Will the COVID-19 pandemic end with the Delta and Omicron variants?

To the Editor: A novel human coronavirus that is now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (formerly called HCoV-19) emerged in Wuhan, China, in late 2019 and is now causing a pandemic. 1 We analyzed the aerosol and surface stability of SARS-CoV-2 and compared it with SARS-CoV-1, the most closely related human coronavirus. 2 We evaluated the stability of SARS-CoV-2 and SARS-CoV-1 in aerosols and on various surfaces and estimated their decay rates using a Bayesian regression model (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). SARS-CoV-2 nCoV-WA1-2020 (MN985325.1) and SARS-CoV-1 Tor2 (AY274119.3) were the strains used. Aerosols (<5 μm) containing SARS-CoV-2 (105.25 50% tissue-culture infectious dose [TCID50] per milliliter) or SARS-CoV-1 (106.75-7.00 TCID50 per milliliter) were generated with the use of a three-jet Collison nebulizer and fed into a Goldberg drum to create an aerosolized environment. The inoculum resulted in cycle-threshold values between 20 and 22, similar to those observed in samples obtained from the upper and lower respiratory tract in humans. Our data consisted of 10 experimental conditions involving two viruses (SARS-CoV-2 and SARS-CoV-1) in five environmental conditions (aerosols, plastic, stainless steel, copper, and cardboard). All experimental measurements are reported as means across three replicates. SARS-CoV-2 remained viable in aerosols throughout the duration of our experiment (3 hours), with a reduction in infectious titer from 103.5 to 102.7 TCID50 per liter of air. This reduction was similar to that observed with SARS-CoV-1, from 104.3 to 103.5 TCID50 per milliliter (Figure 1A). SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard, and viable virus was detected up to 72 hours after application to these surfaces (Figure 1A), although the virus titer was greatly reduced (from 103.7 to 100.6 TCID50 per milliliter of medium after 72 hours on plastic and from 103.7 to 100.6 TCID50 per milliliter after 48 hours on stainless steel). The stability kinetics of SARS-CoV-1 were similar (from 103.4 to 100.7 TCID50 per milliliter after 72 hours on plastic and from 103.6 to 100.6 TCID50 per milliliter after 48 hours on stainless steel). On copper, no viable SARS-CoV-2 was measured after 4 hours and no viable SARS-CoV-1 was measured after 8 hours. On cardboard, no viable SARS-CoV-2 was measured after 24 hours and no viable SARS-CoV-1 was measured after 8 hours (Figure 1A). Both viruses had an exponential decay in virus titer across all experimental conditions, as indicated by a linear decrease in the log10TCID50 per liter of air or milliliter of medium over time (Figure 1B). The half-lives of SARS-CoV-2 and SARS-CoV-1 were similar in aerosols, with median estimates of approximately 1.1 to 1.2 hours and 95% credible intervals of 0.64 to 2.64 for SARS-CoV-2 and 0.78 to 2.43 for SARS-CoV-1 (Figure 1C, and Table S1 in the Supplementary Appendix). The half-lives of the two viruses were also similar on copper. On cardboard, the half-life of SARS-CoV-2 was longer than that of SARS-CoV-1. The longest viability of both viruses was on stainless steel and plastic; the estimated median half-life of SARS-CoV-2 was approximately 5.6 hours on stainless steel and 6.8 hours on plastic (Figure 1C). Estimated differences in the half-lives of the two viruses were small except for those on cardboard (Figure 1C). Individual replicate data were noticeably “noisier” (i.e., there was more variation in the experiment, resulting in a larger standard error) for cardboard than for other surfaces (Fig. S1 through S5), so we advise caution in interpreting this result. We found that the stability of SARS-CoV-2 was similar to that of SARS-CoV-1 under the experimental circumstances tested. This indicates that differences in the epidemiologic characteristics of these viruses probably arise from other factors, including high viral loads in the upper respiratory tract and the potential for persons infected with SARS-CoV-2 to shed and transmit the virus while asymptomatic. 3,4 Our results indicate that aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces up to days (depending on the inoculum shed). These findings echo those with SARS-CoV-1, in which these forms of transmission were associated with nosocomial spread and super-spreading events, 5 and they provide information for pandemic mitigation efforts.

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1-5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2-also termed the Delta variant-is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein.

