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SARS-CoV-2 infection has led to COVID-19 outbreak worldwide. To date, a specific antiviral drug does not exist to treat the disease and control the virus. In this paper, we have explored the potential utility of alpha lipoic acid, an anti-inflammatory and antioxidant molecule, for treatment. Alpha lipoic acid exhibits strong antioxidant properties and modulates the immune system by regulating T cell activation making it a useful therapeutic candidate for cytokine storm triggering SARS-CoV-2 infection. In the present communication, we focused on the therapeutic potential of ALA with respect to its potential role on reducing the severity of symptoms and the adverse effects of other antiviral drugs used. We consider different mechanisms by which modulating ACE2 levels after virus replication and preventing cytokine storm and also focus on a new therapeutic venue that utilizes ALA.
Research Article
Current Topics in Nutraceutical Research 172 May 2021 | Volume 19 | Article 7
ISSN 1540-7535 print, ISSN 2641-452X online, Copyright © 2021 by New Century Health Publishers, LLC
All rights of reproduction in any form reserved
Research Article
Alpha Lipoic Acid as a Potential Treatment for
COVID-19 – A Hypothesis
1,2Serkan Sayıner, 3Ahmet Özer S¸ ehirli and 4Nedime Serakıncı
1Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, Nicosia, Cyprus; 2Diagnostic Laboratory, Animal Hospital, Faculty of Veterinary Medicine,
Near East University, Nicosia, Cyprus; 3Department of Pharmacology, Faculty of Dentistry, Near East University, Nicosia, Cyprus and
4Famagusta Medical Hospital, Famagusta, Cyprus
Received October 28, 2020; Accepted November 17, 2020
Communicated By: Prof. Chandan Prasad
SARS-CoV-2 infection has led to COVID-19 outbreak worldwide. To date, a specific antiviral drug does not exist to treat the
disease and control the virus. In this paper, we have explored the potential utility of alpha lipoic acid, an anti-inflammatory
and antioxidant molecule, for treatment. Alpha lipoic acid exhibits strong antioxidant properties and modulates the immune
system by regulating T cell activation making it a useful therapeutic candidate for cytokine storm triggering SARS-CoV-2
infection. In the present communication, we focused on the therapeutic potential of ALA with respect to its potential role on
reducing the severity of symptoms and the adverse effects of other antiviral drugs used. We consider different mechanisms
by which modulating ACE2 levels after virus replication and preventing cytokine storm and also focus on a new therapeutic
venue that utilizes ALA.
Keywords: ACE2, Alpha lipoic acid, COVID-19, Cytokines, SARS-CoV-2, T cell
Abbreviations Used: Angiotensin-converting enzyme 2, ACE2; Alpha lipoic acid, ALA; Alanine aminotransferase, ALT; Aspartate
aminotransferase, AST; Dihydriolipoic acid, DHLA; Interferon-gamma, IFN-γ; Interleukin-6, IL-6; Monocyte chemoattractant
protein-1, MCP-1; Nuclear factor kappa B, NF-κB; Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2;
Tumor necrosis factor-α, TNF-α
Corresponding Author: Dr. Nedime Serakinci, Famagusta Medical Hospital, Post Code: 99450, Famagusta, Cyprus;
COVID-19 is a disease that is caused by SARS-CoV-2, which
has rapidly spread and evolved into a worldwide outbreak since
December 2019 leading to unsurmountable diculties for
healthcare systems globally (Contini et al., 2020). To date, no active
therapeutic agent has been found to cure severe COVID-19 (Hassan
et al., 2020; Padron-Regalado, 2020; Singhal, 2020; Wang et al.,
2020). Besides, multiple studies on developing vaccines continue
widely for prophylactic eects. To date, two vaccine candidates have
successfully been established recently, thus promising prophylaxis
(Walsh et al., 2020).
