Coronaviruses are an important cause of the common cold, probably second only to rhinoviruses in frequency. In 2002, a new disease, an atypical pneumonia called severe acute respiratory syndrome (SARS), emerged. In 2012, another severe pneumonia called Middle East respiratory syndrome (MERS) emerged in that area of the world. These pneumonias are caused by SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV), respectively.
In December 2019, an outbreak of pneumonia in Wuhan, China caused by a new coronavirus was reported. This virus, now named SARS-CoV-2, is causing a world-wide pandemic. This virus and the disease it causes called COVID-19 are discussed separately in a section entitled “Coronavirus Outbreak and Global Pandemic in 2019-2020”.
Coronavirus has a non-segmented, single-stranded, positive-polarity RNA genome (see Table 38–2). It is an enveloped virus with a helical nucleocapsid. There is no virion polymerase. In the electron microscope, prominent club-shaped spikes in the form of a corona (halo) can be seen (See Figure 38-4). A cross-sectional model of a coronavirus is shown in Figure 38-4.1. Note the spike proteins on the surface and the coiled RNA genome in the interior of the virion.
Electron micrograph of coronavirus. Note crown (corona) of spikes protruding from virion envelope. Arrow points to one of the spikes. (Source: Dr. Fred Murphy and Dr. Sylvia Whitfield, Public Health Image Library, Centers for Disease Control and Prevention.)
Cross-section of a coronavirus. Note the club-shaped spike proteins on the surface that appear as a halo or corona in the electron microscope. Spike proteins attach to receptors on the surface of respiratory tract mucosa. Other surface proteins are shown as well. The genome RNA is depicted as the coiled strand within the virion. Source: Kenneth J Ryan. Sherris Medical Microbiology Seventh Edition. Copyright McGraw-Hill Education. All rights reserved.
There are seven serotypes, four of which cause upper respiratory tract infections, such as the common cold. The other three cause lower respiratory tract infection, such as pneumonia. These three are SARS-CoV, SARS-CoV-2 and MERS- CoV. The antigenicity of the viral spike protein of these three viruses are different from each other. The antigenicity is relatively stable, although variants of SARS-CoV-2 have appeared during the pandemic.
The receptor for the SARS-CoV and SARS-CoV-2 on the surface of human cells is angiotensin-converting enzyme-2 (ACE-2). The other coronaviruses use different cell surface peptidases as their receptor.
Summary of Replicative Cycle
The replicative cycle begins when the spike protein on the surface of the virion binds to the receptor, often the ACE-2 protein, on the cell surface. A cell surface protease cleaves the spike protein to reveal a fusion protein that mediates entry into the cytoplasm, where the virion is uncoated. The positive-strand genome is translated into two large polypeptides, which are cleaved by two virus-encoded proteases into functional viral proteins. One of these proteins is the RNA polymerase that synthesizes both the progeny genome and the mRNAs that are translated into the structural proteins of the progeny virions. The mRNAs form a set of “nested” RNAs that are a characteristic feature of coronaviruses. The virus is assembled and obtains its envelope from the endoplasmic reticulum, not from the plasma membrane. Replication occurs in the cytoplasm.
Transmission & Epidemiology
Coronavirus is transmitted primarily by the respiratory route via sneezing and coughing. Transmission via contact of hands with contaminated surfaces also occurs. Infection occurs worldwide and occurs early in life, as evidenced by finding antibody in more than half of children. Outbreaks occur primarily in the winter on a 2- to 3-year cycle. This seasonality is less dramatic than that of influenza virus.
SARS originated in China in November 2002 and spread rapidly to other countries. As of this writing, there have been 8300 cases and 785 deaths—a fatality rate of approximately 9%. Human-to-human transmission occurs, and some patients with SARS are known to be “super-spreaders.” Early in the outbreak, many hospital personnel were affected, but respiratory infection control procedures greatly reduced the spread within hospitals.
