Coronaviruses are enveloped RNA viruses, characterized by surface protein spikes, which, under electron microscopy, resemble the sun’s corona. Numerous coronaviruses, first discovered in domestic poultry in the 1930’s, cause respiratory, gastrointestinal, liver, and neurologic diseases in animals.
Human Coronavirus Infection (HCoV)
Only 7 coronaviruses cause disease in humans (HCoV).
Four of the 7 HCoV (HCoV-NL63, -229E, -OC43, and -HKU1) cause mild and self-limiting upper respiratory tract infections, such as the common cold, but can cause severe lower respiratory tract infections, including pneumonia, in infants, the elderly, and the immunocompromised. These HCoV infections show a seasonal pattern with most cases occurring in the winter months in temperate climates.
Three of the 7 HCoV (SARS-CoV, MERS-CoV, and SARS-CoV2) have caused major outbreaks of deadly pneumonia in the 21st century.
The first of these outbreaks, severe acute respiratory syndrome (SARS), first emerged in November 2002 in Guangdong province in southern China and caused an epidemic that spread within months to 29 countries and 6 continents. It sickened over 8,000 people and killed almost 800 worldwide. The majority of cases occurred in China and Hong Kong. In the United States, only 8 people had laboratory-confirmed SARS; all 8 had traveled to areas where SARS-CoV transmission was occurring. The overall case fatality rate was 10%, but varied by age, ranging from < 1% in people aged 24 years and younger to > 50% in those aged 65 years and older.
The source of SARS was palm civets (cat-like mammals) that had been sold as food at local live animal markets in Guangdong. Once introduced into humans, SARS-CoV readily spread person-to-person by large respiratory droplets, aerosols, and by fecal-oral transmission (diarrhea is a common manifestation of the infection).
The next HCoV to cause deadly infection was Middle East Respiratory Syndrome coronavirus (MERS-CoV), which emerged in the Arabian Peninsula in September 2012. MERS-CoV has caused recurrent outbreaks that have sickened over 2,500 people with a case fatality rate of about 35%. Most infected people lived in or recently traveled from the Arabian Peninsula. 85% of cases were reported from Saudi Arabia. The largest MERS outbreak outside the Arabian Peninsula occurred in South Korea in 2015, associated with a traveler returning from the Arabian Peninsula.
MERS-CoV, like SARS-CoV, is a zoonosis, spread by direct or indirect contact with dromedary camels. MERS-CoV also spreads human to human by direct contact, fomites, and respiratory droplets. 42% of all cases in 2018-2019 were linked to clusters of human-to-human transmission in households or healthcare facilities. The source was unknown for 60%. MERS-CoV virus is detected respiratory tract secretions, feces, serum, and urine, and virus has been detected in survivors for a month or more after onset.
The seventh HCoV to be discovered is SARS-CoV2, the cause of an outbreak, named COVID-19, that is currently spreading worldwide. The outbreak began in Wuhan, a city of over 11 million, in Hubei Province, Central China. (Wuhan is home to the Wuhan Institute of Virology, a leading center for coronavirus research, although no connection is suspected between the research and the current outbreak.) SARS-CoV-2 is most closely related, with 96% genetic similarity, to a coronavirus isolated from horseshoe bats that were found in caves in Yunnan, China, over 1000 km (about 621 miles) from Wuhan (1).
Similar to the events in the 2002–2003 SARS epidemic, early reports suggested that SARS-CoV-2 had jumped from animals to humans at Wuhan's Huanan Seafood Wholesale Market, where many different species of live animals were clustered in cages, offering opportunities for viral transmission. As a result, the Wuhan market was closed on Jan. 1, 2020, but evidence now suggests this market was not the source of the outbreak. Only the third of the first five human cases with confirmed SARS-CoV-2 infection in Wuhan had any link to the Wuhan market (2) and, although environmental samples from the site in the market where wildlife was sold were positive for SARS-CoV-2, tissue samples from the market's animals were negative for the virus. How this virus thus made the jump from Yunnan bats to human beings remains unknown.