CoVs have been reported to be nonsegmented RNA viruses that
cause zoonotic infections and show steady mortality rate in humans
(Lu et al., 2020).ese viruses consist of four structural proteins
which are E, M, N, and S proteins (Rota et al., 2003). e S protein
is the key constituent that is responsible for invasion of CoV. It
mediates cell membrane fusion (Hulswit et al., 2016). e host cell
receptor for SARS-CoV-2 is the ACE2 present in numerous tissues
including alveolar epithelial cells, endothelial cells of blood vessels,
and smooth muscle cells (Kai et al., 2020). e invasion of SARS-
CoV-2 in host cells occurs via interaction of the S protein and ACE2
(Mathewson et al., 2008). In studies, it was determined that the sit-
uation where ACE2 receptors mediate and cause virus replication
during SARS-CoV-2 invasion causes a decrease in ACE2 levels,
leading to an increase in ACE1-mediated angiotensin II level and
thus lung and heart damage (Guo et al., 2020; Huang et al., 2020).
Angiotensin II eects the formation of free oxygen radicals by inu-
encing the metabolism of smooth muscle cells and increasing the
activity of NADPH oxidase. Free oxygen radicals play an essential
role in virus invasion, organ damage, and systemic inammatory
response (Zhang et al., 2007, 2020a). erefore, increasing ACE2
levels aer viral replication will provide protection (Kai et al., 2020).
Rapidly emerging literature and reports indicate that SARS-
CoV-2 infection aects the CD4 and CD8 proteins on T cells, and
Current Topics in Nutraceutical Research 173 May 2021 | Volume 19 | Article 7
Serkan Sayıner et al. ALA Treatment for COVID-19
plays a role in inammation due to overexpression of cytokines such
as IFN-γ, IL-6, MCP-1, and TNF-α and transcription factor, NF-κB
(Zhai et al., 2016). us, suggesting that cytokine storm may play a
role in the progression of COVID-19 (Liu et al., 2020; Saghazadeh
et al., 2020). erefore, eective suppression of cytokine storm will
be an important way to save the lives and help patients to ght against
COVID-19 (Fu et al., 2020; Ye et al., 2020; Zhang et al., 2020b). de
Queiroz et al. (2015) have shown that ALA plays a role in decreas-
ing cytokine expression by aecting CD4 and CD8 proteins on T
cells which will play a preventative role in tissue damage by increas-
ing the ACE2 activity. Upon SARS-CoV-2 invasion in the cell, viral
replication occurs and cause decrease in the ACE2 activity. is
leads to increase in cytokine expression associated with cardiopul-
monary damage. erapeutic use of ALA decreases ACE2 levels
aer viral replication which will increase the angiotensin II level
that will reduce cardiopulmonary damage. is is accomplished
through angiotensin II reducing the formation of free oxygen radi-
cals by increasing the activity of NADPH oxidase (Fig. 1). Previous
studies have demonstrated that ALA and its metabolite, DHLA with
two thiol groups per molecule, are more potent reductants than
glutathione that inhibits reactive oxygen species such as
superoxide, hydroxyl, and hypochloric acid by suppressing the
FIGURE 1 | SARS-CoV-2 reduces ACE2 levels, increases ACE1 levels through T cell activation after replication, thereby causing cytokine expression. ALA administration after
SARS-CoV-2 replication will alter ACE1 increase and ACE2 decline to prevent cytokine expression and thus cardiopulmonary damage.
Serkan Sayıner et al. ALA Treatment for COVID-19
Current Topics in Nutraceutical Research 174 May 2021 | Volume 19 | Article 7
NADPH oxidase activity (Dulundu et al., 2007; Cakir et al., 2015;
Wang et al., 2016; Savtekin et al., 2018; Aksoy et al., 2019;
Sehirli et al., 2019). Free oxygen radicals trigger the binding of
cytokines such as IFN-γ, TNF-α, MCP1, and IL-6, and the tran-
scription factor NF-κB to membrane receptors by aecting the T
cells. In this case, free oxygen radicals act as a secondary messenger
within the cell (Agostinis et al., 2015; Fei et al., 2016; Aksoy
et al., 2019; Sehirli et al., 2019). Besides, ALA has enhancer eects
also on dierent antioxidants such as coenzyme Q10, vitamins C
and E, and increases intracellular levels of these antioxidants (Busse
et al., 1992; Bharat et al., 2002). In line with these studies, ALA may
decrease the ACE2 activity aer replication of the SARS-CoV-2,
and reduce the NADPH oxidase activity leading to suppression of
the increase in cytokine expression (Fig. 1).
