SARS-CoV-2 evolution has increased resistance to monoclonal antibodies and first-generation COVID-19 vaccines: Is there a future therapeutic role for soluble ACE2 receptors for COVID-19?

COVID-19 has caused calamitous health, economic and societal consequences. Although several COVID-19 vaccines have received full authorization for use, global deployment has faced political, financial and logistical challenges. The efficacy of first-generation COVID-19 vaccines is waning and breakthrough infections are allowing ongoing transmission and evolution of SARS-CoV-2. Furthermore, COVID-19 vaccine efficacy relies on a functional immune system. Despite receiving three primary doses and three or more heterologous boosters, some immunocompromised patients may not be adequately protected by COVID-19 vaccines and remain vulnerable to severe disease. The evolution of new SARS-CoV-2 variants has also resulted in the rapid obsolescence of monoclonal antibodies. Convalescent plasma from COVID-19 survivors has produced inconsistent results. New drugs such as Paxlovid (nirmatrelvir/ritonavir) are beyond the reach of low- and middle-income countries. With widespread use of Paxlovid, it is likely nirmatrelvir-resistant clades of SARS-CoV-2 will emerge in the future. There is thus an urgent need for new effective anti-SARS-CoV-2 treatments. The in vitro efficacy of soluble ACE2 against multiple SARS-CoV-2 variants including omicron (B.1.1.529), was recently described using a competitive ELISA assay as a surrogate marker for virus neutralization. This indicates soluble wild-type ACE2 receptors are likely to be resistant to viral evolution. Nasal and inhaled treatment with soluble ACE2 receptors has abrogated severe disease in animal models of COVID-19. There is an urgent need for clinical trials of this new class of antiviral therapeutics, which could complement vaccines and Paxlovid.

An innovative Indigenous-led model for integrated COVID-19 case management in Auckland, New Zealand: lessons from implementation.

In Aotearoa/New Zealand (NZ), the Indigenous Maori population have been more severely impacted than non-Maori throughout the COVID-19 pandemic, and less well served by NZ's COVID-19 response. This case-study describes an innovative Indigenous-led service delivery model, which was designed and implemented to improve the case and contact management of Maori with COVID-19 in Auckland. We outline the context in which the conventional public health case and contact management was failing Maori and the factors which enabled Indigenous innovation and leadership. We describe the details of the model and how the approach fundamentally differed to the conventional approach to care. Qualitative and quantitative data on impact of the model are shared, along with the key barriers and enablers in the implementation of the model. The Maori Regional Coordination Hub (MRCH) model offers a valuable alternative to the conventional public health case and contact management approach, and this case study highlights lessons which may be applicable to improving the design and delivery of public health services to other Indigenous and marginalized groups.

Soluble wild-type ACE2 molecules inhibit newer SARS-CoV-2 variants and are a potential antiviral strategy to mitigate disease severity in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease of 2019 (COVID-19), has caused havoc around the world. While several COVID-19 vaccines and drugs have been authorized for use, these antiviral drugs remain beyond the reach of most low- and middle-income countries. Rapid viral evolution is reducing the efficacy of vaccines and monoclonal antibodies and contributing to the deaths of some fully vaccinated persons. Others with normal immunity may have chosen not to be vaccinated and remain at risk if they contract the infection. Vaccines may not protect some immunodeficient patients from SARS-CoV-2, who are also at increased risk of chronic COVID-19 infection, a dangerous stalemate between the virus and a suboptimal immune response. Intra-host viral evolution could rapidly lead to the selection and dominance of vaccine and monoclonal antibody-resistant clades of SARS-CoV-2. There is thus an urgent need to develop new treatments for COVID-19. The NZACE2-Patari project, comprising modified soluble angiotensin-converting enzyme 2 (ACE2) molecules, seeks to intercept and block SARS-CoV-2 infection of the respiratory mucosa. In vitro data presented here show that soluble wild-type ACE2 molecules retain the ability to effectively block the Spike (S) glycoprotein of SARS-CoV-2 variants including the ancestral Wuhan, delta (B.1.617.2) and omicron (B.1.1.529) strains. This therapeutic strategy may prove effective if implemented early during the nasal phase of the infection and may act synergistically with other antiviral drugs such as Paxlovid to further mitigate disease severity.

