pathogens, adaptive immune responses recognize specific antigenic sequences of specific pathogens. The required receptor diversity is accomplished by gene rearrangements for antigen receptors or immunoglobulin regions early in the development of T and B cells, respectively. Antigen recognition triggers both cellular activation and clonal expansion. Depending on the frequency of precursor cells and the nature of the stimulus, a period of days to weeks must elapse for the evolution of a primary adaptive immune response.
Table 3.1
Immune Cell Type Overview
| Dendritic Cells | Macrophage | B Cell | CD4+ T cell | CD8+ T cell | |
|---|---|---|---|---|---|
| Location | Skin, mucosal epithelium (Langerhans cells), bone marrow, blood, spleen, thymus, tonsil, liver, lung, intestine, lymph nodes | Throughout the body | Blood, peripheral lymphoid organs | Throughout body | Throughout body |
| Function | Antigen-presenting cell of innate immune system Both extracellular and intracellular antigens |
Antigen-presenting cell of innate immune system Extracellular antigens , |
Adaptive immunity: Antibody production Antigen-presenting cell Effector cell killing of infected cells , |
Effector cell terminating infection B-cell help CD8+ cell help Cellular memory Type 1 intracellular and type 2 extracellular (e.g., helminths) response to infections , |
Effector cytotoxic killing of infected cells Type 1 response to intracellular infections , |
| Specific antigen receptors | No | No | Surface immunoglobulins | TCR | TCR |
| Differentiation | cDC1 and cDC2 | M1 and M2 | Memory B cells Plasma cells |
Tfh-promoting B cell response in lymphoid tissue Treg: Maintenance of immunological tolerance to self and foreign antigen Th1: Eliminates intracellular pathogens and associated with organ-specific autoimmunity Th2: Produces an immune response against extracellular parasites, and play major role in induction and persistence of asthma and other allergic diseases Thl7: Produces immune response against extracellular bacteria and fungi. Also involved in the generation of autoimmune diseases |
Tc1: Immune response against intracellular pathogens and tumors Tc2: Th2-mediated allergic reaction, contributes to arthritis Tc9: Inhibits CD4+ T-cell mediated colitis, propagates Th2-mediated allergic reaction, antitumor response Tc17: Propagates autoimmunity, confers immunity to viral infections, antitumor response CD8+ Treg: Regulates T-cell–mediated responses |
| Costimulation/cytokines | ICOS, CD28 | M1 is induced as a response to infectious stimuli (e.g., LPS and/or IFN-γ) and M2 is induced by resolving stimuli (e.g., IL-4) |
IL-21, IL-4, CD40L | CD28 | CD28 |
| Interferon production | Type I and type III interferons | Type I interferons | IFN-γ | IFN-γ | Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity |
cDC, Classic dendritic cells; ICOS, inducible T-cell costimulator; IFN-γ, interferon-gamma; LPS, lipopolysaccharides;
MHC, major histocompatibility complex; TCR, T-cell receptor; Tfh, T follicular helper cells; Treg, regulatory T cells.
The neutralizing antibodies produced by B lymphocytes and plasma cells play a critical role in preventing SARS-CoV-2 infection in uninfected individuals and restricting viral replication in those already infected. Initial immunoglobulin M (IgM) antibody responses are often of limited binding avidity and functional capacity. The evolution of these responses to include other antibody isotypes with greater avidity and broader functionality (including IgA and IgG subtypes) requires the engagement of T helper (Th) cell lymphocytes. Antigens are presented in the form of short peptides by dendritic cells, macrophages, and B-lymphocytes. Presentation occurs in the context of major histocompatibility complex (MHC) (human leukocyte antigen [HLA]) determinants displayed on the cell surface together with appropriate costimulatory molecules. This process initiates the selection of antigen-specific naïve B and T lymphocytes for further clonal expansion ( Fig. 3.4 ).
