SARS-CoV-2 Omicron: light at the end of the long Pandemic Tunnel or another false dawn for Immunodeficient Patients?

Rohan Ameratunga - BHB, MBChB, PhD, FRACP, FRCPA, FRCP, FRCPATH, FRCPCH, FFSc, ABMLI abc Euphemia Leung - PhDde - See-Tarn Woon, PhD, FFScbc Lydia Chan - MBChBa, Richard Steele - MBChB, FRACP, FRCPAbf Klaus Lehnert - PhDdg and Hilary Longhurst - MBChB, MA, PhD, FRCP, FRCPATHah
Auckland, Wellington, New Zealand

COVID-19 has had a disastrous impact on the world. Apart from at least 6 million deaths, countless COVID-19 survivors are suffering long-term physical and psychiatric morbidity.

Hundreds of millions have been plunged into poverty caused by economic misery, particularly in developing nations. Early in the pandemic, it became apparent certain groups of individuals such as the elderly and those with comorbidities were more likely to suffer severe disease. In addition, patients with some forms of immunodeficiency, including those with T-cell and innate immune defects, were at risk of poor outcomes. Patients with immunodeficiencies are also disadvantaged as they may not respond optimally to COVID-19 vaccines and often have pre-existing lung damage. SARS-CoV-2 Omicron (B.1.529) and its subvariants (BA.1, BA.2, etc) have emerged recently and are dominating COVID-19 infections globally. Omicron is associated with a reduced risk of hospitalization and appears to have a lower case fatality rate compared with previous SARS-CoV-2 variants. Omicron has offered hope the pandemic may finally be coming to an end, particularly for vaccinated, healthy individuals. The situation is less clear for individuals with vulnerabilities, particularly immunodeficient patients. This perspective offers insight into potential implications of the SARS-CoV-2 Omicron variant for patients with immunodeficiencies. Instead of _2022 American. SARS-CoV-2, the agent responsible for COVID-19, has caused havoc around the globe. The true death toll is likely to far exceed the official number of over 6 million. COVID-19 has caused a pandemic of physical and psychiatric morbidity, which will last for generations. Large numbers of children have been orphaned, and the emotional scars will remain for the rest of their lives. Hundreds of millions of individuals have been plunged into abject poverty caused by economic misery in developing countries.1 The economic gains of the last decade or longer have been reversed by the pandemic in some nations. The origin of SARS-CoV-2 is the subject of ongoing scrutiny.2-4 The virus appears to infect individuals in 3 overlapping clinical stages (Figure 1).5 In the initial nasal phase, the virus engages cell-surface angiotensinconverting enzyme 2 (ACE2) receptors. Host proteases including transmembrane serine protease 2 (TMPRSS-2) and furin cleave the viral spike (S) glycoprotein.6 The S2 subunit of the S glycoprotein is then able to fuse with the cell membrane allowing the viral genome to enter and hijack intracellular organelles, leading to the generation of viral progeny. In the second pulmonary phase, the virus infects the lungs, most likely by aspiration from the nose and stomach.7 Patients progressing to this stage experience increasing dyspnea, lethargy, and myalgia. Computerized tomography scans of the thorax may display groundglass appearance. Laboratory parameters in the second stage show an increase in inflammatory markers including C-reactive protein. A small number of patients enter the third systemic phase where they rapidly deteriorate and suffer multiple organ dysfunction, including acute respiratory distress syndrome (ARDS). These patients often require intensive care unit admission, but mortality remains high in spite of invasive ventilation or extracorporeal membrane oxygenation. Complement activation and endothelial damage lead to activation of the coagulation cascade.8 An increase in D-dimers signifies a risk of arterial and venous thromboembolic disease. SARS-CoV-2 Omicron: light at the end of the long Pandemic Tunnel or another false dawn for Immunodeficient Patients? Rohan Ameratunga - BHB, MBChB, PhD, FRACP, FRCPA, FRCP, FRCPATH, FRCPCH, FFSc, ABMLI abc Euphemia Leung - PhDde - See-Tarn Woon, PhD, FFScbc Lydia Chan - MBChBa, Richard Steele - MBChB, FRACP, FRCPAbf Klaus Lehnert - PhDdg and Hilary Longhurst - MBChB, MA, PhD, FRCP, FRCPATHah Auckland, Wellington, New Zealand. Early in the pandemic, it became apparent that there was a steep age-related mortality gradient with poor outcomes in patients over 80 years of age.9 Children are frequently infected but are often asymptomatic. In addition, patients with comorbidities including obesity, diabetes mellitus, coronary artery disease, hypertension, malignancy, renal, and pulmonary disease are at increased risk of severe outcomes.9-11 The basis for these host susceptibilities is incompletely understood. Current data also indicate racial and ethnic differences in adverse outcomes from COVID-19.12 Patients of Black, Hispanic, Maori, Pacifika, and South Asian origin are at risk of severe outcomes. The reasons for these ethnic susceptibilities are not fully understood. Inequitable access to health care and an increased burden of comorbidities may partly underlie these disparities.13

