key: cord-0689813-odhtj8hn
authors: Ameratunga, Rohan; Longhurst, Hilary; Steele, Richard; Lehnert, Klaus; Leung, Euphemia; Brooks, Anna E.S.; Woon, See-Tarn
title: Common Variable Immunodeficiency Disorders, T cell responses to SARS-CoV-2 vaccines and the risk of Chronic COVID-19
date: 2021-06-25
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.06.019
sha: 1f9f6f01a30650b1579ed5a8a23ac5a73c0e5cd3
doc_id: 689813
cord_uid: odhtj8hn

COVID-19 has had a calamitous effect on the global community. In spite of intense study, the immunological response to the infection is only partially understood. In addition to older age and ethnicity, patients with co-morbidities including obesity, diabetes, hypertension, coronary artery disease, malignancy, renal and pulmonary disease, may experience severe outcomes. Some patients with primary and secondary immunodeficiencies also appear to be at increased risk from COVID-19. In addition to their vulnerability to SARS-CoV-2, patients with primary immunodeficiencies (PIDs) often suffer from chronic pulmonary disease and may not respond to vaccines, exacerbating their long-term risks. Patients with Common Variable Immunodeficiency disorders (CVID), the most frequent symptomatic PID in adults and children, have a spectrum of B and T cell defects. It may be possible to stratify their risk of severe COVID-19 based on age, ethnicity, the severity of their T cell defect as well as the presence of other co-morbidities. Patients with CVID and other immunodeficiencies are at risk of chronic COVID-19, a dangerous stalemate between a suboptimal immune response and SARS-CoV-2. Intra-host viral evolution could result in the rapid emergence of vaccine resistant mutants and is a public health emergency. Vaccination and prevention of Chronic COVID-19 in immunodeficient patients is therefore of the highest priority. Having a reliable diagnostic assay for T cell immunity to SARS-CoV-2 is critical for evaluating responses to vaccines in these patients. New treatments such as NZACE2-Pātari for COVID-19, are likely to be of particular benefit to immunodeficient patients, especially those who fail to mount a robust T cell response to vaccines.

COVID-19 has had a disastrous impact on the international community. SARS-CoV-2, the agent 72 responsible for the disease, originated in Wuhan City, China in late 2019. 1 The origin of the infection is 73 the subject of intense study. 2, 3 It has since rapidly spread globally leading to calamitous medical, 74 economic and societal consequences. The current death toll in excess of 3.7M, is likely to continue 75 rising until there is universal deployment of effective vaccines and therapeutics. 76

Of grave concern is the rapid emergence and dominance of several new variants of the virus which are 77 more infectious than the original founder (Wuhan) strain. These include the early D614G variant as well On the more hopeful side has been the successful trials and roll-out of multiple vaccines. The ultimate 82 global death toll will be determined by a race between the deployment of vaccines and emergence of 83 newer escape mutants. 7 Escape mutants will rapidly arise in areas where the virus is not contained and 84 allowed to circulate. 85

COVID-19 appears to progress in three overlapping clinical stages. 8 In the first asymptomatic phase the 87 nasal mucosa is infected. During early infection the spike (S) glycoprotein engages cell surface ACE2 to 88 facilitate viral entry. 9 Host proteases including TMPRSS-2 cleave the S glycoprotein allowing the S2 89 subunit to fuse with the cellular membrane. 10 Fusion of the virus with the cell allows viral RNA to enter 90 and hijack intracellular organelles leading to production of daughter virus. 91

Following this initial stage, which lasts approximately five days, some patients enter a second pulmonary 92 phase, probably from microaspiration of the virus. 11 This is characterized by dyspnea, fatigue and fever. 93 CT scans of the thorax often show ground-glass appearances in this stage of the infection. 94

Patients who progress to the third systemic viremic phase are at high risk of multi-organ failure, leading 95 to Intensive Care Unit (ICU) admission. 12 In spite of invasive ventilation and extracorporeal membrane 96 oxygenation, mortality remains high in those experiencing viral sepsis. 13 97