Several dierent treatment options that have been suggested as
a COVID-19 specic treatment include antiviral treatments,
immune enhancers, even some nutritional interventions, and
few other compounds with potential therapeutic administration.
Nutritional interventions that could have a positive eect on the
host immune response against viral infections have been suggested
as supportive treatment in conjunction with antiviral treatments.
Administration of ALA aer SARS-CoV-2 replication may dimin-
ish ACE1 increase and ACE2 decrease, thereby contributing to the
prevention of cardiopulmonary damage by preventing cytokine
expression. Previously, it has been shown that inuenza virus
(IVFujian01) increases NF-κB and caspase activities in MDCK
cells. Cells with low NF-κB activity are resistant to inuenza virus
infection (Nimmerjahn et al., 2004). us, preventing NF-κB
activation plays a major role in the treatment of inuenza virus
infection. ALA has been shown to inhibit inuenza spread by
blocking NF-κB activation (Bai et al., 2012). Another study has
shown that ALA prevents TNF-α-mediated apoptosis caused by
inuenza A virus (Severa et al., 2007).
Additionally, ALA has been demonstrated to inhibit HIV repli-
cation by regulating the T cell activity such as CD4+ and CD8+ and
by suppressing NF-κB and other cytokines (Jariwalla et al., 2008).
Further, ALA has been found to have a protective eect on alveolar
cells against HCoV 229E infection in pulmonary cells which are
under high oxidative stress due to HCoV 229E infection, and by
reducing the NADPH oxidase activities and increasing GSH levels
(Wu et al., 2008). In line with the above-mentioned studies, use of
ALA prevents growth against the vaccinia virus by regulating the
NK-kB and IFN-γ activations (Spisakova et al., 2009). In addition
to human studies, ALA has also been determined to be a potent
supportive agent in bovine rhinotracheitis disease ın veterinary
medicine (Schmidt et al., 2006).
ALA, a natural substance found in some foods and also syn-
thesized in the body (Reed, 1951), has been shown to ameliorate
heart, so tissue, and bone damage caused by Coxsackievirus B3
(Kim et al., 2013). It has also been stated that it improves ALT and
AST levels against the hepatitis C virus and shows protective eect
by reducing oxidative damage and cytokine expressions (Melhem
et al., 2005). ALA is also shown to be supportive in the therapy
of postinfection olfactory dysfunction. ALA was further shown to
signicantly improve the smell sensitivity measured by “threshold,
discrimination, and identication; TDI” score and lowered the rate
of “parosmia”/“troposmia” (Hummel et al., 2002).
We suggest that ALA, used aer viral replication, may alleviate the
prognosis of the disease by regulating T cell activity and suppressing
NF-κB. Besides, ALA being also used as an immunomodulator
allows us to speculate its potential use and benets of use in combi-
nation with antiviral agents may prove to be a more eective treat-
ment of choice by reducing the side eect potential of those drugs.
is is principally because of the fact that ALA will reduce the
NADPH oxidase activity resulting in decreased cytokine expres-
sion, free oxygen radicals, and thus tissue damage. Inhibiting virus
replication as well as limiting excess inammation is very import-
ant to the treatment of COVID-19. For this purpose, the agents
regulating the immune system should be considered together with
antiviral treatments. ALA, having the potential of inhibiting cyto-
kine expression, allows us to speculate on its potential benet of use
in balancing cytokine storm.
e authors state that there are no conicts of interest to disclose.
SS, AÖ, and NS conceived the idea for the manuscript, performed
literature search, and data analysis. SS and AÖ draed the
manuscript and NS critically revised the manuscript.