There are many animal coronaviruses in both domestic and wild animals. They are suspected of being the source of CoV-SARS. The horseshoe bat appears to be the natural reservoir for CoV-SARS, with the civet cat serving as an intermediate host.
In 2012–2013, a new human coronavirus caused an outbreak of serious, often fatal pneumonia in Saudi Arabia and other countries in that region. The disease is called Middle East respiratory syndrome (MERS), and the virus is called MERS coronavirus (MERS-CoV). As of 2019, approximately 2400 cases of MERS have been reported with a mortality rate of 35%.
The closest relative of MERS-CoV is a bat coronavirus, and bats are thought to be a reservoir. Close contact with camels appears to be the mode of transmission to humans. The risk of person-to-person transmission is low but has occurred in hospitals with inadequate infection control.
Infection by the “common cold” coronaviruses typically is limited to the mucosal cells of the respiratory tract. Approximately 50% of infections are asymptomatic, and it is unclear what role they play in the spread of infection. Immunity following infection appears to be brief, up to two years, and reinfection can occur.
Pneumonia caused by SARS-CoV is characterized by diffuse edema in the alveoli resulting in hypoxia. Infection by SARS-CoV-2 involves not only the lung but other organs as well. See the separate section on SARS-CoV-2 later.
The common cold caused by coronavirus is characterized by coryza (rhinorrhea, runny nose), scratchy sore throat, and low-grade fever. This illness typically lasts several days and has no long-term sequelae. Coronaviruses also cause bronchitis.
SARS is a severe atypical pneumonia characterized by a fever of at least 38°C, nonproductive cough, dyspnea, and hypoxia. Chills, rigors, malaise, and headache commonly occur, but sore throat and rhinorrhea are uncommon. Chest X-ray reveals interstitial “ground-glass” infiltrates that do not cavitate. Leukopenia and thrombocytopenia are seen. The incubation period for SARS ranges from 2 to 10 days, with a mean of 5 days. The clinical findings of MERS are similar to those of SARS.
If SARS or MERS is suspected, PCR-based tests that detect coronavirus RNA in respiratory tract specimens can be used. Antibody-based tests to detect a rise in antibody titer can be used for epidemiologic purposes.
There is no antiviral therapy available for SARS-CoV, MERS-CoV, or any of the common cold strains. Some antiviral drugs may effective against SARS-CoV-2 and are discussed in the next section.
There is no vaccine available against any coronavirus.
Coronavirus Outbreak and Global Pandemic in 2019-2021
Introduction to the Pandemic
In December 2019, an outbreak of pneumonia in Wuhan, China caused by a new, novel Coronavirus occurred. This virus is named SARS-CoV-2 and the disease is named COVID-19. (COVID stands for Coronavirus Infectious Disease and 19 stands for 2019.) The World Health Organization declared a global pandemic on March 11, 2020.
As of this writing on October 14, 2021, the virus has caused approximately 239 million cases, and more than 4.8 million deaths world-wide. The fatality rate is approximately 2.0%. In the United States, approximately 44 million cases and 712 thousand deaths have been reported. The fatality rate in the United States is approximately 1.6%. World-wide, approximately 6.4 billion vaccine doses have been administered.
As of June 2021, the number of cases and deaths from COVID-19 declined significantly, mostly as a result of widespread immunization. However, in July and August 2021, a fourth wave of infections occurred. This increase in infections is the result of three factors, waning immunity induced by the vaccine, the delta variant that has increased transmissibility, and relaxation of public health measures such as masking.
The fundamental reason why this virus caused a global pandemic is that it is a new (novel) strain of coronavirus to which the human population had no pre-existing immunity. The virus emerged from the animal population with spike protein antigens on its surface to which no one had antibodies.
Origin of the Novel Coronavirus
Based on genome RNA sequencing results, SARS CoV-2 closely resembles a coronavirus of bats and that animal is likely to be the natural reservoir. A second, intermediate reservoir, the pangolin, is likely to be involved. Sequences of the pangolin CoV spike protein are found in the SARS CoV-2 spike protein.