J o u r n a l P r e -p r o o f There is a steep age-related mortality gradient with rates approaching 30% in those over 80 years. 14 99

Patients with co-morbidities including obesity, hypertension, coronary artery disease, malignancy, 100 immunodeficiency, renal and pulmonary impairment are at increased risk of adverse outcomes. 14-16 101

Precisely how these conditions predispose to severe disease is incompletely understood. 102

Black and South Asian patients are at increased risk of adverse outcomes. 17 These ethnic predispositions 103 may in part be confounded by sociodemographic disparities including higher prevalence of co-104 morbidities and poor access to healthcare. 18 105

The immunological conundrum posed by SARS-CoV-2 106

The immunological response to SARS-CoV-2 is incompletely understood. 19, 20 In contrast to other 107 viruses, SARS-CoV-2 is able to effectively evade the innate immune system during the first asymptomatic 108 phase of the infection. 21 Anti-interferon antibodies also contribute to disease severity. 23 The complement cascade appears to 112 aggravate COVID-19 and NK cell responses are impeded. 24 Evasion of the innate immune system allows 113 the virus to multiply exponentially, unchallenged, during the first nasal phase of the infection. 114

The virus also subverts the adaptive immune system. 25 Persistent lymphopenia is an ominous marker of 115 severe disease. Antibodies appear to vary in quality and in some patients, the antibody response does 116 not appear to be protective. Many patients dying from COVID-19 had both high viral loads and antibody 117 titres, indicating the antibodies were unable to neutralize the virus. 26 There is also concern antibody 118 disease enhancement (ADE) could occur in some patients. 27 The basis of ADE is only partly 119 understood. 26 120

The role of T cells in early disease remains to be conclusively established. 28 Uncoordinated over or 121 underactivation of T cells may lead to worse outcomes. 29, 30 Low avidity T cell responses were associated 122 with severe disease. 28 Very recent studies suggest an effective early T cell response was correlated with 123 milder disease. 31-33 124 In contrast, long-term protection is linked to the generation of a robust memory T cell response. 34, 35 In 125 many patients with mild COVID-19, antibody responses were muted but these individuals generated an 126 effective cellular response. 35, 36 This would allow a rapid anamnestic reaction to reinfection. High titres 127 J o u r n a l P r e -p r o o f of neutralizing antibodies to SARS-CoV-2 are likely to be a surrogate marker of a robust protective T cell 128 response. 129

Like COVID-19, Common Variable Immunodeficiency Disorders (CVID) are an immunological conundrum. 131 37 By definition, patients with CVID do not have a known cause for their late onset antibody failure 132 leading to immune system failure. 38-40 CVID is the most frequent symptomatic primary 133 immunodeficiency in adults and children. Although regarded as a late onset immunodeficiency, many 134 patients develop symptoms in early childhood. 41, 42 Most CVID patients suffer from recurrent and severe 135 infections, while a substantial minority present with autoimmune and inflammatory sequelae. 43 136

In non-consanguineous populations, approximately 25% of CVID patients have a causative genetic 137 defect. 44, 45 In consanguineous societies, the rates are much higher, mostly due to highly penetrant 138 autosomal recessive mutations. 46 Understanding the spectrum of immunological disease severity in CVID and CVID-like disorders may 157 allow better predictions of who may be at increased risk of COVID-19 complications and which patients 158 may fail to respond to vaccines. Some studies have indicated patients with CVID and CVID-like disorders 159 are at high risk of severe outcomes, 53-58 although this is not consistent. [59] [60] [61] [62] In contrast, patients with X-160 linked agammaglobulinemia (XLA) appear to have milder disease. [63] [64] [65] [66] In some cases, antibodies may 161 have the potential to be harmful (ADE) and patients with XLA may be protected against SARS-CoV-2. 162

These observations also infer T cells play a dominant role in mitigating disease severity in COVID-19. 67 163

