COVID-19 vaccination in patients with α1-antitrypsin deficiency.

COVID-19 is continuing its spread across the world, generating a wake of devastating health, economic, and social consequences. The urgency of the situation has simultaneously driven the development of COVID-19 vaccines to an astonishingly fast pace, with more than 2·1 billion doses administered worldwide). Despite the hugely successful vaccination campaign, the efficacy of COVID-19 vaccines in patients with genetic pulmonary diseases, such as α1-antitrypsin deficiency (AATD), have not been delineated. Inherited AATD is characterised by low concentrations of functional α1-antitrypsin in the blood, predisposing individuals to enzymatic tissue injury and inflammation, most notably in the lungs. Given the unclear timeline for an end to the ongoing pandemic, shedding light onto such issues that might have potentially fatal consequences for the affected individuals is necessary.

The efficacy of COVID-19 vaccines in individuals with AATD might only be inferred from published studies on influenza and pneumococcal vaccination in this population. In an observational study of 939 participants with AATD, influenza vaccination rates were up to 81·6% in patients with AATD, yet this finding did not translate into a decrease in exacerbation rates of chronic obstructive pulmonary disease or decreased health-care use. In another study, the magnitude of the antibody response to pneumococcal vaccination in patients with severe AATD was no less robust than in healthy volunteers. The immune responses to antigen provocation in individuals with AATD appear to be far more complex, and protection from SARS-CoV-2 might not necessarily be afforded with vaccination alone.

We have hypothesised that individuals with AATD might derive limited benefit from the current COVID-19 vaccines for several reasons. First, even though vaccination has been prioritised to more vulnerable populations (such as people with AATD), individuals with AATD are usually not included in clinical trials (as reported in ClinicalTrials.gov), and thus the effectiveness and adverse event profile of vaccination in this population are unknown. Clinical scientists should include the AATD population in clinical trials of COVID-19 vaccines to better characterise the safety and efficacy for individuals with AATD. Second, Kueppers has shown that the increase in trypsin-inhibiting capacity of serum after injection of typhoid vaccine is largely due to the increase of the α1-antitrypsin concentration. Consequently, AATD inhibits the quantitative response of the α1-antitrypsin to such a stimulus. Emerging evidence has shown a strong correlation between concentrations of circulating α1-antitrypsin and the induction of trained immunity. Data from previous studies of severe acute respiratory syndrome, Middle East respiratory syndrome, and other human respiratory viruses allude to a risk of antibody-dependent enhancement associated with SARS-CoV-2 vaccines and antibody-based interventions. Liu and colleagues have recently reported that the concentrations of enhancing and neutralising antibodies were higher in patients with severe COVID-19 than in patients with non-severe COVID-19. For individuals with AATD, there is a possibility that the antibody-dependent enhancement effect might be amplified by SARS-CoV-2 infection or vaccination. Third, AATD eases virus spike protein activation by elastase, resulting in the faster spread of the SARS-CoV-2 subtype with spike 614Gly mutation, which is more virulent and results in greater host morbidity. Fourth, COVID-19 vaccine efficacy might not reach 100%; governmental negligence, socioeconomic inequalities, personal values, and the looming spectre of a SARS-CoV-2 mutation all contribute to suboptimal vaccination rates, lower than that of the flu vaccination. Recent studies are raising concern that current COVID-19 vaccines might not have sufficient efficacy against the new SARS-CoV-2 variants B.1.1.7 and B.1.351.7, 8 In particular, the SARS-CoV-2 variant B.1.351 might decrease SARS-CoV-2 vaccine-derived neutralisation of SARS-CoV-2 by 6–86 times. Finally, Pi*MZ, Pi*SZ, or unknown AATD genotype have been associated with a greater odds of unhealthy behaviours, such as not obtaining the pneumococcal or influenza vaccine, adopting sedentary lifestyles, and smoking. Individuals who do not know their genotype might require additional education and intervention to mitigate the risk of SARS-CoV-2 infection. As the advocacy for COVID-19 vaccination in people with AATD continues, studies need to elucidate a proven vaccine correlation with SARS-CoV-2 strains.

In the meantime, the protective roles of α1-antitrypsin on lung structure and function, on preventing acute lung injury and acute respiratory distress syndrome, and especially on inhibiting SARS-CoV-2 infection renders alpha1-proteinase inhibitor a promising candidate for COVID-19 treatment in select populations.11, 12 For patients with AATD, alpha1-proteinase inhibitor therapy might solve two problems with one single action because it is also the best candidate drug for the treatment of COVID-19. As the ongoing pandemic persists in the foreseeable future, we strongly advocate that public health officials and health-care professionals should encourage the population of people with AATD to adopt protective behaviours, including lifestyle changes, pharmacotherapy, alpha1-proteinase inhibitor therapy, surgery, and other therapeutic approaches in addition to COVID-19 vaccine uptake (panel ). Patient-centric educational messages for patients with AATD that emphasise the severity of COVID-19, particularly the potential long-term negative health sequelae, are needed. We must fight to ensure that all patients with AATD, regardless of race, ethnicity, immigration status, income, and insurance status, have access to essential medications and timely and high-quality care in this difficult time.

Lifestyle changes

Avoid crowded places and mass gatherings

Wear a medical mask in public spaces

Patients should be counselled and receive assistance in smoking cessation

Patients should be advised to avoid environmental risk exposures, such as smog, second-hand tobacco smoke, dusts, and fumes

Maintain a healthy bodyweight and consume a balanced, vitamin-rich, and high-fibre diet

Pharmacotherapy

Patients should receive general medical therapy for chronic obstructive pulmonary disease, including bronchodilators, steroids, and oxygen therapy, as per local chronic obstructive pulmonary disease guidelines

Vaccination

Patients should receive the annual flu vaccine and pneumococcal vaccine as per guidelines

Patients should also receive vaccination against SARS-CoV-2

Augmentation therapy

Intravenous plasma-purified alpha1-proteinase inhibitor should be considered for the treatment of α1-antitrypsin deficiency-related lung disease

Surgery

Lung transplantation could be considered for patients with very severe disease refractory to pharmacotherapy

For more details on COVID-19 data see https://covid19.who.int/

CY is a former postdoctoral fellow at the University Health Network. HZ declares no competing interests.