The Immune Response to Covid-19

The immune response to COVID-19 is now better appreciated. In the initial nasal phase, the innate immune response is muted.14 SARS-CoV-2 is able to silence cytoplasmic viral sensors by a variety of mechanisms including coating double stranded viral RNA in a membrane. Viral RNA is also capped impeding the response of molecules such as melanoma differentiation associated protein 5. Retinoic acid-inducible gene-I-like receptors are ubiquitinated leading to degradation. Consequently, the incubation period is asymptomatic, and infected individuals can unwittingly infect others. Recent data suggest that wearing masks reduces transmission within households.15 Later in the pulmonary and systemic phases, the innate immune system aggravates the disease.16 There is neutrophilia, and recruitment of neutrophils and macrophages (via monocytes) to the lungs can lead to a cytokine storm with the production of high concentrations of IL-6 and tumor necrosis factor. Activation of the inflammasome can lead to pyroptosis. Uncontrolled activation of the innate immune system underlies ARDS and multiple organ dysfunction. Neutralizing anti-interferon antibodies play an important role in amplifying disease severity.17 These antibodies are present in higher titers in many patients who are severely affected by COVID-19. The adaptive immune system is also subverted by the virus. The role of antibodies in the outcome of COVID-19 is uncertain.18 There is evidence for both protection and aggravation of disease by antibodies.18 In severe cases, there is a risk of antibody disease enhancement.19 In contrast, there is increasing evidence that cellular immune responses play a crucial role in both the outcome of COVID-19 and long-term protection after infection or vaccination. 20-22 A low avidity or delayed T-cell response is associated with severe outcomes in COVID-19.20 An efficient early T-cell response can protect against SARS-CoV-2 and even abort the infection before quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) tests become positive.23

Sars-Cov-2 and Immunodeficiency disorders

Patients with primary immunodeficiency disorders have provided valuable insights into the role of various components of the immune system in the protective response to SARS-CoV-2.24 Current data indicate that patients with innate immune system or T-cell defects have worse outcomes, attesting to the importance of these components of the immune response.25 In contrast, most patients with X-linked agammaglobulinemia (XLA), without comorbidities, appear to be protected from severe disease.26-29 This is evidence that antibodies in some circumstances can be harmful. The specific implications of the SARS-CoV-2 Omicron infection for immunodeficient patients are discussed in more detail below.

Viral Evolution

There has been a poorly coordinated global response to COVID-19. Although effective vaccines and therapeutics have been developed, there have been political, financial, and logistical barriers hindering vaccine uptake, resulting in vaccine inequity. A substantial proportion of the African population remains unvaccinated and vulnerable to COVID-19. Vaccine hesitancy in developed countries has also left large numbers of patients unvaccinated. Consequently, the virus has been able to circulate widely resulting in the selection, emergence, and dominance of increasingly infectious variants. These SARS-CoV-2 variants  have presented as successive waves of infection.