Variations in the character and timing of these responses give us clues to the relationship and relative roles of the innate and adaptive immune systems in defenses against COVID-19. Recovery is delayed in the absence of IgG responses (in persons with agammaglobulinemia), with cases reported in which disease progression continued until convalescent serum replacement therapy was administered. Poor outcomes have been reported for individuals requiring treatment with anti–B-cell monoclonal antibodies, with the clinical severity of illness dependent on the extent of the humoral immune deficit. Early decreases in the numbers of lymphocytes or dendritic cells (hindering the clonal expansion of pathogen-specific T and B cells) are similarly associated with sustained viral replication and poor clinical outcomes. , These findings establish a critical role for neutralizing antibodies in defenses against SARS-CoV-2 infection.
Antibody Responses
Two key studies confirm the importance of the SARS-CoV-2 spike protein receptor binding domain (RBD) as a critical antigen for host immune responses. The first study found that RBD antibody accounted for 90% of neutralizing activity in convalescent patient sera. The second found that most convalescent sera with high neutralizing titers specifically targeted the spike protein and its RBD. These findings are consistent with current understanding of the role of the viral spike glycoprotein mediating cell entry by binding to the human angiotensin-converting enzyme-2 (ACE2) receptor. , Additional cross-sectional studies of hospitalized patients acutely infected with COVID-19 detected RBD-specific IgG neutralizing titers within a week of PCR diagnosis, with their magnitude associated with disease severity. In contrast, antibodies against the SARS-CoV-2 nucleocapsid protein are generally nonneutralizing and not associated with severity. These studies confirm the importance of the spike protein as a critical antigen for a beneficial host immune response.
Although SARS-CoV-2 is a new pathogen, it belongs to a yet-evolving extended family of coronaviruses. Researchers have hypothesized that prior immunity to related pathogens might explain the wide diversity of SARS-CoV-2 clinical outcomes. Several studies have examined cross-reactivity of convalescent SARS-CoV-2 patient sera to previously characterized viruses. One study of the spike antigen found no cross-reactivity with the highly homologous pre-pandemic bat coronavirus WIV1-CoV. Another found little correlation between responses to the RBDs of SARS-CoV-2 and the endemic HKU1 and NL63 human coronaviruses or to antigens of influenza or respiratory syncytial virus. A related hypothesis posits that even in the absence of detectable cross-reactivity, individuals with immune memory to related viruses might acquire adaptive responses to SARS-CoV-2 more rapidly. , However, a large study characterizing spike RBD antibody kinetics and isotype profiles in SARS-CoV-2 cases and pre-pandemic controls demonstrated no cross-reactivity with RBDs of Middle East respiratory syndrome coronavirus (MERS-CoV) or endemic human coronaviruses, although cross-reactivity was indeed found for SARS-CoV-1. Together, these findings suggest that common prior viral infections, including endemic human coronaviruses, do not influence the functional evolution of immunity to SARS-CoV-2.
T-Cell Responses and Repertoire
T cells can be characterized according to expressed cell surface proteins detected by flow cytometry. The largest T-cell population, CD4+ helper lymphocytes, recognize peptide fragments from virus proteins complexed with MHC class II molecules ( Fig. 3.5 ). CD4+ T cells can be differentiated further into T follicular helper (Tfh), Th1 or Th2 cells, and others. Tfh cells are essential for antibody affinity maturation and isotype switching. They provide help to B cells in lymph nodes and influence naïve B cells to differentiate to become antibody-producing plasma cells. Tfh cells also are able to provide help to accelerate responses in cases of reinfection or in vaccinated individuals. Th1 cells show antiviral properties such as IFN-γ production. T cells that are already optimized as a result of previous viral antigen exposure and often reside in respiratory epithelium are termed resident memory T cells (Trms). Their cellular properties and anatomic location facilitate rapid responses to infection. The Th2 signature pathway for CD4+ cells has not been a significant feature of SARS-CoV-2 infection. This is fortunate, given its relationship to antibody-dependent disease enhancement and cytokine profiles associated with poor clinical outcomes in other viral diseases, including the experience and lessons learned from respiratory syncytial virus (RSV) infection after formalin-inactivated RSV vaccine administration. , CD4+ T cells additionally recruit innate immune cells to sites of infection and support the clonal expansion of CD8+ T cells. CD8+ T cells in turn can eliminate infected cells through the cytolytic activities of granzyme, perforin, IFN, and TNF-a.