By the first of this year, there were 41 cases in Wuhan. A week later, Chinese investigators reported that they identified the cause was a new coronavirus and its genetic sequence was published on an open-access database. On Jan 18, when the case count had risen to almost 200, more than 10,000 families in Wuhan attended an annual banquet to celebrate the Lunar New Year. Days later, on the eve of Lunar New Year when many people travel to their home towns for family reunions, Chinese authorities responded to increasing case counts by locking down millions of people living in Hubei Province.
The borders of Wuhan were blocked — allowing no one in or out. People were required to remain in their apartments, increasing the physical distance between people outside of households. Schools and universities closed. All types of recreational venues and most public places closed. Only essential businesses were allowed to remain open. However, an estimated five million people had left Wuhan before the lockdown began and consequently the number of cases surged in the surrounding Chinese provinces. By early February, the virus had spread to all provinces of mainland China (37,000 cases) and cases with a history of travel from Wuhan also began appearing outside China, in places such as Hong Kong and Singapore, and the West Coast of the US.
Despite the lockdown in Hubei, by early February, the confirmed case count in Hubei was about 25,000 and a month later, 64,000. After 9 weeks of sustained transmission, Hubei Province reported 64,084 confirmed cases with 2,346 deaths. The actual number of cases was probably much higher as only the most severe cases were likely included in reports due to shortages of testing kits. The presence of many undiagnosed mild infections probably limited efforts to control further spread of this infection. The rapidity of spread is high with a reported R0 of 5.7 (range, 3.8-8.9), when compared to the 2003 SARS outbreak with an R0 of 2-3, suggesting SARS-CoV2 is much more transmissible than SARS-CoV (3). To explain its greater transmissibility, SARS-CoV-2 is most contagious in the several days before an infected person becomes symptomatic (unlike SARS-CoV, which is most contagious at the time symptoms begin), permitting unwitting spread of the infection by asymptomatic individuals. SARS-CoV-2 also has a much higher affinity for the angiotensin-converting enzyme 2 (ACE2) host cell surface receptor on the nasal epithelium than the 2003 SARS virus (4), perhaps providing a molecular basis for the greater contagiousness of SARS-CoV-2.
By early February 2020, the Hubei lockdown began to show an effect; the rate of increase in the daily new case counts first began to slow and then the number of new cases each day began falling in mid-February. On March 8, for the first time since mid-January the number of newly reported cases in a 24-hour period was less than 50 and a week later there were no new locally acquired cases in Hubei province. In mid-March, the lockdown in Hubei was gradually lifted and new case counts have remained low. China, the world’s most populous country and the original epicenter of the COVID-19 outbreak, was able to reduce transmission to a manageable level. Currently, most new infections in China are imported from outside the country and community spread is being limited by isolating cases, tracing contacts, and quarantining contacts.
On March 11, 2020, when community spread was occurring in multiple locations throughout the world and 36 % of the total number of COVID-19 cases were being reported outside mainland China, WHO declared COVID-19 was pandemic. By then the outbreak in China had subsided and Western Europe, mainly Italy, Spain, Germany, France, and the UK, had become the new hotspots. The rapid rise in the number of new cases each day in these European countries prompted lockdowns and within the next 14 days (one incubation period for COVID-19), the daily new case counts, after peaking, began dropping. As in Hubei, the impact of lockdowns was seen only when at least one incubation period had passed, allowing for manifestation of symptoms in newly infected individuals who were still in their incubation period at the start of the lockdown.
The next hotspot was in mid-March in the northeastern region of the US. With rapidly rising daily case counts, New York, New Jersey, Connecticut, and Massachusetts imposed statewide stay-at-home orders and closure of all non-essential businesses on or about March 22, 2020. The daily new case counts continued to increase, peaking in the first week of April, and then falling during the next 14 days, to reach stable lower levels of fewer than 1000 newly infected cases daily in mid-June, a pattern similar to the response to lockdowns in China and Europe. Nevertheless, if New York, the state with most confirmed cases were considered a country, the state’s current total case count of over 430,000 cases would be the 5th largest, after the US as a whole (3.6 million), Brazil (almost 2 million), India (almost 1 million), and Russia (almost 750,000). More than half of the state's cases were in New York City, where nearly half the state's population lives.