In May 2021, the original hypothesis that SARS-COV-2 spread from an animal to people at "wet animal" market in Wuhan, China was questioned. An alternative possibility that workers at the Virus Laboratory in Wuhan China may have been accidently infected and unintentionally spread the virus to others was raised.
Sequencing of the spike protein gene during the course of this pandemic revealed several mutations that are causing disease in many areas. For example, a mutation designated D614G in the gene encoding the spike protein favors an “open” configuration of the receptor binding domain on the spike protein thereby increasing the ability of the virus to infect the cell. The mutant D614G virus (also called G strain) was, at the time, the most common virus isolated from COVID-19 patients world-wide.
In December 2020, a new mutant strain designated B.1.1.7 (now known as Alpha variant) was reported to be spreading widely. This variant has 17 mutations, 8 of which are in the gene for the spike protein. This variant is more transmissible but not more virulent than the existing strain. Further, the current vaccines elicit antibodies that appear to be protective against this new variant. In April 2021, the B.1.1.7 variant became the dominant strain in the United States.
In January 2021, additional variants appeared in South Africa, Brazil, India, and in the United States. Initial studies showed that these variants have increased transmission, and may be more virulent, that is, cause death more frequently. In addition to the B.1.1.7 variant mentioned above, the B.1.351 (Beta) variant that emerged in South Africa, the P.1 (Gamma) variant that emerged in Japan and Brazil, and the B.1.617.2 (Delta) variant that emerged in India, are all circulating in the United States. The Delta variant is now the dominant strain in the United States. Recent studies have shown that two doses of the existing vaccines will provide reasonable protection against these new variants. These four variants, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) have been designated "Variants of Concern" by WHO and CDC.
Attachment and Entry of Virus into Cell
The main receptor for SARS CoV-2 is the ACE-2 receptor on the surface of respiratory tract epithelium. The spike protein on the surface of the virus binding to the ACE-2 receptor is the first step in the entry of the virus into the cell. After binding, the cell surface protease, TMPRSS-2, cleaves the spike protein to reveal a fusion sub-unit that mediates fusion of the virus with the cell membrane and entry of the virion into the cytoplasm.
Antibody to the virus elicited either by natural infection or by a vaccine (when available) neutralizes the virus by preventing the binding of the spike protein to the ACE-2 receptor. The relatively low number of cases of COVID-19 in children is attributed to the low number of the ACE-2 receptor displayed on their cells.
A second newly identified receptor on the cell surface is neuropilin-1 (NRP-1). The spike protein of the virus binds to NRP-1 and the virus can enter the cell. Antibody to NRP-1 prevents infection of the cell suggesting that it could be an additional target for drugs or vaccines.
The primary mode of transmission is inhalation of respiratory droplets generated by coughing, sneezing, or talking during face-to-face contact. Respiratory aerosols also play important role in transmission of this virus. Note that aerosols are smaller than droplets so stay in the air longer and can be distributed over a distance more than 6 feet by air currents. Shedding of virus by an infected patient typically begins 2 to 3 days before symptom onset and lasts for about seven days. Shedding of virus prior to the appearance of symptoms explains the well-recognized phenomenon of asymptomatic transmission.
Transmission by hand contact with surfaces containing virus also occurs. Fingers transport the virus on the surface to the recipient’s eyes, nose, or mouth.
The majority of infections are acquired by transmission from asymptomatic carriers, probably by droplets/aerosols generated by talking, singing, or shouting. This indicates that a large amount of virus is present in the upper respiratory tract. People with asymptomatic infections are thought to be capable of transmitting the virus during a period that begins several days after the time of infection and lasts for about a week. A rough approximation is, therefore, about ten days after the time of infection.
Vertical transmission from an infected mother to the fetus is very rare. Transmission from an infected parent to a neonate is uncommon but can result in symptomatic COVID-19 disease in the neonate.
“Super-spreader” events at which large numbers of people have been infected have been observed. These typically involve large numbers of people gathering, often indoors, and not wearing masks or observing the 6 foot social distance. It is thought that ”super-spreading” is caused not by an individual producing exceptionally large amounts of infectious virus but rather by the combined effect of the environmental factors conducive to spread mentioned in the previous sentence.
