SARS-CoV-2 and the Angiotensin-Converting Enzyme 2 Receptor: Angiotensin-Converting Enzyme Inhibitor/Angiotensin 2 Receptor Blocker Utilization and a Shift Towards the Renin-Angiotensin-Aldosterone System Classical Pathway

Review

Author: Riskin, Suzanne I ; Felber, Randy ; New, William

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, uses the surface angiotensin-converting enzyme 2 (ACE2) receptor as the site of entry into host cardiac, respiratory, intestinal, renal, and nervous system cells. Predisposing risk factors such as cardiovascular disease increase the risk of developing severe disease. Hypertension is characterized by the stimulation of the renin-angiotensin-aldosterone system (RAAS). Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin 2 receptor blockers (ARBs), medications used to treat hypertension, inhibit RAAS and its downstream effects; however, they have also been shown to upregulate ACE2 receptors. In this review, we aim to evaluate the effectiveness of ACEi/ARBs as an adjunct therapy in patients with SARS-CoV-2 as well as examine the possible protective effects and impact on infection rate and disease severity. A PubMed literature search excluding sources outside the United States and duplicates was performed using the following search criteria: "COVID-19 AND cardiovascular disease AND ACEi AND ARB", "SARS-COVID-19 OR COVID-19, AND ACEi AND ARB AND Infection rate", "COVID-19 AND ACEi and ARB", "Omicron BA.1 and BA.2 AND ACE2 OR ARBs", "Omicron AND ACEi AND ARBs". This resulted in 33 final sources. The review concluded that ACEi/ARB therapy may continue to improve COVID-19 survival as previous treatment is associated with positive clinical outcomes. Patients taking ACEis or ARBs were found to have a decreased risk of hospitalization, reduced severity of COVID-19 pneumonia, a lesser need for mechanical ventilation, and an overall reduction in mortality rate. No statistically significant association between ACEi/ARB use and enhanced COVID-19 infectivity was found. The Omicron variant is theoretically more infectious and was associated with increased negative clinical outcomes in those undertreated with ACEis/ARBs. The majority of the literature supports the current guidelines from the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC), and Heart Failure Society of America (HFSA), which state that ACEi and ARB medications should not be withdrawn from or initiated on patients with cardiovascular disease who are infected with SARS-CoV-2. More research needs to be conducted on the association between the emerging COVID-19 variants and ACEis/ARBs to give clinicians confidence when treating patients within this subgroup of the population.

01 Dec 2023·Journal of Medical Virology

Autoantibodies against angiotensin‐converting enzyme 2 (ACE2) after COVID‐19 infection or vaccination

Article

Author: Lam, Winston Jim ; Chan, Kwok Hung ; Chan, Brian Pui Chun ; Situ, Jianwen ; Sridhar, Siddharth ; Kwan, Mike Yat Wah ; Yuen, Kwok Yung ; Chen, Lin Lei ; Yeung, Man Lung ; Leung, Joy Ka Yi ; Cai, Jianpiao ; Shun, Estie Hon Kiu ; To, Kelvin Kai Wang ; Wong, Joshua Sung Chih ; Tsoi, James Yiu Hung ; Li, Xin

AbstractAutoantibodies against angiotensin‐converting enzyme 2 (ACE2) are frequently reported in patients during coronavirus disease 2019 (COVID‐19) with evidence for a pathogenic role in severe infection. However, little is known of the prevalence or clinical significance of ACE2 autoantibodies in late convalescence or following COVID‐19 vaccination. In this study, we measured ACE2 autoantibodies in a cohort of 182 COVID‐19 convalescent patients, 186 COVID‐19 vaccine recipients, and 43 adolescents with post‐mRNA vaccine myopericarditis using two ACE2 enzymatic immunoassays (EIAs). ACE2 IgM autoantibody EIA median optical densities (ODs) were lower in convalescent patients than pre‐COVID‐19 control samples with only 2/182 (1.1%) convalescents testing positive. Similarly, only 3/182 (1.6%) convalescent patients tested positive for ACE2 IgG, but patients with history of moderate‐severe COVID‐19 tended to have significantly higher median ODs than controls and mild COVID‐19 patients. In contrast, ACE2 IgG antibodies were detected in 10/186 (5.4%) COVID‐19 vaccine recipients after two doses of vaccination. Median ACE2 IgG EIA ODs of vaccine recipients were higher than controls irrespective of the vaccine platform used (inactivated or mRNA). ACE2 IgG ODs were not correlated with surrogate neutralizing antibody levels in vaccine recipients. ACE2 IgG levels peaked at day 56 post‐first dose and declined within 12 months to baseline levels in vaccine recipients. Presence of ACE2 antibodies was not associated with adverse events following immunization including myopericarditis. One convalescent patient with ACE2 IgG developed Guillain−Barre syndrome, but causality was not established. ACE2 autoantibodies are observed in COVID‐19 vaccine recipients and convalescent patients, but are likely innocuous.

01 Sep 2023·Biochemistry. Biokhimiia

Dimeric ACE2-FC Is Equivalent to Monomeric ACE2 in the Surrogate Virus Neutralization Test.

Article

Author: Gaiamova, Elizaveta A ; Vorobiev, Ivan I ; Kolesov, Denis E ; Orlova, Nadezhda A

Angiotensin-converting enzyme 2 (ACE2) is the main cellular receptor for the dangerous sarbecoviruses SARS-CoV and SARS-CoV-2. Its recombinant extracellular domain is used to monitor the level of protective humoral immune response to a viral infection or vaccine using the surrogate virus neutralization test (sVNT). Soluble ACE2 is also considered as an option for antiviral therapy potentially insensitive to the changes in the SARS-CoV-2 spike protein. Extensive testing of the samples of patient's serum by the sVNT method requires using preparations of ACE2 or ACE2 conjugates with constant properties. We have previously obtained a cell line that is a producer of a soluble monomeric ACE2 and showed that this ACE2 variant can be used in sVNT, preferably as a conjugate with horseradish peroxidase. A cell line that generates an ACE2-Fc fusion protein with high productivity, more than 150 mg/liter of the target protein when cultured in a stirred flask, was obtained for producing a stable and universally applicable form of soluble ACE2. The affinity-purified ACE2-Fc fusion contains a mixture of dimeric and tetrameric forms, but allows obtaining linear response curves for inhibition of binding with the receptor-binding domain of the SARS-CoV-2 spike protein by antibodies. The ACE2-Fc-HRP-based sVNT testing system can be used for practical measurements of the levels of virus-neutralizing antibodies against various circulating variants of the SARS-CoV-2 virus.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronavirus Infections	Preclinical	DE	Secarna Pharmaceuticals Gmbh & Co.	24 May 2023
Coronavirus Infections	Preclinical	US	the First Affiliated Hospital of Sun Yat-Sen University	24 May 2023

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