Analogous to XLA, patients with CVID who have a pure antibody defect may be at lower risk than those 164 with mostly cellular defects (Figure 1) . Some of the more severe outcomes in CVID and CVID-like 165 patients may have occurred in those with predominant impairment of T cell function. 55, 57 It is also likely 166 the immune defect in CVID will be exacerbated by older age, ethnicity and by other well-known co-167 morbidities including obesity, diabetes etc. (Figure 1) . A recent study suggested some CVID patients 168

have Common Cold Coronavirus (HCoV) cross-reacting T cells, which could potentially protect against 169 SARS-CoV-2. 68 All of these complexities may explain the varying outcomes of CVID patients with COVID-170

The outcome of COVID-19 in CVID patients might be predicted by assessing both pathogen and host risk vaccines, which are in various stages of production and deployment (Table 1) . Several vaccines have 188 now received emergency authorization for use. Their efficacy varies between 50% to over 90% in 189 preventing disease following exposure to SARS-CoV-2. In the short term, global deployment of vaccines 190 will face significant financial and logistical challenges. Eventual broad vaccine uptake will lead to herd 191 immunity and reduced transmission of the virus, with a lower probability of vaccine-resistant mutants 192 evolving. 193 Currently there are many different strategies for immunization against SARS-CoV-2 ( Table 1) Two recent studies support this approach. The NZHS is a long-term prospective study of patients with 206 hypogammaglobulinemia who did not meet criteria for CVID at the time of enrolment. 49 It describes the 207 natural history of patients with milder forms of hypogammaglobulinemia. The majority of 208 asymptomatic patients with mild hypogammaglobulinemia (IgG 5-6.9 g/l) have remained well for over a 209 decade. It was apparent most patients in the NZHS had excellent responses to Haemophilus influenzae 210 type B (HIB) vaccine and tetanus toxoid. In contrast, responses to diphtheria toxoid and S pneumoniae 211 were muted and did not differentiate patients who remained well from those who progressed to 212 SCIG/IVIG treatment. These observations demonstrate vaccine responses are not uniformly impaired in 213 patients with mild hypogammaglobulinemia. 214

Similarly, in the recent NZ CVID study (NZCS) many patients who underwent vaccine challenge responses 215 prior to SCIG/IVIG treatment had excellent responses to HIB and tetanus toxoid but not to diphtheria or 216 S. pneumoniae. 42, 83 It is apparent there is considerable heterogeneity in responses to vaccines within 217 the spectrum of CVID. 218

These observations raise critical questions about the efficacy of COVID-19 vaccination in patients with 219 CVID. It seems likely patients with CVID will have variable responses to different COVID-19 vaccines, 220 compared to persons with normal immune function. There is for example, insufficient data to indicate if 221 mRNA based vaccines will be more effective in immunodeficient patients than those based on an 222 adenovirus carrier, as seen in healthy individuals. 84 It is hoped that responses to SARS-CoV-2 mRNA 223 vaccines are similar to tetanus and HIB responses seen the NZHS and NZCS. 49, 83 Both vaccine factors and 224 host immunological factors shown in Figure 1 will influence the probability of protection in individual 225 CVID patients. It is possible patients with poor T cell responses will require multiple doses or 226 combinations of vaccines for optimal protection. COVID-19 vaccination will require a nuanced, 227 individualized approach to patients with CVID and other immunodeficiency disorders. 228

A major challenge will arise in determining protective immunity to COVID-19 in both healthy persons 230 and patients with immunodeficiency. With greater community prevalence of COVID-19 as well as 231 increased vaccine uptake, many plasma donors will be seropositive to SARS-CoV-2. As a result, most 232 SCIG/IVIG preparations will soon have high titres of SARS-CoV-2 antibodies. 85 Conversely, some 233 antibody deficient patients (e.g. XLA) may have protective T cell immunity to SARS-CoV-2 following 234 COVID-19 infection or vaccination, but will be unable to produce antibodies to the virus. It will not be 235 possible to determine which immunodeficient patients are susceptible and who may have protective 236 immunity based on antibody tests. 237