The Omicron Variant of Sars-Cov-2

Omicron (B.1.529) and its subvariants (BA.1, BA.2 etc) are the latest highly infectious SARS-CoV-2 strains to emerge in November 2021.30 Within a few weeks of its first discovery in Southern Africa, Omicron has displaced the previous incumbent, Delta (B.1.617.2), and now dominates global COVID-19 infections.31 Omicron reaches very high viral loads during the nasal incubation period, which may underlie its infectiousness.32,33 Omicron is also able to infect vaccinated individuals as well as those previously infected with other SARS-CoV-2 variants.34,35 These observations underlie its high reproduction number (R0). Apart from being highly transmissible, Omicron appears to fundamentally differ from previous SARS-CoV-2 strains. From a clinical perspective, the disease seems to be less severe with a lower rate of ARDS, hospitalization, and death.36 Anosmia, which was a characteristic feature of previous SARS-CoV-2 variants, appears to be much less common with Omicron. In contrast, gastrointestinal symptoms including vomiting and diarrhea are more prominent features of Omicron infection SARS-CoV-2 Omicron infections have implications for the treatment of COVID-19. Immunosuppressive drugs such as dexamethasone, tocilizumab, and baricitinib are effective in patients suffering from ARDS from previous SARS-CoV-2 variants. Given that Omicron is less prone to cause ARDS, this may alter the risk ratio for administering dexamethasone, given the increased risk of mucormycosis in diabetic patients. Omicron may also be less prone to cause inappropriate complement activation and endothelial damage, leading to activation of the clotting cascade. Arterial and venous thromboembolic events may be less likely. Trials of anticoagulants may need to revisited, as the risk of adverse effects from these medicines may exceed the risks of thromboembolic disease caused by Omicron. At the time of writing, it is unknown if Omicron will cause sequelae of COVID-19 including long COVID. Long COVID is a disabling syndrome where patients experience lethargy, chest pain and neurological symptoms including autonomic instability and loss of clarity of thought (brain fog).37 If long COVID is due to a dysfunctional immune response, this syndrome might be less likely to occur with SARS-CoV-2 Omicron infection. SARS-CoV-2 could also cause long COVID by invading the brain through the olfactory nerves.38 Given the lower rate of anosmia with Omicron, this might suggest a lower risk of long COVID. A third nonmutually exclusive possibility is that long COVID is the result of microthrombi causing organ ischemia.39 If the thromboembolic risk is lower with Omicron, it might indicate a lower incidence of long COVID. It also remains to be determined if Omicron is associated with the same risk of severe autoimmunity or other rare syndromes such as multisystem inflammatory syndrome of children, seen with previous SARS-CoV-2 variants.40

Molecular Differences between Omicron and other Sars-Cov-2 Variants

There have been recent insights into the molecular biology of SARS-CoV-2 Omicron, which may underlie some of these clinical and epidemiological observations. The S glycoprotein of Omicron has over 30 mutations, and the nucleocapsid protein has 2 mutations compared with previous variants. This changes its conformation and allows the virus to bind with high affinity to ACE2, but it seems to be less susceptible to the action of proteases such as TMPRSS-2.41-44 This impedes cellular fusion, and Omicron appears to infect pulmonary alveoli at a much lower frequency compared with previous SARSCoV-2 variants. This is seen in vitro, where Omicron is less infectious for lung alveoli than other SARS-CoV-2 variants.45 The lower tropism for alveolar and other cells is presumably why ARDS and multiple organ dysfunction are less severe with Omicron. The disease outcome of COVID-19 is primarily determined by the dysregulated immune response to SARS-CoV-2.46 Its milder nature suggests that Omicron is less prone to provoke a severe cytokine storm leading to ARDS and multiple organ dysfunction. It also suggests that Omicron is less likely to cause severe T-cell dysregulation compared with previous SARS-CoV- 2 variants.46 Dysregulated T-cell immunity is one of the key correlates of severe COVID-19.18

Implications For Diagnosis, Prevention, And Treatment Of Sars-Cov-2 Omicron Infections