Several elegant studies have examined adaptive immune responses and SARS-CoV-2 epitopes at different points of time in COVID-19 disease, from acute infection to convalescence or terminal illness. Two studies paved the way for vaccine development by demonstrating that SARS-CoV-2 infection induces natural immunity and protects against reinfection in nonhuman primates and that neutralizing antibodies against the SARS-CoV-2 spike protein played a key role in protection. , T-cell responses to the spike protein can be detected within 7 days of infection; these are followed by B-cell responses associated with symptom onset (IgM and IgA by days 5–7, IgG by days 7–10). Antibody and T-cell levels decline after the acute phase of infection; serological memory is maintained by a small number of long-lived bone marrow plasma cells that constitutively secrete antibody and subsequently provide accelerated booster responses after reexposure.
Studies of T cells in patients from the SARS-CoV-1 outbreak in 2003 showed evidence of long-lived recognition of the nucleocapsid (N) structural protein of the virus; when similar assays were performed in convalescent COVID-19 patients, there was evidence of CD4+ and CD8+ T-cell recognition of multiple epitopes on the SARS-CoV-2 N protein as well. In studies with all proteins of SARS-CoV-2 represented, the transmembrane (M) and spike (S) proteins were codominant, with N proteins indicating a different pattern of response to epitopes than with the SARS-CoV-1 outbreak in 2003. A small study of 12 patients characterized cellular immunity, antibody levels, and respiratory SARS-CoV-2 viral load by PCR cycle time and demonstrated that moderate and severe disease status had higher SARS-CoV-2 antibody responses compared with mild clinical syndromes in which early IFN-g production indicated a T-cell response correlated with mild disease and a shorter illness. More recently in a study of nearly 100 convalescent COVID-19 patients evaluating T-cell immunodominance, the S and M SARS-CoV-2 proteins determined CD4+ helper cells’ functional roles for both B-cell help producing RBD antibodies and to CD8+ T-cell responses. CD8+ T cells also have been found to have an important role in decreasing severity of illness; in studies using peptide pools, CD8+ cells are notable for a broad response to viral protein epitopes albeit with different patterns of immunodominance compared with CD4+ cells. CD4+ cell responses to SARS-CoV-2 antigens are most robust in persons recovering from mild COVID-19 disease, whereas antibody production and killing of infected cells by CD8+ T cells predominate in persons with severe disease. Studies with candidate vaccines have demonstrated that SARS-CoV-2 spike induces multiple arms of the immune system, including specific CD4+ and CD8+ T cells and nonneutralizing antibodies that mediate antibody-dependent cytotoxicity. ,
Coverage of Emerging Variants
As SARS-CoV-2 propagates among the global human and nonhuman population, the virus continues to accumulate mutations as a result of natural evolution and immune pressure. Although coronaviruses have been reported to be 10-fold less error-prone than other RNA viruses because of the presence of a proofreading replicase enzyme, natural viral evolution during the pandemic has spawned SARS-CoV-2 variants with distinct mutations in the spike protein. For these emerging variants, we have different levels of scientific understanding of their transmissibility, pathogenicity, and ability for immune escape, though undoubtedly the variants have significantly changed our understanding and concerns regarding the COVID-19 pandemic. Variants were noted, beginning with the notable D614G spike protein mutant that has shown a modest ability for faster spread, and the mink variant with multiple mutations (e.g., “cluster 5”) that demonstrate spillover transmission across species and highlights the risk for incrementally evolved SARS-CoV-2 viruses with broad host range and/or greater pathogenicity. More recently the global public health community has increased the monitoring of emerging SARS-CoV-2 variants more purposefully with stepped up genomic surveillance and a classification scheme of (1) variant being monitored-primarily where data indicates association with increase in transmissibilty or disease severity but surveillance shows very low levels of circulation; (2) variant of interest—primarily with a predicted increase in transmissibility or disease severity; (2) variant of concern—primarily with evidence of an increase in transmissibility, pathogenicity (i.e., causing more severe disease), significant reduction in antibody neutralization, and vaccine effectiveness of treatments or vaccines; and (3) variant of high consequence—with clear evidence that prevention measures or medical countermeasures have significantly reduced effectiveness. , Among the prominent identified variants: alpha (B.1.1.7, first detected in the United Kingdom), beta (B.1.351; first detected in South Africa), and gamma (P.1; first detected in Brazil), were variants of concern but are now being monitored, and current variants of concern include delta (B.1.617.2 and AY lineages; first detected in India), but no identified variants of high consequence. , , The latest nomenclature uses Greek letters for variants of concern and is a departure from the influenza virus naming convention using place of origin and critical mutations.