These 4 northeastern US states have not seen a second spike in the daily new case counts and the number of deaths has remained stable, despite gradual easing of lockdowns. Their successful response resembles the success of China and the European countries in bringing the pandemic under control. This is in sharp contrast to many other US states, especially in the south and southwest regions, where the new cases counts each day either have spiked after an initial decline or just continued to climb (currently over 12,000 new cases in a day in Texas and over 15,000 in Florida) , exceeding the highest daily new case count in New York State. This is likely the result of the inability of the population in these states to practice physical distancing and use face masks.
Although the rise in new case counts could partially be due to increased testing, COVID-19 hospitalizations and deaths, indicators not influenced by increased testing, are also rapidly rising in these states. Also, the frequency of positive PCR tests is rising faster than the increase in testing in these states (5). The number of new cases for the US as a whole occurring each day is now above 70,000, which is approaching the total number of cases of COVID-19 in China over the past 8 months (about 83,000).
To control recurrent local outbreaks, some countries, such as China, Singapore, Spain, Australia, and Germany, have reintroduced regional lockdowns, which is likely what will be necessary in the US (6). Lockdowns have had proven efficacy. Once community spread has been greatly lessened, lockdowns can then be gradually eased in conjunction with containment procedures that involve testing, isolating cases, and promptly tracing and quarantining their contacts. Countries will still face reintroductions from endemic regions outside their borders, as has happened in China and South Korea, so containment strategies must be ongoing.
Resurgence of COVID-19 after relaxation of lockdown measures has occurred in countries that have previously controlled their outbreaks. These outbreaks have often been characterized by a large number of people who attended a particular event, where transmission was heighten by closed indoor spaces, crowded settings, and close contacts with others without use of any personal protection like face masks. For example, more than 100 cases were linked to nightlife venues in the Seoul, South Korea, after lockdown measures were eased. Bars and night clubs where the combination of alcohol intoxication, crowding, people not wearing face masks trying to talk above each other and over loud music are typical high-risk settings. Shouting propels viral loaded respiratory droplets further. Air conditioners may contribute to spread, potentially blowing respiratory droplets along the path of the air conditioner’s airflow. An additional factor is likely the use of public restrooms, with high-touch surfaces contaminated by unwashed hands, coupled with aerosols generated by flushing lid-free toilets with SARS-CoV-2-contaminated feces.
Transmission of SARS-CoV2
SARS-CoV2 is thought to spread mainly by
- Inhalation of large respiratory droplets containing live virus sprayed within a 1-meter radius of a coughing or sneezing infected person
Other modes of transmission include
- Inhaling small airborne respiratory emissions containing the virus
- Touching virus-contaminated surfaces and then touching the eyes, nose or mouth
- Possibly fecal-oral transmission
Superspreaders played an extraordinary role in driving the 2003 SARS outbreak and are likely playing a significant role in the current COVID-19 outbreak. A super-spreader is an individual who transmits an infection to a significantly greater number of other people than the average infected person. Multiple factors contribute to superspreading, including host behavior that increases the number and length of contacts with susceptible individuals, crowding, poor ventilation, improper isolation procedures, unnecessary movement of infectious individuals, misdiagnosis, virulence and viral load, and co-infection with another pathogen.
One COVID-19 superspreader, a British businessman, contracted SARS-CoV2 at a conference in Singapore on Jan 20-22, 2020 that was attended by 109 people from many different countries, at least one of whom was from Hubei, before traveling to France, where he spread the disease to 11 fellow guests at a ski chalet in the French Alps. He then flew home to the United Kingdom via Switzerland before discovering he harbored SARS-CoV2. Six others who attended the Grand Hyatt conference also developed COVID-19: a Malaysian, two South Koreans, and three Singaporeans.
The most important preventive measure is avoidance of exposure to SARS-CoV2 by means of
- Respiratory and contact precautions
Respiratory precautions involve using face masks. Two types of face masks are available, surgical (whether medical products or other cloth masks) and N-95. Patients should wear a surgical mask, which helps contain their respiratory secretions, thus protecting others. However, surgical masks do not fit tightly enough to definitively protect uninfected people from inhaling infected respiratory emissions (although they may limit transfer of virus from hands to nose and mouth). Thus, people in contact with infected patients (eg, health care providers, household members) should wear N-95 masks, which fit very tightly, and protect the wearer from airborne respiratory emissions.