Nursing homes, prisons, and homeless shelters have high rates of infection due to the crowded living conditions. Nursing homes in particular have many serious infections because the population is elderly.
Coronavirus infections exhibit less seasonality that do influenza virus infections. The increase in SARS CoV-2 infections in the summer of 2020 indicates that this coronavirus is not exhibiting a drop-off in infections during the warmer months the way influenza does. Nevertheless, a world-wide study performed in January to March 2020 indicated a correlation of outbreaks of COVID-19 within a narrow band of latitude with low temperature and low humidity.
The incubation period ranges from 2 to 14 days with a mean of 5 days. A quarantine period of 14 days has, therefore, been instituted.
The main clinical findings are fever, dry cough, and shortness of breath. Sore throat may occur but is not a prominent feature. Systemic symptoms such as fatigue, shaking chills, headache, and myalgia also may occur.
In addition to the respiratory tract, other organs such as the heart, kidney, brain, and gastrointestinal tract can be affected (see Table 38-5). A severe myocarditis with symptoms resembling a myocardial infarction has occurred in some patients. Loss of ability to smell (anosmia) and abnormal ability to taste (dysgeusia) are the initial symptoms in some patients. Anosmia and dysgeusia are important diagnostic features of COVID-19. Encephalopathy has also been observed. Nausea, vomiting, and diarrhea have occurred in some patients. Blood clots occur in some patients resulting in thrombosis or emboli leading to an increased risk of stroke.
Table 38–5Clinical Features of COVID-19 ||Download (.pdf) Table 38–5 Clinical Features of COVID-19
|Organ Affected ||Clinical Manifestation |
|Lung ||Pneumonia, ARDS with “cytokine storm” |
|Heart ||Myocarditis |
|Nervous system/Brain ||Encephalopathy, anosmia, dysgeusia |
|Gastrointestinal tract ||Nausea, vomiting, diarrhea |
|Kidney ||Renal failure |
|Blood vessels ||Thrombi, emboli |
Many of these findings are caused not by the virus directly but by the Cytokine Release Syndrome, also known as “Cytokine storm”. Viral infection triggers an overproduction of cytokines such as interferon-gamma, tumor necrosis factor, interleukin-6, bradykinin, and other pro-inflammatory cytokines (see Pathophysiology section below).
Other clinical findings include inflammation of the toes (“Covid toes”) and a Kawasaki disease-like syndrome that has occurred in children. The latter has been given the name “pediatric multisystem inflammatory syndrome”. It is also known as multisystem inflammatory syndrome in children (MIS-C). Another important clinical finding is is the observation that superimposed bacterial infections in the respiratory tract or blood occur in many patients.
Lymphopenia is common. Serum C-reactive protein and lactate dehydrogenase are elevated. Elevated D-dimers in the plasma occur in some patients resulting from clotting abnormalities. Respiratory tract specimens are typically negative for other respiratory viruses, including influenza virus.
Chest x-ray typically reveals bilateral opacities, often with a “ground-glass” appearance. No pleural effusions are seen. Mechanical ventilation is often required in patients with severe disease.
Death is due to hypoxemic respiratory failure. Cytokine storm contributes to death in some patients. A common listed cause of death is Acute Respiratory Distress Syndrome (ARDS).
Overall hospital mortality rates range from 15 to 20 but up to 40% for ICU admissions. Mortality rates differ greatly by age. The death rate per 1000 CVID-19 cases is 1.1 for those in the 18 to 29 year age group but 210.5 for those 75 to 84 years old and 304.9 for those 85 years or older.
In patients who have recovered from COVID-19 disease, the duration of antibody-mediated immunity appears to be at least 6 months. IgG antibody to spike protein was detectable for more than 6 months as were memory B cells. However, CD-4 positive T cells and CD-8 positive T cells declined with a half-life of 3 to 5 months.