SARS-CoV-2 Omicron infection has implications for diagnostic testing. Because the receptor binding domain (RBD) of Omicron has multiple mutations, the current testing strategy may need to be revised. Rapid antigen tests (RATs) may not detect Omicron with the same accuracy as previous SARS-CoV-2 variants.47,48 The BA.2 variant of Omicron may not be identified by some current RT-qPCR tests and has been described as a “stealth virus” in the popular press.49 Retrospective sero-epidemiological antibody tests may also be negative in unvaccinated, Omicron infected individuals when measured by older assays. The antigenic target may have to be altered to the Omicron RBD. It will be important for such antibody assays to be carefully evaluated in external quality assurance programs to determine their sensitivity and specificity for different SARS-CoV-2 variants. Of even more concern, current data suggest that Omicron is able to evade vaccine-induced antibodies.50-53 A booster vaccine however mitigates some of this loss of vaccine efficacy in healthy persons.54-57 Fortunately, T-cell responses to Omicron are mostly preserved in healthy vaccinated individuals.58-61 As noted, T cells play a crucial role in the outcome of COVID-19 as well as longterm protection after either infection or vaccination. This indicates that the apparent loss of vaccine efficacy against Omicron is overestimated by antibody neutralization assays alone. Because of the antigenic shift caused by multiple RBD mutations, Omicron appears to evade several previously effective monoclonal antibodies.62 Most monoclonal antibodies have been derived from COVID-19 survivors of the ancestral Wuhan variant or mice immunized with early SARSCoV-2 variants. The E484A and N501Y mutations of the Omicron RBD underlie much of the monoclonal and vaccine antibody evasion.63- 65 Some monoclonal antibodies, which bind outside the RBD, such as sotrovimab, have retained efficacy for early subvariants of Omicron.66 On the positive side, Omicron appears to be at least as susceptible to remdesivir and molnupiravir, compared with previous SARS-CoV-2 variants.67 Paxlovid has also retained its efficacy to Omicron. Given that the nasal phase is much shorter, these drugs will have to be administered early in the infection. This will require access to accurate diagnostic testing with a rapid turnaround time. Alternatively, these drugs could be used as prophylaxis in high-risk situations

Discussion: Implications of Sars-Cov-2 Omicron Infection for Immunodeficient Patients

The emergence and global dominance of the Omicron (and its subvariants) of SARSCoV-2 has far-reaching implications for the pandemic in general and immunodeficient patients, in particular. SARS-CoV-2 Omicron will lead to revision of the current understanding of the immunopathology of COVID-19. Omicron may need to be considered a new infection with some overlapping features of previous SARSCoV-2 variants.18 SARS-CoV-2 Omicron infection is likely to impact the disease severity and prognosis of immunodeficient patients.68 Immunodeficient patients often have pre-existing chronic lung disease including bronchiectasis.69 Older immunodeficient patients with chronic lung disease and other comorbidities may be less susceptible to severe outcomes from Omicron infection compared with previous SARS-CoV-2 variants.70 As with the general population, the case fatality rate in immunodeficient patients may be lower with Omicron. Future data will confirm the accuracy of this prediction. The increased susceptibility of patients with impaired innate immunity or T-cell defects, noted with previous variants, will need to be determined for Omicron. Future case series or registries should specify the SARS-CoV-2 variant infecting each immunodeficient patient, either by viral genotyping or epidemiological information on the variant(s) circulating in the community at the time. Apart from the potential inaccuracy of RATs, RT-qPCR, and antibody tests, there are specific implications for the diagnosis of Omicron in immunodeficient patients. Patients with XLA, for example, are unable to generate antibodies but have preserved cellular immune responses to COVID-19 vaccines.71 Furthermore, subcutaneous and intravenous immunoglobulin preparations now have high titers of SARS-CoV-2 antibodies.72 There is thus an urgent need for diagnostic T-cell assays for SARS-CoV-2, for immunodeficient patients.73 T-cell assays using the Omicron RBD and other antigens including the Nucleocapsid protein may identify breakthrough infections. Commercial T-cell assays to SARS-CoV-2 are likely to become obsolete given the rapid viral evolution noted to date. Diagnostic laboratories with the relevant experience should develop these assays urgently.74,75 The RBD can be rapidly altered by these laboratories in the event a new SARS-CoV-2 variant emerges. In the future, these assays may indicate the efficacy of vaccines in immunodeficient patients and provide valuable information on the need for other treatments such as prophylactic drugs or monoclonal antibodies. SARSCoV2 T-cell assays will enable personalized medicine for COVID-19 in immunodeficient patients.