Contact precautions include
- Avoiding close contact with people having COVID-19
- Avoiding touching one’s eyes, nose, and mouth with unwashed hands
- Washing hands often with soap and water for at least 20 seconds or using an alcohol-based hand sanitizer that contains at least 60% alcohol if soap and water are not available.
Environmental surfaces that are frequently touched by multiple people (eg, doorknobs, bathroom fixtures, keyboards elevator buttons) should be cleaned using disposable wipes before each use.
Quarantine is essential. For patients, illness severity helps determine whether they are isolated in a hospital or at home. Well individuals who had close contact with a COVID-19-infected patient are quarantined at home for the duration of the incubation period, ie, 14 days after the last exposure.
Indoor restaurants and large parties or social gatherings at people's homes where people will be eating, drinking, and talking to each other in close proximity not wearing face mask, as well as indoor sporting events where people are cheering and shouting are high-risk venues for a “superspreader” event in which a single or a few infected people can trigger a large outbreak. Recommendations are that such events where large numbers of people can be exposed in a high-risk setting, such as such as nightclubs and bars, festivals, conferences, and sporting events be postponed until the level of community transmission is low, especially for people with a higher risk of developing severe cases of COVID-19 (7).
Epidemiology and Transmission References
1. Zhou P, Yang XL, Wang XG, et al: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579: 270-273, 2020.
2. Li Q, Guan X, Wu P, et al: Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 382: 1199-1207, 2020 Epub 29 Jan. 2020. doi: 10.1056/NEJMoa2001316
3. Sanche S, Lin YT, Xu C, et al: High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2. Emerging Infectious Diseases 26 (7):1470-1477, 2020. doi:10.3201/eid2607.200282
4. Wrapp D, Wang N, Corbett KS, et al: Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367 (6483):1260-1263, 2020. doi: 10.1126/science.abb2507
5.The COVID Tracking Project at The Atlantic: State of the States: Florida. https://covidtracking.com/data/state/florida#historical Accessed July 23,2020.
6. Centers for Disease Control and Prevention: Coronavirus Disease 2019 (COVID-19): Implementation of Mitigation Strategies for communities With Local COVID-19 transmission. Atlanta, GA, US Department of Health and Human Services, Centers for Disease Control and Prevention. Updated May 27, 2020. Accessed July 23, 2020. https://www.cdc.gov/coronavirus/2019-ncov/community/community-mitigation.html
7. Centers for Disease Control and Prevention: Coronavirus Disease 2019 (COVID-19): Considerations for Events and Gatherings. Atlanta, GA, US Department of Health and Human Services, Centers for Disease Control and Prevention. Updated July 7, 2020. Accessed July 23, 2020. https://www.cdc.gov/coronavirus/2019-ncov/community/large-events/considerations-for-events-gatherings.html
COVID-19: Therapeutic and Prophylactic Agents Update July 30, 2020
Remdesivir: Remdesivir is an adenosine nucleoside analog that is administered intravenously as a prodrug, to which the host cell is more permeable (1). The prodrug is converted within the host cell to the active metabolite that interferes with RNA-dependent RNA polymerase (an enzyme that catalyzes the replication of RNA from an RNA template), thereby stopping virus replication. Remdesivir, which has been shown to inhibit SARS-CoV-2 in vitro and in animal models, was the first drug to get emergency authorization from the FDA for use in COVID-19 on May 1, 2020. The results of several clinical trials assessing the effectiveness of remdesivir in COVID-19 have been published in peer-reviewed medical journals.
The first of these clinical trials was published in the Lancet on May 16, 2020 (2). This randomized, double-blind, placebo-controlled clinical trial in adults hospitalized in Wuhan, China with severe COVID-19 pneumonia and hypoxia while breathing room air was terminated before attaining the prespecified sample size because the COVID-19 outbreak in China had been brought under control. No statistically significant benefits were observed for remdesivir treatment (200 mg IV on day 1 followed by 100 mg on days 2 to 10 in single daily infusions in 150 patients) beyond those of standard of care treatment in 76 patients. However, the primary endpoint of time to clinical improvement was numerically shorter in the remdesivir group than in the control group, particularly in patients treated within 10 days of symptom onset. The duration of invasive mechanical ventilation, although not significantly different between groups, was also numerically shorter in remdesivir recipients than in the control group. The investigators suggested that future studies should include earlier treatment, higher-dosing regimens of remdesivir, and remdesivir combined with other antiviral drugs or with SARS-CoV-2 neutralizing antibodies in patients with severe COVID-19 to better understand remdesivir’s potential effectiveness.