Patients with previous immediate hypersensitivity reactions to polyethylene glycol can safely receive the BNT162b2 mRNA COVID-19 vaccine.

Previous anaphylaxis or immediate allergic reaction to polyethylene glycol (PEG; also known as macrogol) is considered a contraindication to the BNT162b2 mRNA COVID-19 vaccine, which contains 50 ug of PEG at a molecular weight of 2000, and this component is thought to account for the higher rate of anaphylaxis seen with this vaccine (4.7 per million doses) than with other non-mRNA vaccines. However, there is evidence that both anaphylaxis to PEG and anaphylaxis to the Pfizer COVID-19 reaction may not be IgE-mediated, with patients with anaphylaxis to first dose of the Pfizer COVID-19 vaccine receiving their second dose of vaccine without no or milder reactions in a high-risk clinic setting. In New Zealand, non-PEG-containing COVID-19 vaccines were not available until late 2021. Therefore, we offered patients with known or suspected PEG anaphylaxis their first dose of Pfizer COVID-19 vaccine in a high-risk hospital clinic. Eleven patients with previous hypersensitivity to PEG (including eight with anaphylaxis) successfully received their first dose with mild or no reactions; all have now had their second doses in the community without significant reaction. Record review also showed that most patients with previous hypersensitivity reactions to pegylated asparaginase have also been successfully vaccinated. This demonstrates that previous PEG hypersensitivity, including anaphylaxis, does not exclude immunisation with the Pfizer COVID-19 vaccine.

A new paradigm for regulation of protein phosphatase 2A function via Src and Fyn kinase-mediated tyrosine phosphorylation.

Protein phosphatase 2A (PP2A) is a major phospho-Ser/Thr phosphatase and a key regulator of cellular signal transduction pathways. While PP2A dysfunction has been linked to human cancer and neurodegenerative disorders such as Alzheimer's disease (AD), PP2A regulation remains relatively poorly understood. It has been reported that the PP2A catalytic subunit (PP2Ac) is inactivated by a single phosphorylation at the Tyr307 residue by tyrosine kinases such as v-Src. However, multiple mass spectrometry studies have revealed the existence of other putative PP2Ac phosphorylation sites in response to activation of Src and Fyn, two major Src family kinases (SFKs). Here, using PP2Ac phosphomutants and novel phosphosite-specific PP2Ac antibodies, we show that cellular pools of PP2Ac are instead phosphorylated on both Tyr127 and Tyr284 upon Src activation, and on Tyr284 following Fyn activation. We found these phosphorylation events enhanced the interaction of PP2Ac with SFKs. In addition, we reveal SFK-mediated phosphorylation of PP2Ac at Y284 promotes dissociation of the regulatory Bα subunit, altering PP2A substrate specificity; the phosphodeficient Y127/284F and Y284F PP2Ac mutants prevented SFK-mediated phosphorylation of Tau at the CP13 (pSer202) epitope, a pathological hallmark of AD, and SFK-dependent activation of ERK, a major growth regulatory kinase upregulated in many cancers. Our findings demonstrate a novel PP2A regulatory mechanism that challenges the existing dogma on the inhibition of PP2A catalytic activity by Tyr307 phosphorylation. We propose dysregulation of SFK signaling in cancer and AD can lead to alterations in PP2A phosphorylation and subsequent deregulation of key PP2A substrates, including ERK and Tau.

The effect of needle length and skin to deltoid muscle distance in adults receiving an mRNA COVID-19 vaccine.