The critical question is whether patients with CVID (and other immunodeficiency disorders) will 238 generate robust memory T cell responses to these vaccines. Commercial T cell assays based on the S 239 glycoprotein may rapidly become obsolete because of viral evolution resulting in the emergence of 240 multiple variants. The case for diagnostic laboratories urgently developing in-house T cell assays to 241 SARS-CoV-2 has been made. 86 It will be important for diagnostic laboratories to verify the precision of 242 the assay in vitro and validate its accuracy clinically to ISO 9001 and 17025 standards. The NZACE2-Pātari project and other potential SARS-CoV-2 treatments for immunodeficient patients 270 (Pātari -Māori verb for decoy, which will lead to interception) 271

There is currently no widely available curative treatment for COVID-19. Repurposing existing drugs for 272 COVID-19 has been disappointing. Given its subversion of the immune system, absence of reliable 273 treatments and the scale of the pandemic, all therapeutic approaches must be urgently funded and 274 trialed, either alone or in combination. 275 J o u r n a l P r e -p r o o f Passive immunotherapy with convalescent sera is used in some cases. 90, 91 At this time it is unknown if 276 SARS-CoV-2 antibody containing SCIG/IVIG preparations or therapeutic CoVIg hyperimmune globulin will 277 reduce mortality from 93 There is a risk these preparations may enhance intra-host viral 278 evolution. 94, 95 If used in CVID patients it is also uncertain if such preparations will help or hinder 279 protective T cell responses to COVID-19 vaccines. This may be determined by the type of vaccination as 280 well as the timing of such treatments. It is possible CoVIg hyperimmune globulin or SCIG/IVIG 281 containing antibodies to SARS-CoV-2, given at the time of vaccination may enhance T cell responses by 282 facilitating antigen uptake from subunit vaccines. In the case of live vaccines, such antibody preparations 283 may neutralize the virus and impede T cell responses. This is less relevant for CVID as live vaccines are 284 contraindicated in patients with T cell defects. For mRNA vaccines, the timing of such antibody 285 preparations may not have any effect on the cellular immune response to the virus. 286

Monoclonal antibodies such casirivimab, bamlanavimab, imdevimab and etesevimab have received 287 emergency authorization for mild disease. As noted above, viral evolution including the E484K mutation 288 could render some of these drugs ineffective. 5-7 TMPRSS-2 inhibitors such as camostat mesilate have 289 not proven effective in clinical trials. 96 Other SARS-CoV-2 protease inhibitors are in development. 97 The 290 catalytic site of ACE2 is distant to the SARS-CoV-2 binding site and ACE inhibitors (captopril, quinapril 291 etc.) do not prevent infection. 292

The NZACE2-Patari project was recently described (Figure 2 ). 98 The NZACE2-Pātari project comprises 293 modified ACE2 molecules (N90D, R273A) to intercept the virus in the nose to mitigate the pulmonary 294 and systemic phases. 99 NZACE2-Patari will be administered on several occasions over two days by a 295 nasal dropper at the onset of infection. 99 The NZACE2-Pātari/SARS-CoV-2 complexes would be 296 swallowed leading to hydrolytic destruction of the virus in the stomach. If proven safe and effective in 297 clinical trials, this treatment would be particularly attractive for CVID patients who have poor T cell 298 responses to SARS-CoV-2. 299

The importance of the NZACE2-Pātari project and other anti-viral treatments was underscored by recent 300 cases of vaccine induced thrombosis and thrombocytopenia (VITT). VITT appears to be mostly linked to 301 some adenovirus based COVID-19 vaccines. 100, 101 These rare adverse events may cause reputational 302 damage to COVID-19 vaccines in general, leading to increased vaccine hesitancy and delay in achieving 303 herd immunity. In turn, there will be many more unvaccinated persons in the community allowing the 304 virus to circulate and potentially mutate.