The next study, done at multiple international sites, was also a randomized, double-blind, placebo-controlled clinical trial of remdesivir (200 mg IV loading dose on day 1, followed by 100 mg daily for up to 9 additional days); it appeared in the New England Journal of Medicine on May 22, 2020 (3). In this trial in adults hospitalized with COVID-19 and lower respiratory tract involvement, the 538 patients who received remdesivir recovered 4 days faster (11 days) than the 521 who received placebo (15 days; P < 0.001). Recovery was defined by either discharge from the hospital or hospitalization for infection-control purposes only. The shorter time to recovery led the data and safety monitoring board to recommend early unblinding of the data to study team members from the National Institute of Allergy and Infectious Diseases because of its potential clinical benefits.
The shorter time to recovery was most apparent in patients with moderate disease. The median time to recovery in those who did not require supplemental oxygen was similar in the remdesivir (5 days) and placebo (6 days) groups, and remdesivir did not appear to improve outcomes in patients who required mechanical ventilation or extracorporeal membrane oxygenation (ECMO). Also, the difference in mortality at 14 days was not significant; 7.1% of patients taking remdesivir died and 11.9% of those given placebo died. However, a subsequent analysis based on additional data found a significant reduction of 62% (7.6 % mortality rate at day 14 for patients treated with remdesivir compared with 12.5 % in controls; P < 0.001—4).
Another study compared the outcome for 5 days (200 patients) versus 10 days (197 patients) of remdesivir therapy in hospitalized patients with COVID-19 who had radiologic evidence of pneumonia and were hypoxic while breathing room air but did not require mechanical ventilation or ECMO (5). Nevertheless, the 10-day treatment group had greater disease severity at baseline than the 5-day treatment group; more patients were on mechanical ventilation prior to initiation of treatment in the 10-day than in the 5-day group. After adjustment for baseline clinical status, clinical improvement occurred by day 14 in 64% of patients in the 5-day group and in 54% in the 10-day group.
The US National Institutes of Health (NIH) COVID-19 treatment-guideline panel recommends using remdesivir at most for 5 days. If a patient who is receiving supplemental oxygen while receiving remdesivir progresses to requiring high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO, remdesivir should be stopped because of uncertainty whether remdesivir confers clinical benefit in these patients. The guidelines do not currently make a recommendation for or against starting remdesivir in patients who already are on high-flow oxygen, noninvasive or invasive mechanical ventilation, or ECMO, because of the uncertainty regarding clinical benefit in these patients (6).
A randomized, placebo-controlled clinical trial is currently evaluating a nebulized, inhaled version of remdesivir in adults aged 18 to 45 years in the US to treat COVID-19 in the outpatient setting when the infection is in an early stage, thereby aborting progression to a more severe stage that would require hospitalization. An inhaled formulation of remdesivir will also deliver the drug directly to the primary sites of SARS-CoV-2 infection in the upper and lower respiratory tract (7). However, it should be noted that in the previous clinical trial, intravenous remdesivir did not shorten the time to recovery in patients who did not require supplemental oxygen. In these patients, time to recovery was similar in the remdesivir (5 days) and placebo (6 days) groups. Therefore, it is not clear whether nebulized remdesivir will work in very early infection.
Other Anti-Viral Drugs: Favipiravir is a guanosine nucleoside analogue that selectively inhibits RNA-dependent RNA polymerase. It is a prodrug that is metabolized within host cells to its active triphosphate that inhibits viral replication. The drug is available for oral and intravenous administration and is approved for the treatment of influenza in Japan. It is being marketed for the treatment of COVID-19 in China, India, and Russia, and is undergoing clinical trials in the US. Having an oral antiviral drug, like favipiravir, could allow outpatient therapy at an early stage when the infection is not severe enough to require hospitalization.