BACKGROUND: The mRNA COVID vaccines are only licensed for intramuscular injection but it is unclear whether successful intramuscular administration is required for immunogenicity. METHODS: In this observational study, eligible adults receiving their first ComirnatyTM/BNT162b2 dose had their skin to deltoid muscle distance (SDMD) measured by ultrasound. The relationship between SDMD and height, weight, body mass index, and arm circumference was assessed. Three needle length groups were identified: 'clearly sufficient' (needle exceeding SDMD by >5 mm), 'probably sufficient' (needle exceeding SDMD by ≤ 5 mm), and 'insufficient' (needle length ≤ SDMD). Baseline and follow-up finger prick blood samples were collected and the primary outcome variable was mean spike antibody levels in the three needle length groups. RESULTS: Participants (n = 402) had a mean age of 34.7 years, BMI 29.1 kg/m2, arm circumference 37.5 cm, and SDMD 13.3 mm. The SDMD was >25 mm in 23/402 (5.7%) and >20 mm in 61/402 (15.2%) participants. Both arm circumference (≥40 cm) and BMI (≥33 kg/m2) were able to identify those with a SDMD of >25 mm, the length of a standard injection needle, with a sensitivity of 100% and specificities of 71.2 and 79.9%, respectively. Of 249/402 (62%) participants with paired blood samples, there was no significant difference in spike antibody titres between needle length groups. The mean (SD) spike BAU/mL was 464.5 (677.1) in 'clearly sufficient needle length' (n = 217) compared with 506.4 (265.1) in 'probably sufficient' (n = 21, p = 0.09), and 489.4 (452.3) in 'insufficient needle length' (n = 11, p = 0.65). CONCLUSIONS: A 25 mm needle length is likely to be inadequate to ensure vaccine deposition within the deltoid muscle in a small proportion of adults. Vaccine-induced spike antibody titres were comparable in those vaccinated with a needle of sufficient versus insufficient length suggesting deltoid muscle deposition may not be required for an adequate antibody response to mRNA vaccines.

Fatal epistaxis in a case of common variable immunodeficiency: A case report and review of the literature.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease. We present a case of a patient with CVID complicated by rhinosinusitis with granulomatous inflammation. Treatment for this patient was challenging with regards recognition of the granulomatous manifestation as well as treatment in the setting immunodeficiency and was ultimately unsuccessful.

Autoinflammatory syndromes in neurology: when our first line of defence misbehaves.

Autoinflammatory syndromes result from a defective innate immune system. They are characterised by unexplained fever and systemic inflammation involving the skin, muscle, joints, serosa and eyes, along with elevated acute phase reactants. Autoinflammatory syndromes are increasingly recognised as a cause of neurological disease with a diverse range of manifestations. Corticosteroids, colchicine and targeted therapies are effective if started early, and hence the importance of recognising these syndromes. Here, we review the neurological features of specific autoinflammatory syndromes and our approach (as adult neurologists) to their diagnosis.

National audit of a hereditary and acquired angioedema cohort in New Zealand.

BACKGROUND: Hereditary angioedema (HAE) leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies, which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert), and Icatibant are available in New Zealand (Aotearoa), there are no published data available on their use. AIM: To present a national audit of HAE and acquired angioedema (AAE) in 2019. METHODS: Patients were identfied and demographical and clinical data on HAE were collected retrospectively by interview and notes review. RESULTS: The total number of known adult (48) and children (3) HAE and AAE (3) patients is 54. Of these, 41/54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant has been available for the treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis, but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one-fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested. CONCLUSIONS: Corrective actions arising from this audit will improve our capacity to provide long-term care for HAE patients and their families.

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

Background: COVID-19 has caused calamitous health, economic and societal consequences globally. Currently, there is no effective treatment for the infection. Areas covered: We have recently described the NZACE2-Patari project, which seeks to administer modified Angiotensin Converting Enzyme 2 (ACE2) molecules early in the infection to intercept and block SARS-CoV-2 binding to the pulmonary epithelium. Expert opinion: Since the nasopharyngeal mucosa is infected in the first asymptomatic phase of the infection, treatment of the nose is likely to be safe and potentially effective. The intercepted virus will be swallowed and destroyed in the stomach. There is however a limited window of opportunity to alter the trajectory of the infection in an individual patient, which requires access to rapid testing for SARS-CoV-2. The proposed strategy is analogous to passive immunization of viral infections such as measles and may be of particular benefit to immunodeficient and unvaccinated individuals.