Some patients who have recovered from the initial severe symptoms, continue to have symptoms, such as prolonged cough, shortness of breath, chest pain, joint pain, fatigue, dizziness, and confusion for several months. These after-effects cause significant limitations on the ability on the quality of life. This occurs in many who did not have prior pre-existing conditions, had mild initial disease, or were young adults. Some also continue to have positive PCR tests indicating that virus is still present. The World Health Organization has named this syndrome “Long COVID”. These patients are referred to as ”long haulers”. These long-term symptoms are also called “post-acute sequelae of SARS-CoV-2” abbreviated PASC. Approximately 37% of COVID-19 patients had one or more symptoms of Long COVID between 3 to 6 months after their diagnosis.
Approximately 50% of infections are asymptomatic and many others have only mild respiratory tract disease. Older adults (especially those over 70 years of age), people with compromised immunity, diabetics, and those with chronic heart, kidney, or respiratory tract disease are more likely to have serious COVID-19 disease. Obese people, specifically those with a body mass index or 30 or greater, are at high risk of serious disease. People with a history of smoking or vaping have a significant risk of severe COVID-19 disease.
In general, the symptoms of COVID-19 in children are less severe and death occurs much less often. This is attributed to two observations: that there are fewer ACE-2 receptors in children than adults and that children mount a stronger innate immune response than do older adults.
In August 2020, reports of reinfection began to appear. For example, a patient with documented COVID-19 infection in April 2020, recovered, and tested negative. In August, although asymptomatic, he tested positive again. Genome analysis revealed he was infected with two different clades of the virus.
Initial studies showed that people with ABO blood group A have a higher risk of contracting COVID-19 than people with the O group. This is attributed not to the presence of the A antigen but rather to the absence of the A antibody. It is speculated that A antibodies in the plasma of people who have O group may bind to sugars on the viral spike protein and inhibit entry of the virus into the cell. Recent studies have found that people with blood group A are not at much greater risk.
Men have more COVID-19 infections than women. This is attributed to the up-regulation by testosterone of TMPRSS-2, a protease on the cell surface involved with entry of the virus into the cell.
A disproportionate percentage of COVID-19 cases occurs in minority populations. For example, a report from the Centers for Disease Control and Prevention described a community in which 33% of COVID-19 patients were Black and 45% were White whereas the percentage in the community at large was 18% Black and 59% White.
Microscopic examination of the lung tissue of deceased patients showed marked alveolar damage, edema, and infiltration of T lymphocytes. Severe endothelial damage was observed. Widespread thrombosis of capillaries was seen in many organs. Microangiopathy and angiogenesis were also observed.
The respiratory manifestations are likely to have two pathogenetic mechanisms: one is the killing of alveolar cells by the virus. Accumulated cell debris blocks diffusion of oxygen into the capillaries resulting in hypoxia.
The other is killing of the endothelial cells of the capillaries lining the alveoli. This triggers blood clots and an immune-mediated “cytokine storm” (also known as cytokine release syndrome) resulting in further damage to the alveolar membrane and acute respiratory distress syndrome (ARDS). High levels of pro-inflammatory cytokines such as IL-1, IL-6, bradykinin, and tumor necrosis factor (TNF) are found.
Damage to endothelial cells and the resulting blood clots is the cause of many of the extra-respiratory manifestations of COVID-19 disease.
SARS CoV-2 inhibits interferon synthesis, an important part of the innate immune response. The N (nucleocapsid) protein blocks the action of the RIG receptor that detects dsRNA in the cytoplasm thereby inhibiting interferon synthesis.
There are three types of laboratory tests. Two of these detect the presence of the virus, either by PCR test detecting the viral RNA or by enzyme immunoassay detecting a viral antigen. The third type of test detects antibodies to the virus in a person’s serum.