Lopinavir and ritonavir, a combination approved to treat HIV/AIDS, has been shown to inhibit replication of SARS-CoV-2 in vitro, but this combination failed in clinical trials. In early July, the World Health Organization suspended trials on patients hospitalized for COVID-19. The NIH COVID-19 treatment guidelines recommend against using lopinavir/ritonavir or other HIV protease inhibitors for the treatment of COVID-19, except in a clinical trial (8).
Chloroquine and a less toxic version, hydroxychloroquine (HCQ), can inhibit SARS-CoV-2 from replicating in cells in vitro, but HCQ failed to prevent infection in monkeys, and, HCQ, either alone or in combination with azithromycin, failed to treat infected monkeys (9). HCQ also failed in a randomized clinical trial to treat early COVID-19 in outpatients (10) and failed to treat COVID-19 in hospitalized patients (11); it has also been found harmful in these patients (12).
The World Health Organization (13) and the NIH (14) halted trials of HCQ as a treatment for COVID-19. The US Food and Drug Administration (FDA) revoked emergency approvals for both chloroquine and HCQ, warning that the drugs can cause serious side effects to the heart and other organs when used to treat COVID-19 (15). The NIH COVID-19 treatment guidelines recommend against using HCQ with or without azithromycin for the treatment of COVID-19, except in a clinical trial (16).
In contrast to remdesivir, which has its most favorable effect in hospitalized patients early in the course of the infection when viral replication is driving the pathogenic process, Drs. Lane and Fauci point out in an editorial in the New England Journal of Medicine that an immunosuppressive drug, such as dexamethasone, or immune modulators may be more efficacious later in the course of the infection, when viral load has fallen and immune and inflammatory responses may be the main drivers (17).
In mid-June 2020, a beneficial effect was reported for a 6-day course of methylprednisolone in 56 adults with hypoxic COVID-19 pneumonia and biochemical evidence of hyperinflammation (18). A month later, a much larger study from the RECOVERY Collaborative Group at Oxford University was published in the New England Journal of Medicine, in which British patients hospitalized with COVID-19 were randomized to receive either oral or IV dexamethasone, 6 mg/day for up to 10 days (2,104 patients) or usual care (4,321 patients) (19). A beneficial effect of dexamethasone occurred in the group receiving invasive mechanical ventilation (mortality 29.3% vs 41.4%) and in the group receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not in the group receiving no respiratory support at randomization (17.8% vs. 14.0%). The use of dexamethasone has been endorsed by the NIH for up to 10 days for the treatment of COVID-19 in patients who are mechanically ventilated and in patients who require supplemental oxygen but who are not mechanically ventilated (20). The Panel recommends against using dexamethasone for COVID-19 patients who do not require supplemental oxygen.
Recombinant angiotensin-converting enzyme 2 (ACE-2): Human, soluble, recombinant ACE-2 protein created in the laboratory might be able to bind to SARS-CoV-2 before it can attach to host cell-bound ACE2 protein, reducing the amount of virus available to infect vulnerable host cells. Human, soluble recombinant ACE-2 has already been tested in phase 1 and phase 2 clinical trials in acute respiratory distress syndrome (21, 22 and can inhibit SARS-CoV-2 infection of human cells, as well as blood vessel and kidney “organoids” in vitro (23), but recombinant ACE2 has not yet been tested in animal models or in people.
Interleukin-6 (IL-6): Cytokines are proteins produced by certain cells that signal a coordinated immunologic response to the presence of infection, immune responses, inflammation, and trauma. SARS-CoV-2 infection induces production of so-called proinflammatory cytokines, IL-1 beta, IL-6, tumor necrosis factor alpha, that are involved in the up-regulation of inflammation. When produced in excess, cytokines can trigger the immune system to overreact to infections, in a process called a cytokine storm. Researchers have created a number of drugs to halt cytokine storms, and they have proven effective against inflammatory disorders.