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

Introduction: Diagnostic tests play a critical role in the management of Sars-CoV-2, the virus responsible for COVID-19. There are two groups of tests, which are in widespread use to identify patients who have contracted the virus. The commonly used reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) test becomes negative once viral shedding ceases by approximately 2-3weeks. Antibody tests directed to viral antigens become positive after the second week of infection. IgG antibody responses to the virus are muted in children, pregnant females, and those with mild symptoms. IgA and IgM antibodies rapidly wane, although IgG antibodies directed to the receptor-binding domain (RBD) of the spike (S) glycoprotein are more durable. Current data show variability in the sensitivity of commercial and in-house antibody tests to SARS-CoV-2.Areas covered: The role of T cells in acute illness is uncertain, but long-term protection against the virus may rely on memory T cell responses. Measuring memory T cell responses is important for retrospective confirmation of cases, who may have been infected early in the pandemic before reliable RT-qPCR tests were available and whose SARS-CoV-2 antibodies may have become undetectable. Relevant peer-reviewed published references from PubMed are included up to 15 March 2021.Expert opinion: After surveying the literature, the authors present the case for urgent development of diagnostic T cell assays for SARS-CoV-2 by accredited laboratories.

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

COVID-19 is a new zoonotic disease caused by the SARS-CoV-2 virus. Since its emergence in Wuhan City, China, the virus has rapidly spread across the globe causing calamitous health, economic and societal consequences. It causes disproportionately severe disease in the elderly and those with co-morbidities, such as hypertension and diabetes. There is currently no proven treatment for COVID-19 and a safe and effective vaccine is at least a year away. The virus gains access to the respiratory epithelium through cell surface angiotensin converting enzyme 2 (ACE2). The receptor binding domain (RBD) of the virus is unlikely to mutate without loss of pathogenicity and thus represents an attractive target for antiviral treatment. Inhaled modified recombinant human ACE2, may bind SARS-CoV-2 and mitigate lung damage. This decoy strategy is unlikely to provoke an adverse immune response and may reduce morbidity and mortality in high-risk groups.

Penicillin Allergy De-labeling Results in Significant Changes in Outpatient Antibiotic Prescribing Patterns.

Unverified penicillin allergies are common but most patients with a penicillin allergy label can safely use penicillin antibiotics. Penicillin allergy labels are associated with poor clinical outcomes and overuse of second-line antibiotics. There is increasing focus on penicillin allergy "de-labeling" as a tool to improve antibiotic prescribing and antimicrobial stewardship. The effect of outpatient penicillin allergy de-labeling on long-term antibiotic use is uncertain. We performed a retrospective pre- and post- study of antibiotic dispensing patterns, from an electronic dispensing data repository, in patients undergoing penicillin allergy assessment at Auckland City Hospital, New Zealand. Over a mean follow-up of 4.55 years, 215/304 (70.7%) of de-labeled patients were dispensed a penicillin antibiotic. Rates of penicillin antibiotic dispensing were 0.24 (0.18-0.30) penicillin courses per year before de-labeling and 0.80 (0.67-0.93) following de-labeling with a reduction in total antibiotic use from 2.30 (2.06-2.54) to 1.79 (1.59-1.99) antibiotic courses per year. In de-labeled patients, the proportion of antibiotic courses that were penicillin antibiotics increased from 12.81 to 39.62%. Rates of macrolide, cephalosporin, trimethoprim/co-trimoxazole, fluoroquinolone, "other" non-penicillin antibiotic use, and broad-spectrum antibiotic use were all lower following de-labeling. Further, antibiotic costs were lower following de-labeling. In this study, penicillin allergy de-labeling was associated with significant changes in antibiotic dispensing patterns.

Implementation of a pharmacist-led penicillin allergy de-labelling service in a public hospital.