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... Additionally, peripheral CD14+ and CD16 + monocytes expressed in different tissues, including the lungs and periodontal tissues, mediate inflammatory effects through the secretion of pro-inflammatory cytokines (Jagannathan et al. 2014;Zhou et al. 2020b). However, melatonin, an important regulator of the sleep-wake cycle and also immune system that stimulates the secretion of cytokines (Carrillo-Vico et al. 2013;Haldar et al. 2001), may antagonize these inflammatory effects through suppression of CD147, which contributes to the cytokine storm in the lungs during SARS-CoV-2 invasion (Sayiner et al. 2021;Sehirli et al. 2020). ...
The physiological processes of most living organisms follow a rhythmic pattern, which is controlled by the interaction between environmental cues and the internal circadian timing system. Different regulatory circadian genes are expressed in most cells and tissues, and disruptions in the sleep–wake cycle affect these genes, which may result in metabolic disorders and cause alterations of the immune system. The manifestations of these disrupted genes are evident in inflammatory conditions such as periodontitis and some viral diseases, including COVID-19. The brain and muscle ARNT-like protein-1 (Bmal1), an important circadian regulatory gene, decreases when the sleep–wake cycle is disrupted. Circadian genes have been linked to different events, including cytokine storm in inflammatory conditions and virus invasion. The evaluation of the effects of these regulatory circadian genes, especially Bmal1, in periodontitis and viral infection suggests that both diseases may have a common pathogenesis via the NF-κB pathway. This brief review highlights the role and importance of the circadian clock gene Bmal1 in the disease process of periodontitis and suggests its role and importance in viral infections, including COVID-19.
... According to previous reports, alpha-lipoic acid (ALA) may decrease ACE2 activity after SARS-CoV-2 replication and rmight reduce NADPH oxidase activity, leading to suppression of expression of inflammatory cytokines (Sayiner et al., 2020). ...
Full-text available
SARS-CoV-2 infects host cells mainly through the interaction between the virus's Spike protein and the viral receptors namely Angiotensin-Converting Enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Both are highly expressed in the gastrointestinal tract, in the nasal and bronchial epithelium, as well as in the type II alveolar epithelial cells. The aim of this review is to report the evidences from the scientific literature on the pathophysiology and the available treatments for olfactory-gustatory disorders in patients with COVID-19. The mechanisms involved in these disorders are still unclear and studies on specific therapies are scarce. However, it has been hypothesized that a decrease in the sensitivity of the sensory neurons as well as the co-expression of ACE2 and TMPRSS2 in the alveolar epithelial cells are the main causes of olfactory-gustatory disorders. The possible mechanisms described in the literature for changes in taste perception in patients with COVID-19 include olfactory disorders and a competitive activity of COVID-19 on ACE2 receptors in the taste buds. In addition, SARS-CoV-2 can bind to sialic acid receptors in the taste buds. In general, evidences show that there is no specific treatment for olfactory-taste disorders induced by SARS-CoV-2, even though some treatments have been used and have shown some promising results, such as olfactory training, intranasal application of sodium citrate and vitamin A, as well as systemic use of omega-3 and zinc. Corticosteroids have also been used as a pharmacological approach to treat patients with olfactory dysfunction with some contradictory results. The knowledge of the mechanisms by which SARS-CoV-2 influences the sensory systems and how effective therapies can treat the loss of smell and taste will have important implications on the understanding and clinical management of olfactory-taste disorders.
... The fact that ACE2 and TMPRSS, which play a crucial role in the invasion of SARS-CoV-2, are also localized in the mouth. Thus, the virus may also influence inflammation in the periodontal tissues and cytokine storm [9,10]. ...
Daily new information emerges regarding the COVID-19, infection of SARS-CoV-2, which is considered a global pandemic. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) are required to complete the viral invasion pathway and are present in the oral mucosa, gingiva and periodontal pocket. Thus, increasing the likelihood of periodontitis and gingivitis caused by COVID-19. The cytokine storm during COVID-19 similarly arises during periodontal inflammation. Studies have reported that NOD-Like Receptor family pyrin domain-containing 3 (NLRP3) inflammasome is significant in the cytokine storm. Recently, the course of the COVID-19 has been related to the melatonin levels in both COVID-19 and periodontal diseases. It is known that melatonin prevents the activation of NLRP3 inflammasome. In light of these findings, we think that melatonin treatment during COVID-19 or periodontal diseases may prevent the damage seen in periodontal tissues by preventing the activation of NLRP3 inflammasome.