Several of these drugs, including tocilizumab, sarilumab, and anakinra, which are approved for the treatment of other immune and/or inflammatory syndromes, have been studied in COVID-19. Tocilizumab and sarilumab are recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibodies that bind to IL-6 receptors, blocking IL-6 from exerting its pro-inflammatory effects. Anakinra is recombinant and slightly modified version of the human interleukin 1 receptor antagonist. Anakinra blocks the biological activity of IL-1 by competitively inhibiting IL-1 from binding to the interleukin-1 type I receptor.
Tocilizumab: Several small trials, some observational, some non-randomized, studied COVID-19 patients treated with tocilizumab. Most reported resolution of fever, resolution of elevated inflammatory markers, and improvement in oxygenation (24-30). Some of these studies noted tocilizumab was associated with an increased incidence of bacterial superinfections.
Sarilumab: The drug companies, Regeneron and Sanofi, announced that sarilumab failed clinical trials in 194 COVID-19 patients requiring mechanical ventilation compared to best supportive care alone (31). Detailed results will be submitted to a peer-reviewed publication later this year.
Anakinra: In small observational and retrospective cohort studies of patients with COVID-19, treatment with anakinra was safe and associated with clinical improvement (32). Confirmation of efficacy, though, will require controlled trials.
The NIH COVID-19 treatment guidelines panel found the data were insufficient to recommend for or against use of any IL-1 or IL-6 inhibitors for the treatment of COVID-19 (20).
Vaccines stimulate a person’s immune system to produce immunity to a specific disease, protecting the person from that disease. Protective immunity involves production of neutralizing antibodies, which bind to a virus and trigger the rest of the immune system to destroy it. Immunity also involves development of infection- or vaccine-induced SARS-CoV-2 – specific T-cells.
There are as yet no vaccines available that can prevent a person from contracting SARS-CoV-2 infection or stop its further spread, but more than 100 candidate vaccines are being developed and tested around the world (33). Most of these vaccines target the spike protein that covers the surface of the coronavirus virus and is thought to be crucial for its ability to cause disease (34). Antibodies that develop following infection or vaccination attach to the spike protein and prevent its adherence and entry into host cells. To prevent a mutant strain of the virus from escaping detection by an immune response, the vaccine should optimally target several different critical sites on the spike protein (35).
There are various types of coronaviral vaccines that are being developed. Some vaccines contain the whole virus that either has been killed or in some way weakened (attenuated) and unable to cause disease. Recombinant vaccines are another type of vaccine in which genes for a viral protein (in this case the spike protein) are inserted into yeast, bacterial, or other types of cell, which then make the spike protein in the laboratory; the spike protein is harvested and put into a vaccine. Yet another type of coronaviral vaccine delivers the gene that encodes the spike protein to the vaccine recipient’s cells, which read the gene to assemble spike proteins that then provoke an immune response. The spike protein gene can be delivered into recipient’s cells directly by a special device, or via a vehicle, either an attenuated adenovirus (called a vector) or a lipid nanoparticle. The results of studies in human volunteers on three of these vaccine candidates have recently been published in peer-reviewed medical journals:
The Moderna/US National Institute of Allergy and Infectious Diseases vaccine uses the SARS-CoV-2 spike protein gene (in the form of messenger RNA or mRNA) encapsulated in a lipid nanoparticle to deliver the viral gene into host cells. The results of a study of the Moderna vaccine in 45 volunteers were published in the New England Journal of Medicine on July 14, 2020; it is the first vaccine candidate to have its study results published in a peer-reviewed medical journal. This vaccine induced an immune response similar to that following natural infection in all of the volunteers with only mild side effects -- fatigue, chills, headache, muscle pain, and pain at the injection site; the reactions tended to be more frequent and more severe with higher doses of the vaccine and after the second dose of the 2 dose vaccination schedule (36). Phase 3 efficacy trials are set to begin in late July 2020.
The Oxford University/Astra-Zeneca vaccine uses a chimpanzee adenoviral vector (ChAdOx1) that expresses the spike protein. This vaccine was studied in over 1,000 adults aged 18 to 55 years, and results were published on July 20, 2020, in the Lancet (37). This vaccine elicited an increase in spike protein-specific antibody and T-cell immune responses by day 28 and, after a booster dose, neutralizing antibody in all participants. When compared to the control group, the ChAdOx1 vaccine group was said to have experienced minor side effects, some of which were relieved by acetaminophen. Phase 3 efficacy trials are in progress.