One study of convalescent patient sera found cross-neutralization of both wild-type and D614G mutant SARS-CoV-2 spike antigens. However, immune evasion was thought partly responsible for a resurgence of COVID-19 cases in Manaus, Brazil in November 2020, which occurred despite previously high levels of infection. The resurgence was temporally associated with the emergence of new SARS-CoV-2 lineage (P.1) with three mutations in the spike protein, potentially increasing ACE2 binding and reducing neutralization by wild-type convalescent sera. Partial antibody resistance also has been described for variants alpha and beta causing second waves of infection in the United Kingdom and South Africa. ,
Interpretation of these findings is handicapped by an incomplete understanding of the relationship of neutralizing antibody titers to protection from infection and/or disease. Neutralization assays may use either authentic SARS-CoV-2 viruses, or pseudoviruses in which specific SARS-CoV-2 proteins are expressed in other viral vectors such as human immunodeficiency virus-1 (HIV-1) or vesicular stomatitis virus, using well-characterized assay systems. A prototypical study early in the pandemic that collected convalescent sera from 149 patients of varying severity found a wide range of half-maximal neutralizing titers (NT 50 s). Only 1% of samples showed very high titers (>5000); the majority were less than 1000, and one-third were less than 50. Interestingly, nonhuman primate challenge studies have reported circulating neutralizing antibody titers of 1:20 or greater in animals protected from SARS-CoV-2 infection. Generally, however, the levels in most convalescent sera are broadly comparable to those after full vaccination in individuals receiving mRNA, adenoviral vector, or whole-virus inactivated vaccines.
To date, all variants tested have been neutralized in vitro by immune sera from individuals vaccinated with mRNA, viral vector, or inactivated vaccines, although reduction in neutralization titers have been observed with particular variants. , Studies have shown that certain mutations and variants (E484K mutation in particular) are able to escape neutralization by convalescent plasma and monoclonal antibodies that target single epitopes. , , Vaccine-elicited sera were able to neutralize engineered SARS-CoV-2 viruses containing key variant spike mutations in vitro, such as E484K, L452R, and N501Y mutations. , Studies of cellular immune responses to SARS-CoV-2 variants in recovered COVID-19 patients demonstrated that CD4+ and CD8+ T cells have broad responses to multiple epitopes compared with neutralizing antibodies to the S protein involved with humoral immunity; this could bode well for the durability of vaccine-induced T-cell responses, given ongoing mutations of SARS-CoV-2 virus that have demonstrable effects in vitro on the amount of antibody needed to neutralize SARS-COV-2.