The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19.
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Coronavirus (COVID-19) is an enveloped RNA virus that is diversely found in humans and wildlife. A total of six species have been identified to cause disease in humans. They are known to infect the neurological, respiratory, enteric, and hepatic systems. The past few decades have seen endemic outbreaks in the form of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome related coronavirus (SARS-CoV). Yet again, we see the emergence of another outbreak due to a new strain called the SARS-CoV-2 virus. The most recent outbreak initially presented as pneumonia of unknown etiology in a cluster of patients in Wuhan, China. The epicenter of infection was linked to seafood and exotic animal wholesale markets in the city. SARS-CoV-2 is highly contagious and has resulted in a rapid pandemic of COVID-19. As the number of cases continues to rise, it is clear that these viruses pose a threat to public health. This review will introduce a general overview of coronavirus and describe the clinical features, evaluation, and treatment of COVID-19 patients. It will also provide a means to raise awareness among primary and secondary healthcare providers during the current pandemic. Furthermore, our review focuses on the most up-to-date clinical information for the effective management, prevention, and counseling of patients worldwide.
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The emergence of the strain of coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and its impact on global health have made imperative the development of effective and safe vaccines for this lethal strain. SARS-CoV-2 now adds to the list of coronavirus diseases that have threatened global health, along with the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) coronaviruses that emerged in 2002/2003 and 2012, respectively. As of April 2020, no vaccine is commercially available for these coronavirus strains. Nevertheless, the knowledge obtained from the vaccine development efforts for MERS and SARS can be of high value for COVID-19 (coronavirus disease 2019). Here, we review the past and ongoing vaccine development efforts for clinically relevant coronavirus strains with the intention that this information helps in the development of effective and safe vaccines for COVID-19. In addition, information from naturally exposed individuals and animal models to coronavirus strains is described for the same purpose of helping into the development of effective vaccines against COVID-19.
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Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.
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18 years ago, in 2002, the world was astonished by the appearance of Severe Acute Respiratory Syndrome (SARS), supported by a zoonotic coronavirus, called SARS-CoV, from the Guangdong Province of southern China. After about 10 years, in 2012, another similar coronavirus triggered the Middle East Respiratory Syndrome (MERS-CoV) in Saudi Arabia. Both caused severe pneumonia killing 774 and 858 people with 8700 cases of confirmed infection for the former, and 2494 for the latter, causing significant economic losses. 8 years later, despite the MERS outbreak remaining in certain parts of the world, at the end of 2019, a new zoonotic coronavirus (SARS-CoV-2) and responsible of coronavirus Disease (COVID-19), arose from Wuhan, Hubei Province, China. It spread rapidly and to date has killed 3,242 persons with more than 81,000 cases of infection in China and causing over 126,000 global cases and 5,414 deaths in 166 other countries around the world, especially Italy. SARS-CoV-2 would seem to have come from a bat, but the intermediate reservoir continues to be unknown. Nonetheless, as for SARS-CoV and MERS CoV, the Spillover effect linked to animal-human promiscuity, human activities including deforestation, illegal bush-trafficking and bushmeat, cannot be excluded. Recently, however, evidence of inter-human only transmission of SARS-CoV-2 has been accumulated and thus, the outbreak seems to be spreading by human-to-human transmission throughout a large part of the world. Herein we will provide with an update on the main features of COVID-19 and suggest possible solutions how to halt the expansion of this novel pandemic.
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Abstract An acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.