The CanSino Biologics vaccine also uses an adenovirus (Ad5) vector that expresses the spike protein. This vaccine was studied in 508 healthy adults aged 18 to 80 years at 2 different doses, and the results also were published on July 20, 2020, in the Lancet (38). This vaccine elicited neutralizing antibodies and more than 90% of the recipients showed T-cell responses with both doses. People aged 55 years and older and those who had earlier exposure to the adenovirus vector had somewhat lower humoral antibody responses, but these factors didn't affect T-cell response. No serious adverse events were noted. The Chinese military approved the vaccine on June 25, 2020, for a year as a “specially needed drug” for soldiers.
The Pfizer/BioNTech vaccine is similar to the Moderna vaccine, using mRNA and a lipid nanoparticle vehicle, and early study results have been posted online but have not as yet appeared in a peer-reviewed journal article. Phase 3 efficacy trials are set to begin in late July 2020.
The Inovio vaccine uses DNA plasmids (small circles of double-stranded DNA) encoded to produce spike protein. The plasmids are introduced directly into host cells using an intradermal or intramuscular injection using a special patented device that produces a brief electrical pulse that reversibly opens small pores in the host cell to allow the plasmids to enter. Human study results from the manufacturer have only appeared online (39).
The Bacillus Calmette-Guerin (BCG) vaccine, developed in the early 1900s, is used to protect infants against tuberculous meningitis and miliary tuberculosis. Although there is no evidence BCG can mitigate coronavirus infection, the first of several randomized controlled trials intended to test the vaccine’s effectiveness against the coronavirus were started in April 2020, in physicians, nurses, respiratory therapists, and other health care workers in Australia (40).
Plasma of people who have recovered from COVID-19 has antibodies that are thought capable of neutralizing the virus.
An open-label, randomized clinical trial compared convalescent plasma with SARS-CoV-2 spike-receptor antibody titer greater than or equal to 1:640 with standard care in 103 hospitalized patients with severe or life-threatening COVID-19 in 7 medical centers in Wuhan, China. The study was terminated early due to control of the COVID-19 outbreak in Wuhan; there was no significant difference between the groups in the primary outcome of time to clinical improvement within 28 days (41). However, the convalescent plasma was given approximately 1 month after disease onset.
Another small trial reported a benefit from convalescent plasma with a neutralizing titer dilution of greater than 1:320 in 39 hospitalized patients who did not require intubation in comparison to retrospectively matched control patients (42). As a result, the FDA authorized use of convalescent plasma in patients with serious or immediately life-threatening COVID-19 infections if the patient’s physician requests a single patient emergency IND (43). Also, the “Expanded Access to Convalescent Plasma for the Treatment of Patients with COVID-19” program is an ongoing, open-label, nonrandomized protocol in the US primarily designed to provide adult patients who have severe or life-threatening (critical) COVID-19 with access to convalescent plasma (44). Patients are transfused with 1 or 2 units (200 to 500 mL) of convalescent plasma.
Monoclonal antibodies (Mabs) are laboratory-produced and designed to attack specific antigens; in the case of SARS-CoV-2, the Mabs target the ACE2 receptor-binding domain on the spike protein. Humanized Mabs are a type of antibody made in the laboratory by combining a human antibody with a small part of mouse or rabbit Mabs that bind to the target antigen; and the human part makes it less likely to be destroyed by the human body's immune system.
Some products will include a combination of 2 Mabs targeting different sites on the spike protein. Having a mixture of Mabs that target several different critical sites on the ACE2 receptor binding region of the spike protein make it less likely that viral mutation will result in emergence of a resistant strain (compared to an antibody that targets only one particular site—45).
Because of the long half-life of most Mabs (about 3 weeks), a single infusion is thought to be sufficient. Mabs have the potential to be used for both prevention in people who have been exposed to someone with COVID-19 and treatment of infection in people with COVID-19. For example, Mabs could be used to protect older individuals and those with underlying comorbid conditions who might not mount a robust protective response after vaccination. Mabs administered to nursing home residents during an outbreak might limit spread of the infection.
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