Emergence of newer virulent strains will leave 305 immunodeficient patients even more vulnerable to Patients with primary and secondary immunodeficiencies, including CVID, have been described with 307 prolonged viral shedding, termed Chronic 66, [102] [103] [104] [105] [106] Chronic COVID-19 infection may be a 308 stalemate between SARS-CoV-2 and a sub-optimal cellular immune response. Intra-host viral evolution 309 in chronic COVID-19 could lead to the emergence of dangerous vaccine-evasion mutants as well as 310 variants resistant to monoclonal antibodies. 94, 95, 107 Most patients developing chronic COVID-19 appear 311 to have had combined immune defects. Chronic COVID-19 is a public health emergency and preventing 312 this condition should be of the utmost priority. This emphasizes the importance of urgently vaccinating 313 and evaluating T cell responses to SARS-CoV-2 variants in immunodeficient patients to reduce the risk of 314 chronic It is gratifying that far fewer patients with PIDs have been reported in the literature than might have 316 been expected based on global numbers of COVID-19 infections. Although there may be under-317 reporting, it also suggests patients with PIDs were successfully advised to shelter in place early in the 318 pandemic to avoid infection. The critical question is whether these uninfected immunodeficient 319 patients will respond to vaccines and whether vaccine combinations might compensate for their 320 immune system failure. Having a validated diagnostic assay for T cell responses to SARS-CoV-2 is an 321 essential part of management of these patients. 86 322 323 J o u r n a l P r e -p r o o f

A pneumonia outbreak associated with 325 a new coronavirus of probable bat origin

COVID-19: animals, 327 veterinary and zoonotic links

The genetic structure of SARS-CoV-2 does not rule out a laboratory 329 origin: SARS-COV-2 chimeric structure and furin cleavage site might be the result of genetic 330 manipulation

Tracking Changes in 332 SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus

CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Structural and functional 338 ramifications of antigenic drift in recent SARS-CoV-2 variants

Escape from neutralizing 340 antibodies by SARS-CoV-2 spike protein variants

Clinical features of patients infected with 2019 342 novel coronavirus in Wuhan, China

Characterization of the receptor-binding 344 domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral 345 attachment inhibitor and vaccine

Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease 348 Inhibitor

Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

Baseline Characteristics 353 and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy 354 Region

Extracorporeal Membrane Oxygenation for 356

Coronavirus Disease 2019-Induced Acute Respiratory Distress Syndrome: A Multicenter 357 Descriptive Study

Clinical course and risk factors for mortality of adult 359 inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical course and mortality risk of severe COVID-19

Impacts of immunosuppression and immunodeficiency on 364 COVID-19: A systematic review and meta-analysis

Evidence mounts on the disproportionate effect of COVID-19 on ethnic minorities

Economic, and 368 Health Inequality and COVID-19 Infection in the United States

Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2) and Implications for Vaccines

Immune determinants of COVID-19 disease presentation and severity

A Comprehensive Review of Severe Acute Respiratory 376 Syndrome Coronavirus 2

Innate immune evasion by SARS-CoV-2: Comparison with SARS-CoV

Auto-antibodies 380 against type I IFNs in patients with life-threatening COVID-19

Complement cascade in severe forms of COVID-19: 382 Recent advances in therapy

T cell responses in patients with COVID-19

CoV-2 antibodies from a convalescent donor associates with distinct epitopes on the RBD

Is antibody-dependent enhancement playing a role in COVID-19 pathogenesis? Swiss 389

Low-Avidity CD4(+) T Cell 391 Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19

Phenotype and 394 kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress 395 syndrome

Early induction of 400 functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in 401 COVID-19 patients

Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and 404 Disease Severity

CoV-2 infections in health care workers with pre-existing T cell response: a prospective cohort 407 study

CoV-2 assessed for up to 8 months after infection

Robust T Cell 411 Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19

CoV-2-Specific Immune Memory Persists after Mild COVID-19

Defining Common Variable Immunodeficiency Disorders in 416 2020

New diagnostic criteria for common 418 variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or 419 subcutaneous immunoglobulin