Laboratory diagnosis for the presence of viral RNA is made by PCR testing on respiratory tract specimens, such as nasopharyngeal swabs. Although very sensitive and specific, PCR test can be falsely-negative if the specimen is taken too soon after infection. The test is most sensitive at 3 days after symptom onset. A rapid isothermal amplification assay for use in the field has been developed. This test does not require cycles of heating and cooling. A CRISPR-based test for the presence of virus has also been developed.
Rapid laboratory tests for viral antigen, typically the spike protein, are also available. These enzyme immunoassay tests are not as sensitive as PCR tests so false-negative results can occur. A negative result does not rule out infection. The advantage of this type of test is that they are rapid, inexpensive, and can be done by the user at home, much like a pregnancy test. In August 2020, the FDA approved a “point-of-care” antigen test that detects the nucleocapsid antigen of SARS-CoV-2 using a nasal swab specimen. As of this writing, several antigen tests such as BinaxNOW, QuickVue, and Flowflex, are available. Inexpensive home tests that provide rapid results seem likely to be important tools to identify those who are infected and therefore need to quarantine.
Tests to detect IgM and IgG antibodies to the virus have become available. IgM antibodies can be detected by 5 days after infection but IgG antibodies are first detected 14 days after symptom onset. Note that these tests indicate an antibody response but they do not indicate that the virus is present at the time of the test. A positive test indicates that the person has been infected but not that the person can transmit the virus to others.
Antibody tests have greater than 95% specificity. Tests that detect total (IgM and IgG) antibody are the most sensitive. There is a question about which antigen, the nucleocapsid (NC) protein or the spike protein (or both) should be used in the tests. The nucleocapsid (NC) protein is most abundant so testing for that protein would be most sensitive. But tests that detect antibody to the spike protein are most likely to detect neutralizing antibody.
Another question is how long antibody elicited by infection, as distinct from immunization, will protect from reinfection. In July 2020, a study reported that patients with mild disease showed a rapid decline in antibody titer during the 3 months following recovery. Note that the duration of detectable antibody in patients from the SARS outbreak in 2003 lasted about 2 to 3 years.
PCR tests for viral RNA are likely to be positive during the first week of symptomatic infection but antibody tests are likely to be positive only after 3 weeks of symptomatic infection. It is recommended that people wait at least 3 weeks after symptoms appear to have antibody testing done.
PCR tests are currently reported as either positive or negative, not as the viral load as is done with HIV infection. There is a proposal to report the Cycle Threshold (CT) as an indirect measure of the amount of virus present in the patient’s specimen. The PCR test undergoes repeated cycles of heating and cooling hence the use of the term “Cycle”. If no viral RNA is detected after 40 cycles, the test is reported as negative, Note that if the specimen turns positive at a low CT then there is a large amount of virus present. Knowing this would be helpful in evaluating how likely the patient was to transmit this virus to others.
Supportive care including supplemental oxygen should be instituted. Some hospitalized patients need respiratory support provided by mechanical ventilators. Prone positioning helps patients to breathe.
Therapeutic treatment modalities fall into four categories. There are drugs directed against viral replication, antibodies directed against viral replication, drugs directed against cytokine storm and antibodies directed against cytokine storm (see Table 38-6).
Table 38–6Important Treatment Modalities Used in COVID-19 ||Download (.pdf) Table 38–6 Important Treatment Modalities Used in COVID-19
|Therapeutic Purpose ||Drug ||Antibody |
|Inhibit viral replication ||Remdesivir (EUA) || |
1. Cocktail of two monoclonal antibodies (EUA); either casirivimab and imdevimab or bamlanimumab and etesevimab
2. Bamlanimumab (EUA)
3. Convalescent plasma (EUA)
|Inhibit cytokine release syndrome (Cytokine Storm) || |
2. Baricitinib and remdesivir (EUA)
|Monoclonal antibody against IL-6 receptor (e.g. tocilizumab) (EUA) |
On October 22, 2020, the FDA approved the use of remdesivir in hospitalized patients. Clinical trials showed that remdesivir shortened the hospital stay of seriously ill patients by 4 days and decreased mortality from 11% to 7%. Remdesivir is an adenosine analogue that inhibits viral RNA-dependent RNA polymerase. It is a “chain-terminating” drug. Favipiravir, another RNA polymerase inhibitor, is also being tested. Hydroxychloroquine, the anti-malarial drug, is not effective. There is no published data on the effectiveness of oleandrin.