Reduced efficacy against clinical disease was observed in late-stage vaccine clinical trials in regions with high circulation of emerging variants. Interim analysis in January 2021 for an adenoviral vector vaccine (Ad26.COV2.S) in a single-dose regimen reported 66% efficacy overall against moderate to severe COVID-19, with 72% efficacy in the United States and 66% efficacy in Latin America cohorts, but efficacy dropped to 57% in the South African cohort, wherein 95% of the accrued cases were caused by the beta variant. , Similarly, phase III results for the adjuvanted protein subunit vaccine NVX-CoV2372 showed 89.3% efficacy in the UK cohort, in which more than 50% of accrued cases were caused by the alpha variant; efficacy in the South African cohort was 51%, with 93% of the accrued cases caused by the beta variant. On the other hand, reassuring real-world vaccine effectiveness data have been accumulating from national immunization programs for COVID-19 vaccines. Two doses of BNT162b2 mRNA vaccine demonstrated high real-world vaccine effectiveness against circulating variants of concern: in Israel, BNT162b2 demonstrated 90% to 96% effectiveness against SARS-CoV-2 infection, asymptomatic infection, symptomatic COVID-19, severe and critical hospitalizations, and deaths during the period of high circulation (94%) of the alpha variant. Similarly, from Qatar’s national immunization program, a two-dose regimen of BNT162b2 demonstrated 89% effectiveness against alpha variant infection; 75% against beta variant infection; and 100% against severe, critical, or fatal COVID-19 caused by alpha or beta variants. A two-dose regimen of mRNA-1273 demonstrated 100% effectiveness against alpha infection; 96% against beta infection; and 96% against severe, critical, or fatal COVID-19 caused by these two variants. In the UK national immunization program, two-dose BNT162b2 mRNA effectiveness was 93.4%, with alpha cases and 87.9% with delta cases, and two-dose ChAdOx1 effectiveness was 66% with alpha cases and 59.8% with delta cases. Vaccine effectiveness against the delta variant has been reported from national immunization programs in the United Kingdom and Canada. A two-dose regimen of BNT162b2 or ChAdOx1 vaccine demonstrated between 83% and 88% and 61% and 67% effectiveness, respectively, against symptomatic COVID-19. Scotland reported 79% and 60% effectiveness against SARs-CoV-2 infection; Canada reported that a two-dose regimen of BNT162b2 was 95% effective against hospitalization or death. Data for two doses of an inactivated SARS-CoV-2 vaccine (Coronavac) from Chile indicated 66% to 90% effectiveness against COVID-19, hospitalization, intensive care unit (ICU) admission, and COVID-19–related death. Brazil reported that in adults older than 70 years, effectiveness was 42% against symptomatic COVID-19, 59% against hospitalization, and 71% against death. Systematic reviews of vaccine effectiveness data across multiple vaccine platforms, dosing intervals, varied geographies and assorted SARS-CoV-2 variants in circulation are now available. , In addition, the first real world data are now available for effectiveness of maternal vaccination using mRNA vaccines: 2-dose COVID-19 mRNA maternal vaccination during pregnancy showed 61% VE against COVID-19 hospitalization in infants <6 months, during a period of delta and omicron variant predominance in the USA. Although no substantial clinical evidence of variant escape from vaccine-mediated protection has emerged, vaccine manufacturers and regulatory bodies are building clinical evidence and frameworks for redesigning vaccines and/or booster vaccines using either the ancestral strain of SARS-CoV-2 or the emerging variants, if the need arises. The most recently emerged SARS-CoV-2 variant – oicron (B.1.1.529 and BA lineages) has at least 30 mutations in the spike protein, half of which are in receptor binding domain , (RBD) that interacts with the host ACE2. receptor Furthermore, omicron does not appear to be the result of a linear progression from its immediate predecessor – delta, prevalent in 2021 – in an easily predictable fashion, but rather it appears to have evolved from the alpha variant prevalent in 2020. In part due to it’s significantly divergent sequence that enables immune evasion, omicron is highly transmissible and has spread rapidly to become the dominant circulating strain in most parts of the world. , Initial observations indicate a comparatively mild clinical phenotype, and multiple studies have shown that neutralizing antibody responses are substantially diminished post-2-dose vaccination while T-cell responses appear to be preserved, and a 3rd vaccine dose confers protection against omicron-related hospitalization and severe disease. , ,
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