International Consensus Document (ICON): Common Variable Immunodeficiency Disorders

The European 424 Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of 425 Inborn Errors of Immunity

Clinical picture 427 and treatment of 2212 patients with common variable immunodeficiency

Bronchiectasis is 430 associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable 431 Immunodeficiency Disorders cohort study

Assessing Disease Severity in Common Variable Immunodeficiency Disorders 433 (CVID) and CVID-Like Disorders

Perspective: Application of the American College of 437

Medical Genetics Variant Interpretation Criteria to Common Variable Immunodeficiency 438 Disorders

Clinical implications of 440 systematic phenotyping and exome sequencing in patients with primary antibody deficiency

Common Variable Immunodeficiency Disorder in the Era of Genome Sequencing

Keeping it in the family: the 446 case for considering late-onset combined immunodeficiency a subset of common variable 447 immunodeficiency disorders

The Natural History of Untreated Primary 449 Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common 450 Variable Immunodeficiency Disorders (CVID)

Epistatic interactions 452 between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency 453 disorder and systemic lupus erythematosus

Digenic inheritiance and epistasis in Primary Immunodeficiency Disorders

Consortium UPC-. COVID-19 in patients with primary 461 and secondary immunodeficiency: The United Kingdom experience

Severe COVID-19 in Patients 464 with B Cell Alymphocytosis and Response to Convalescent Plasma Therapy

Severe SARS-CoV-2 467 disease in the context of a NF-kappaB2 loss-of-function pathogenic variant

The clinical observation of a patient with 470 common variable immunodeficiency diagnosed as having coronavirus disease 2019

Impact of 473 SARS-CoV-2 Pandemic on Patients with Primary Immunodeficiency

Coronavirus disease 2019 in 476 patients with inborn errors of immunity: An international study

COVID-19 infection in 10 479 common variable immunodeficiency patients in New York City

A fatal case of coronavirus disease 2019 in a patient with common 482 variable immunodeficiency

Minor Clinical Impact of 484 COVID-19 Pandemic on Patients With Primary Immunodeficiency in Israel

Rapid clinical 487 recovery of a SARS-CoV-2 infected common variable immunodeficiency patient following the 488 infusion of COVID-19 convalescent plasma

A possible role for B cells 490 in COVID-19? Lesson from patients with agammaglobulinemia

Three patients with X-linked 493 agammaglobulinemia hospitalized for COVID-19 improved with convalescent plasma

Rapid recovery of a SARS-496

CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent 497 plasma

Report: 499 Convalescent Plasma, a Targeted Therapy for Patients with CVID and Severe COVID-19

SARS-CoV-2-Associated T-Cell Responses in the Presence of 502

HCoV-and 504 SARS-CoV-2 Cross-Reactive T Cells in CVID Patients

Defective 506 antigen-induced lymphocyte proliferation in the X-linked hyper-IgM syndrome

Personal protective equipment protecting 509 healthcare workers in the Chinese epicentre of COVID-19

Lightening the viral load to lessen covid-19 severity

Viral Load and the Clinical Course of COVID-19

Risk and predictive 515 factors of prolonged viral RNA shedding in upper respiratory specimens in a large cohort of 516 COVID-19 patients admitted to an Italian reference hospital

Phase I/II study of 518 COVID-19 RNA vaccine BNT162b1 in adults

An mRNA 520 Vaccine against SARS-CoV-2 -Preliminary Report

Broad and strong memory CD4(+) and 522 CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

Safety and 525 immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a 526 phase 1/2, single-blind, randomised controlled trial

The COVID-19 Vaccine Race: Challenges and 528 Opportunities in Vaccine Formulation

Viral targets for vaccines against COVID-19

BNT162b2 mRNA Covid-19 531 Vaccine in a Nationwide Mass Vaccination Setting

Diagnostic criteria for primary immunodeficiencies

Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society 534 for Immunodeficiencies)