In addition to the viral polymerase, a second drug target is the virus-encoded protease. Unfortunately, a trial of the protease inhibitor combination lopinavir/ritonavir reported no clinical improvement. A trial of the protease inhibitor, atazanavir, is in progress.
In August 2020, the use of convalescent plasma received emergency use authorization from the FDA. Clinical trials using convalescent plasma to treat COVID-19 are ongoing. Preliminary data shows this may be helpful, but results from larger studies are needed. Note that plasma is being used, not hyperimmune globulins. Note also that the plasma must be matched to the recipient as anti-ABO antibodies are present in the plasma.
Humanized monoclonal antibodies can be used for either treatment and prevention. Monoclonal antibodies avoid the risk of using human plasma which may transmit viruses in the donor plasma. On November 9,2020, the FDA approved emergency authorization for bamlanivimab, an IgG monoclonal antibody directed against the spike protein of SARS CoV-2. It should be used to treat those who have tested positive, have mild-to moderate disease, and are at risk of developing severe disease. It is not for hospitalized patients with severe disease.
On November 21, 2020, the FDA granted emergency use authorization (EUA) for a combination of two monoclonal antibodies (casirivimab and imdevimab) for the treatment of mild to moderate COVID-19. These two antibodies bind to different areas on the Receptor Binding Domain of the spike protein. In February 2021, the FDA approved an EUA for the use of a second monoclonal antibody combination containing bamlanimumab and etesevimab. These monoclonal antibodies target different sections of the receptor binding domain of the spike protein.
Nanobodies are single domain antibodies composed of the variable region of the heavy chain of an immunoglobulin. Their small size makes them very stable, an attribute that allows delivery via aerosol into the respiratory tract. Nanobodies directed against the CoV spike protein (termed Aeronabs) are being considered for either treatment of early disease or for prophylaxis.
A trial of intra-nasal interferon-beta showed treated patients were significantly more likely to recover than patients who did not receive the drug.
Regarding the treatment of cytokine storm, both dexamethasone, a corticosteroid, and tocilizumab, a monoclonal antibody against the interleukin-6 (IL-6) receptor, are approved for use. One recommended regimen consists of dexamethasone with or without remdesivir plus either tocilizumab or baricitinib, a Janus kinase inhibitor (see next paragraph).
Baricitinib and ruxolitinib (Janus kinase (JAK) inhibitors), are also being evaluated as an inhibitor of cytokine release. A combination of baricitinib and remdesivir reduced time to recovery in hospitalized patients in a recent clinical trial. On November 19, 2020, the FDA granted emergency use authorization (EUA) for the combination of baricitinib and remdesivir.
Antioxidant compounds, such as glutathione (GSH) and N-acetyl cysteine inhibit NF kappa-B, a proinflammatory transcription factor. A trial using GSH to treat ARDS has shown some efficacy. Mesenchymal stem cell therapy is also undergoing clinical trial to reduce the effects of cytokine storm.
There are three vaccines that have received an Emergency Use Authorization (EUA) as of February 27, 2021. On December 11, 2020, the FDA approved the Pfizer m-RNA vaccine and one week later an EUA for the Moderna m-RNA vaccine was granted. Both vaccines contain the mRNA for the coronavirus spike protein enclosed in a lipid nanoparticle. On August 23, 2021, the FDA gave full approval to the Pfizer vaccine.
On February 27, 2021, the FDA approved an EUA for the Johnson & Johnson vectored vaccine. This vaccine contains a replication-deficient human adenovirus into which the DNA encoding the spike protein of SARS CoV-2 has been inserted. Table 38-7 describes the leading vaccines that have either received an EUA or are in advanced clinical trials.