BACKGROUND: Inaccurate allergy labelling results in inappropriate antimicrobial management of the patient, which may affect clinical outcome, increase the risk of adverse events and increase costs. Inappropriate use of alternative antibiotics has implications for antimicrobial stewardship programmes and microbial resistance. METHODS: All adult inpatients labelled as penicillin allergic were identified and screened for eligibility by the study pharmacist. An accurate allergy and medication history was taken. Patients were 'de-labelled', underwent oral challenge or were referred to an immunology clinic, if study criteria were met. All patients included in the study were followed-up 1 year after intervention. RESULTS: Two hundred and fifty eligible patients with a label of 'penicillin allergy' were identified. The prevalence of reported penicillin allergy at Middlemore Hospital was 11%. We found that 80% of study patients could be 'de-labelled'. Of those, 80% were 'de-labelled' after an interview with the pharmacist alone, 16% had an uneventful oral challenge and 4% were deemed to be inappropriately labelled after referral to an immunology clinic. Appropriately labelled patients accounted for 20% of the study population. Changes to inpatient antibiotic therapy were recommended in 61% of 'de-labelled' patients, of which no patients had adverse events after commencing on penicillin antibiotics. At the 1 year follow-up, 98% of patients who were 'de-labelled' had no adverse events to repeated administration of penicillin antibiotics. CONCLUSIONS: This study showed that a pharmacist-led allergy management service is a safe option to promote antimicrobial stewardship and appropriate allergy labelling.

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

INTRODUCTION: Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune defect in adults. Within the broad spectrum of CVID, a proportion of patients present with a predominant T cell phenotype associated with increased mortality. These patients are termed late-onset combined immunodeficiency (LOCID) and are currently separated from patients suffering from CVID. Areas covered: We have recently codiscovered a new CVID-like disorder caused by mutations of the NFKB1 gene. Members of this non-consanguineous New Zealand kindred have a very diverse spectrum of phenotypes in spite of carrying the identical mutation. The proband appears to have the autoimmune variant. The proband's recently deceased sister best matched LOCID while other family members are less severely affected, including one asymptomatic adult brother, who has an affected daughter. Differences in genetics was one of the main arguments for separating these disorders in the past. Expert commentary: Given the recent advances in the understanding of the genetic basis of these conditions, we present the case that LOCID should now be considered a subset of CVID, rather than a separate disorder. At a clinical level, this distinction is less important but it is imperative these patients are carefully evaluated, the relevant complications are treated, and they are offered prognostic information.

The case for a national service for primary immune deficiency disorders in New Zealand.

Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

Application of diagnostic and treatment criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders, with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.

Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID), characterized by recurrent infections, is the most prevalent symptomatic antibody deficiency. In ∼90% of CVID-affected individuals, no genetic cause of the disease has been identified. In a Dutch-Australian CVID-affected family, we identified a NFKB1 heterozygous splice-donor-site mutation (c.730+4A>G), causing in-frame skipping of exon 8. NFKB1 encodes the transcription-factor precursor p105, which is processed to p50 (canonical NF-κB pathway). The altered protein bearing an internal deletion (p.Asp191_Lys244delinsGlu; p105ΔEx8) is degraded, but is not processed to p50ΔEx8. Altered NF-κB1 proteins were also undetectable in a German CVID-affected family with a heterozygous in-frame exon 9 skipping mutation (c.835+2T>G) and in a CVID-affected family from New Zealand with a heterozygous frameshift mutation (c.465dupA) in exon 7. Given that residual p105 and p50­translated from the non-mutated alleles­were normal, and altered p50 proteins were absent, we conclude that the CVID phenotype in these families is caused by NF-κB1 p50 haploinsufficiency.

Reversible hypertensive encephalomyelopathy - the spinal variant of the posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is characterised clinically by encephalopathy, headache, visual disturbance and/or focal neurological symptoms. Bilateral cerebral oedema on T2 MRI sequences within the posterior cerebral white matter is the radiological hallmark, although involvement of the frontal lobe, basal ganglia and brainstem can occur. PRES with spinal cord involvement has been rarely reported and is under-recognised due to lack of myelopathic features in nearly half of the reported cases. We report a patient with PRES with spinal cord involvement and review the literature.