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There is a new public health crises threatening the world with the emergence and spread of 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus originated in bats and was transmitted to humans through yet unknown intermediary animals in Wuhan, Hubei province, China in December 2019. There have been around 96,000 reported cases of coronavirus disease 2019 (COVID-2019) and 3300 reported deaths to date (05/03/2020). The disease is transmitted by inhalation or contact with infected droplets and the incubation period ranges from 2 to 14 d. The symptoms are usually fever, cough, sore throat, breathlessness, fatigue, malaise among others. The disease is mild in most people; in some (usually the elderly and those with comorbidities), it may progress to pneumonia, acute respiratory distress syndrome (ARDS) and multi organ dysfunction. Many people are asymptomatic. The case fatality rate is estimated to range from 2 to 3%. Diagnosis is by demonstration of the virus in respiratory secretions by special molecular tests. Common laboratory findings include normal/ low white cell counts with elevated C-reactive protein (CRP). The computerized tomographic chest scan is usually abnormal even in those with no symptoms or mild disease. Treatment is essentially supportive; role of antiviral agents is yet to be established. Prevention entails home isolation of suspected cases and those with mild illnesses and strict infection control measures at hospitals that include contact and droplet precautions. The virus spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), but has lower fatality. The global impact of this new epidemic is yet uncertain.
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States. Methods In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle–formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor–binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 μg, 20 μg, 30 μg, and 100 μg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 μg of BNT162b1), participants received one dose. Results A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. Conclusions The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2–3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; number, NCT04368728.)
The rapid spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an ongoing pandemic of coronavirus disease 2019 (COVID-19). Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for SARS-CoV-2 to enter host target cells. Given that angiotensin receptor blockers (ARBs) and an ACE inhibitor (ACEI) upregulated ACE2 expression in animal studies, the concern might arise regarding whether ARBs and ACEIs would increase the morbidity and mortality of COVID-19. On the other hand, animal data suggested a potential protective effect of ARBs against COVID-19 pneumonia because an ARB prevented the aggravation of acute lung injury in mice infected with SARS-CoV, which is closely related to SARS-CoV-2. Importantly, however, there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS-CoV-2 or aggravate the severity and outcomes of COVID-19 at present. Until further data are available, it is recommended that ARB and ACEI medications be continued for the treatment of patients with cardiovascular disease and hypertension, especially those at high risk, according to guideline-directed medical therapy based on the currently available evidence.
Introduction: At the end of 2019, Wuhan, a city in China with a population of about 11 million, witnessed the outbreak of unusual pneumonia. As of March 29, 2020, the disease has spread to more 199 countries and territories worldwide. The 2019 novel coronavirus, 2019-nCoV, is known as the probable causative agent of the illness. Areas covered: Here, the epidemiological dynamics of the disease that stand in close relation to distinct immunogenetic characters of the pathogen are discussed, to understand the ability and inability of the immune system in combatting the 2019-nCoV infection. Expert opinion: The elderly population is at increased risk of developing and dying from the 2019-nCoV infection. Comorbidity is present in more than 30% of cases infected with the 2019-nCoV. Except for less than 1% of the total, a chronic condition has been found in all cases that died from 2019-nCoV. Men are more than 1.5 times more likely to die from the 2019-nCoV disease. Evidence links aging to cytokine dysregulation and T-cell repertoire reduction, male population to relatively reduced anti-viral immunity, and 2019-nCoV-related comorbidities to hyper inflammation. The transmission of 2019-nCoV is influenced by the host-related factors that are known to be associated with immune dysregulation.
We noted that the DCt values of severe cases were significantly lower than those of mild cases at the time of admission (appendix). Nasopharyngeal swabs from both the left and right nasal cavities of the same patient were kept in a sample collection tube containing 3 mL of standard viral transport medium. All samples were collected according to WHO guidelines.5 The mean viral load of severe cases was around 60 times higher than that of mild cases, suggesting that higher viral loads might be associated with severe clinical outcomes. We further stratified these data according to the day of disease onset at the time of sampling. The DCt values of severe cases remained significantly lower for the first 12 days after onset than those of corresponding mild cases (figure A). We also studied serial samples from 21 mild and ten severe cases (figure B). Mild cases were found to have an early viral clearance, with 90% of these patients repeatedly testing negative on RT-PCR by day 10 post-onset. By contrast, all severe cases still tested positive at or beyond day 10 post-onset. Overall, our data indicate that, similar to SARS in 2002–03,6 patients with severe COVID-19 tend to have a high viral load and a long virus-shedding period. This finding suggests that the viral load of SARS-CoV-2 might be a useful marker for assessing disease severity and prognosis.