As noted, remdesivir and molnupiravir may be more effective for Omicron than previous SARS-CoV-2 variants. This is likely to disproportionately benefit immunodeficient patients infected with SARS-CoV-2 Omicron. It is possible that combinations of such drugs will prove very effective in mitigating severe outcomes in immunodeficient patients and others with comorbidities. Currently, there is a global shortage of these newer more effective drugs. Early variants of Omicron have fortunately retained sensitivity to Evusheld (tixagevimab and cilgavimab), sotrovimab and bebtelovimab.76 These can be used as prophylaxis or in the early stages of Omicron infection to reduce the risk progression to the pulmonary and systemic phases. It is likely to be of disproportionate benefit to immunodeficient patients as well as others at high risk of adverse outcomes. Currently available monoclonal antibodies will need to be re-evaluated for efficacy against Omicron and each of its subvariants.77 It is likely that new monoclonal antibodies will need to be developed from Omicron convalescent individuals. In contrast to many monoclonal antibodies, the NZACE2-Patari project may prove to be very effective against SARSCoV- 2 Omicron as it is based on modified ACE2 receptors.7,78 The project aims to intercept SARS-CoV-2 in the nose and reduce the burden of virus infecting the lungs. Viral evolution leading to reduced ACE2 binding is unlikely to be tolerated and will lead to loss of pathogenicity. If successful in future trials, this drug could be used in combination with other antiviral drugs. If proved to be effective, it could be used as prophylaxis particularly in patients with suboptimal responses to vaccines. Immunodeficient patients are at risk of chronic COVID-19.79,80 In chronic COVID-19, there is a stalemate between SARS-CoV-2 and a suboptimal immune response. Patients with chronic COVID-19 shed virus for weeks or months and are at risk of intrahost viral evolution leading to the emergence of dangerous vaccine and antibody evasion mutants. It is a public health emergency and must be prevented at all costs. It is currently too early to determine the risk of chronic COVID-19 with Omicron and its newer subvariants. If Immunodeficient patients are vaccinated and have early access to effective antiviral therapeutics, chronic COVID-19 may be less likely. Omicron will lead to reassessment of previously ineffective COVID-19 therapies.81 Treatments such as convalescent plasma infusions might be more effective for SARS-CoV-2 Omicron than for previous variants. In immunodeficient patients suffering from chronic COVID-19 from previous SARS-CoV-2 variants, convalescent plasma infusions resulted in the emergence of vaccine and monoclonal antibody Resistant clades.82 Although chronic COVID-19 may be less likely with Omicron, in the event of such cases, convalescent plasma infusions from Omicron survivors may be more efficacious compared with previous SARS-CoV-2 variants. It would be sensible to recruit younger Omicron survivors as plasma donors, who are less likely to have neutralizing anti-interferon antibodies. Given that there may be less perturbations of cellular immunity, perhaps protection against Omicron is more dependent on antibodies compared with previous SARSCoV-2 variants. Future studies will need to test this hypothesis. The protective role of subcutaneous immunoglobulin/intravenous immunoglobulin preparations containing high titres of anti-Omicron antibodies will also need to be studied. Preventing COVID-19 by vaccination is problematic in immunodeficient patients, as by definition many have suboptimal responses to vaccines.83,84 Two recent studies of common variable immunodeficiency disorders (CVID) however have shown that at least some of these patients are able to respond to vaccine challenges.85 The majority of patients had excellent responses to tetanus toxoid and Haemophilus influenzae type B vaccine in the NZ hypogammaglobulinemia and CVID studies.86 Two studies have shown that patients with CVID are able to respond partially to COVID-19 vaccines.87,88 It is possible that this partial response to COVID-19 vaccines confers disproportionate protection for immunodeficient patients. Three or 4 primary COVID-19 vaccine doses may provide adequate protection against severe outcomes in such patients.89,90 Heterologous vaccination with an mRNA vaccine followed by an adenovirusbased or subunit vaccine provides robust immunity in healthy persons.91 Such a strategy should be considered in immunodeficient patients. The risk of SARS-CoV-2 infection far exceeds the very small risk of COVID-19 vaccines in healthy and immunodeficient patients.92 Hybrid immunity, in patients who have had COVID-19 followed by vaccination, provides robust long-term protection in healthy93 and immunodeficient patients.94 If Omicron has a low case-fatality rate, it could serve as a highly effective “live attenuated virus vaccine” in both vaccinated healthy persons and many vaccinated immunodeficient patients. Omicron may boost those with pre-existing immunity and could “immunize” others who are unvaccinated. Omicron may therefore protect against future more virulent strains of SARS-CoV-2 and herald the end of the current pandemic. If this optimistic prediction proves accurate, Omicron may be the light at the end of the very long pandemic tunnel rather than another false dawn for immunodeficient patients. J.Allergy Clin Immun Vol 10, no 9. AMERATUNGA ET A