Diagnostic criteria for common variable immunodeficiency 536 disorders

Comparison of Diagnostic Criteria for Common 538

Variable Immunodeficiency Disorders (CVID) in the New Zealand CVID Study

COVID-19 vaccine efficacy and effectiveness-the elephant 541 (not) in the room. The Lancet Microbe 2021

Non-neutralizing antibodies and limitations of 543 serologic testing for severe acute respiratory syndrome coronavirus 2 in patients receiving 544 immunoglobulin replacement products

Perspective: diagnostic 546 laboratories should urgently develop T cell assays for SARS-CoV-2 infection

Interferon-549 gamma release assay for accurate detection of SARS-CoV-2 T cell response

Pre-existing T-cell 552 immunity to SARS-CoV-2 in unexposed healthy controls in Ecuador

Interferon-Gamma Release Assay

Cellular 555 Immunity in COVID-19 Convalescents with PCR-Confirmed Infection but with Undetectable 556 SARS-CoV-2-Specific IgG

A Little) Clarity on Convalescent Plasma for Covid-19

Association of 559 Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A 560 Systematic Review and Meta-analysis

Convalescent plasma or 562 hyperimmune immunoglobulin for people with COVID-19: a rapid review

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a 565 randomised controlled, open-label, platform trial

Case Study: 567 Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised 568 Individual with Cancer

SARS-CoV-2 evolution during 570 treatment of chronic infection

Efficacy of the 572 TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind 573 randomized controlled trial

Identification of high-575 affinity inhibitors of SARS-CoV-2 main protease: Towards the development of effective COVID-576 19 therapy

Inhaled modified 578 angiotensin converting enzyme 2 (ACE2) as a decoy to mitigate SARS-CoV-2 infection

Perspective: The nose 581 and the stomach play a critical role in the NZACE2-Pātari* (modified ACE2) drug treatment 582 project of SARS-CoV-2 infection

Thrombotic Thrombocytopenia after COVID-19 585 Vaccination: In Search of the Underlying Mechanism

Mechanisms of Immunothrombosis in Vaccine-587

Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

Covid-19 and Primary Immunodeficiency: 590 One-Year Experience

COVID-19: Prolonged viral 592 shedding in an HIV patient with literature review of risk factors for prolonged viral shedding and 593 its implications for isolation strategies

SARS-CoV-2) Infectiousness Among Three 596 Immunocompromised Patients: From Prolonged Viral Shedding to SARS-CoV-2 Superinfection

Prolonged viral shedding of 599 SARS-CoV-2 in an immunocompromised patient

Prolonged SARS-CoV-2 Replication in a CAR-T-cell Therapy Recipient: A Case Study

Persistence and Evolution of 604 SARS-CoV-2 in an Immunocompromised Host

 Figure 1 . Host factors in CVID patients which could contribute to severe outcomes in COVID-19. Virus associated 607 factors include the relevant strain and the inoculum leading to infection. The severity of the T cell defect is likely 608 to compound well known risk factors including hypertension, obesity diabetes etc. Patients with severe T cell 609 defects can be identified by the types of infections, naïve and memory T cell numbers as well as in vitro 610 lymphocyte proliferation studies. 40, 69 BAME-Black and Asian Minority Ethnic, HGUS-hypogammaglobulinemia of 611 uncertain significance (defined as IgG 5-6.9 g/l). 37 LOCID-Late Onset Combined Immunodeficiency.612 Figure 2 . The NZACE2-Pātari project. Patients will be identified early in the infection by RT-qPCR or rapid antigen 613 testing. The NZACE2-Pātari will be administered several times a day to intercept SARS-CoV2, which will be 614 swallowed leading to hydrolytic destruction in the stomach. 77, 78 This is not a comprehensive list but illustrates the diverse approaches to induce protective immunity to SARS-CoV-2. The reader should consult the WHO website for up-to-date information on the rapidly changing status of vaccines against SARS-CoV-2. VITTvaccine induced thrombosis and thrombocytopenia.