Table 38–7Important Types of Vaccines against COVID-19 ||Download (.pdf) Table 38–7 Important Types of Vaccines against COVID-19
|Type of Vaccine ||Immunogen in Vaccine ||Comment |
|RNA ||Messenger RNA for spike protein ||Enclosed in lipid nanoparticles. Pfizer/BioNTech and Moderna vaccines approved for EUA. |
|Protein subunit ||Recombinant spike protein ||Saponin-based adjuvant added. |
|Vector ||Human adenovirus (serotype 26) containing DNA encoding spike protein ||Adenovirus is engineered to be non-replicating. Johnson & Johnson vaccine approved for EUA. |
|Vector ||Chimpanzee adenovirus containing DNA encoding spike protein ||Chimpanzee adenovirus is non-replicating and non-pathogenic in humans. Oxford/ Astra-Zenica vaccine approved by WHO. |
Note that these vaccines are monovalent and stimulate an immune response to the spike protein of the original strain of SARS CoV-2. To address the emergence of new viral variants, multivalent vaccines and booster doses are being prepared.
As of August 2021, a third dose (booster dose) of the two mRNA vaccines is being administered to immunocompromised people. Because of waning immunity and the surge of delta variant cases, booster doses are planned for the general population in September 2021. On September 22, 2021, the FDA approved a booster dose for those who received two doses of the Pfizer vaccine at least 6 months previously and were at least 65 years or older or had a high risk for severe COVID-19. Booster doses for the Moderna mRNA vaccine and for the Johnson & Johnson vectored vaccine are expected to be approved shortly.
The effectiveness of the vaccines to induce neutralizing antibody, to prevent transmission by inducing IgA, and the duration of its protection are important aspects. The short term and long term safety of the vaccines must be evaluated.
Despite a vaccine effectiveness of 80 to 90 % in preventing severe COVID disease, people immunized with two doses nevertheless have contracted COVID-19 disease. In most cases, this "breakthrough" disease was mild, although in some, it was severe and a few patients died.
An unusual adverse effect of these m-RNA vaccines is a rash at or near the site of infection called "COVID-Arm. It appears to be a delayed hypersensitivity response to some component of the vaccine. Onset of the rash occurred approximately 8 days after inoculation and the rash resolved without sequelae. Most patients did not experience a rash upon receiving the second dose but a few did.
Monoclonal antibodies can be used for prevention as well as treatment. These antibody preparations can be used either pre-exposure in people working in high risk situations or post-exposure in people known to be exposed to the virus. These antibodies can provide immediate protection that can last for weeks to months. The FDA has issued an EUA for two monoclonal antibody combinations, casirivimab/imdevimab and bamlanivimab/etesevimab, for prophylaxis in a person who had close-contact with a COVID-19 patient.
Prevention centers on public health and hygiene measures to interrupt transmission. Wearing a mask and social (physical) distancing at least 6 feet are the most important measures. Other basic measures include frequent hand washing, practicing cough and sneeze etiquette, avoiding touching eyes, nose, and mouth, avoiding people with respiratory symptoms, and staying at home if you are sick.
Those infected should be isolated. Isolation should be maintained for at least 10 days after onset of symptoms. Those who have been exposed but who are not known to be infected should be quarantined for 14 days.
Contact tracing to identify those who have been exposed is another important tool to interrupt the chain of transmission. Personal protective equipment (PPE) for medical personnel is essential to interrupt transmission in hospitals.
In the global pandemic of 2020, many schools and colleges were closed or classes presented remotely. Large gatherings such as sporting events and concerts were cancelled or postponed. Many states issued “Stay at Home” orders, allowing only essential services to remain open.
The safe transition to the “New Normal” will depend on the presence of antibodies in the individual acquired either by the infection or by the vaccine. If enough people develop immunity, then herd immunity may protect those who are still susceptible. The percentage of immune people required to develop effective herd immunity against SARS-CoV-2 is unknown at this time.
Whether this virus becomes endemic and recurs at regular intervals or, like the SARS-2003 coronavirus no longer causes disease in humans, remains to be seen.