The outbreak of novel coronavirus (2019-nCoV) pneumonia initially developed in one of the largest cities, Wuhan, Hubei province of China, in early December 2019 and has been declared the sixth public health emergency of international concern by the World Health Organization, and subsequently named coronavirus disease 2019 (COVID-19). As of February 20, 2020, a total of >75,000 cumulative confirmed cases and 2130 deaths have been documented globally in 26 countries across 5 continents. Current studies reveal that respiratory symptoms of COVID-19 such as fever, dry cough, and even dyspnea represent the most common manifestations at presentation similar to severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome in 2012, which is firmly indicative of droplet transmission and contact transmission. However, the incidence of less common features like diarrhea, nausea, vomiting, and abdominal discomfort varies significantly among different study populations, along with an early and mild onset frequently followed by typical respiratory symptoms. 1 Mounting evidence from former studies of SARS indicated that the gastrointestinal tract (intestine) tropism of SARS coronavirus (SARS-CoV) was verified by the viral detection in biopsy specimens and stool even in discharged patients, which may partially provide explanations for the gastrointestinal symptoms, potential recurrence, and transmission of SARS from persistently shedding human as well. 2 Notably, the first case of 2019-nCoV infection confirmed in the United States reported a 2-day history of nausea and vomiting on admission, and then passed a loose bowel movement on hospital day 2. The viral nucleic acids of loose stool and both respiratory specimens later tested positive. 3 In addition, 2019-nCoV sequence could be also detected in the self-collected saliva of most infected patients even not in nasopharyngeal aspirate, and serial saliva specimens monitoring showed declines of salivary viral load after hospitalization. 4 Given that extrapulmonary detection of viral RNA does not mean infectious virus is present, further positive viral culture suggests the possibility of salivary gland infection and possible transmission. 4 More recently, 2 independent laboratories from China declared that they have successfully isolated live 2019-nCoV from the stool of patients (unpublished). Taken together, a growing number of clinical evidence reminds us that digestive system other than respiratory system may serve as an alternative route of infection when people are in contact with infected wild animals or sufferers, and asymptomatic carriers or individuals with mild enteric symptoms at an early stage must have been neglected or underestimated in previous investigations. Clinicians should be careful to promptly identify the patients with initial gastrointestinal symptoms and explore the duration of infectivity with delayed viral conversion. To date, molecular modelling has revealed by the next-generation sequencing technology that 2019-nCoV shares about 79% sequence identify with SARS-CoV, indicative of these 2 lineage B β-coronaviruses highly homologous, and angiotensin-converting enzyme II (ACE2), previously known as an entry receptor for SARS-CoV, was exclusively confirmed in 2019-nCoV infection despite amino acid mutations at some key receptor-binding domains. 5 , 6 It is widely accepted that coronavirus human transmissibility and pathogenesis mainly depend on the interactions, including virus attachment, receptor recognition, protease cleaving and membrane fusion, of its transmembrane spike glycoprotein (S-protein) receptor-binding domain, specific cell receptors (ACE2), and host cellular transmembrane serine protease (TMPRSS), with binding affinity of 2019-nCoV about 73% of SARS-CoV. 7 Recent bioinformatics analysis on available single-cell transcriptomes data of normal human lung and gastrointestinal system was carried out to identify the ACE2-expressing cell composition and proportion, and revealed that ACE2 was not only highly expressed in the lung AT2 cells, but also in esophagus upper and stratified epithelial cells and absorptive enterocytes from ileum and colon. 8 With the increasing gastrointestinal wall permeability to foreign pathogens once virus infected, enteric symptoms like diarrhea will occur by the invaded enterocytes malabsorption, which in theory indicated the digestive system might be vulnerable to COVID-19 infection. In contrast, because ACE2 and TMPRSS especially TMPRSS2 are co-localized in the same host cells and the latter exerts hydrolytic effects responsible for S-protein priming and viral entry into target cells, further bioinformatics investigation renders additional evidence for enteric infectivity of COVID-19 in that the high co-expression ratio was found in absorptive enterocytes and upper epithelial cells of esophagus besides lung AT2 cells. However, the exact mechanism of COVID-19–induced gastrointestinal symptom largely remains elusive. Based on these considerations, ACE2-based strategies against COVID-19 such as ACE2 fusion proteins and TMPRSS2 inhibitors should be accelerated into clinical research and development for diagnosis, prophylaxis, or treatment. Last, mild to moderate liver injury, including elevated aminotransferases, hypoproteinemia, and prothrombin time prolongation, has been reported in the existing clinical investigations of COVID-19, whereas up to 60% of patients suffering from SARS had liver impairment. The presence of viral nucleic acids of SARS in liver tissue confirmed the coronavirus direct infection in liver, and percutaneous liver biopsies of SARS showed conspicuous mitoses and apoptosis along with atypical features such as acidophilic bodies, ballooning of hepatocytes, and lobular activities without fibrin deposition or fibrosis. 9 It is believed that SARS-associated hepatotoxicity may be likely with viral hepatitis or a secondary effect associated with drug toxicity owing to high-dose consumption of antiviral medications, antibiotics, and steroids, as well as immune system overreaction. However, little is known about 2019-nCoV infection in liver. Surprisingly, recent single cell RNA sequencing data from 2 independent cohorts revealed a significant enrichment of ACE2 expression in cholangiocytes (59.7% of cells) instead of hepatocytes (2.6% of cells), suggesting that 2019-nCoV might lead to direct damage to the intrahepatic bile ducts. 10 Altogether, substantial effort should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation, and early intervention.