COVID-19 Variants

Coronavirus 2019 (COVID-19) disease is the clinical illness caused by the novel coronavirus that was initially called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; SARS-2). ^{[1, 2]}  SARS-CoV-1 (SARS-1), a different strain of coronavirus, caused illness during 2002-2004. It also caused severe respiratory disease, then essentially eradicated. ^[3]

COVID-19 first was identified during an outbreak of respiratory illness in Wuhan, the capital of Hubei province, China. The first cases were observed in November 2019, with COVID-19 quickly producing an epidemic in the Hubei province and surrounding regions of China. ^[4]

The World Health Organization (WHO) was notified of the outbreak in Wuhan on December 31, 2019. Cases continued to spread outside the area, and then across the world. The first case in the United States was identified on January 21, 2020. In late January 2020, COVID-19 was reported as a global health emergency by the World Health Organization (WHO). As the worldwide case numbers increased, the WHO declared on March 11, 2020, that COVID-19 had reached the pandemic stage. 

It is important to define the terms used to describe the extent of viral infections, although there is considerable overlap, and the terms often are used interchangeably. An outbreak  is a sudden increase in the incidence of disease in a defined location. It can progress to an epidemic  if it affects many people within a community, population, or region. A pandemic  is an epidemic that is spread over multiple countries or continents. Endemic defines a disease that remains in a particular country or region with periodic outbreaks. The best example is influenza, which has been endemic in the United States for centuries.

Please see Coronavirus 2019 (COVID-19) and Coronavirus Disease 2019 (COVID-19) in Children.

 

 

Human coronaviruses (HCoVs) first were identified in 1965 as a common cause of mild upper and lower respiratory infections in children and adults, similar to illness produced by rhinoviruses and respiratory syncytial virus. ^[3]  The name corona comes from the electron microscopic presence of surface projections that give virions the appearance of a crown. Signs and symptoms are flulike, and include primarily upper respiratory congestion, cough, and low-grade fever. Other presentations are fatigue, sore throat, acute otitis media, reactive airway disease, bronchiolitis, pneumonia, and gastroenteritis. However, disease is reported to be more severe in some animals, causing encephalitis, hepatitis, and peritonitis. Coronaviruses commonly colonize bats, but illness has not been characterized in these animals. ^[3]

Many HCoV strains have been identified, the most common designated as 229E, OC43, B814, NL63, and HKU1. These strains rarely have required more than symptomatic treatment. Human coronavirus strains have remained endemic in the United States since 1965, when these viruses first were isolated and characterized. Before the emergence of SARS-1 and Middle East respiratory syndrome (MERS), all coronaviruses were thought to only cause trivial respiratory illness and occasionally gastroenteritis, so little research focused on these viral pathogens.

SARS CoV-1 – 2002 to 2004   

In 2002, a new strain of coronavirus emerged that caused severe acute respiratory syndrome 1 (SARS-1), designated SARS-CoV-1. This was an infection with much greater morbidity and mortality than previous viruses from the Coronaviridae family.

An outbreak of this new coronavirus began in 2002-2003 in the Guangdong province of southern China, spreading and causing serious illness in more than 8000 persons worldwide. With simple control measures, this viral infection was eradicated. No cases have been identified since 2005. ^[3]

The clinical illness followed a biphasic pattern, initially presenting with a flulike prodrome characterized by fever, myalgia, malaise, headache, and anorexia. Some patients also had sore throat, nausea, vomiting, and diarrhea. This was followed after 3 to 7 days by the lower respiratory symptoms of cough, dyspnea, hypoxia, and respiratory failure in the more severe cases. No treatment other than respiratory support was found to be effective. SARS-CoV-1 never reached pandemic proportions.  

MERS – 2012 to present

Similar to SARS CoV-1, MERS caused by MERS-CoV first was identified in Saudi Arabia in 2012. ^{[4, 5]}  It causes severe disease primarily in adult males who have underlying comorbidities. MERS is associated with a fatality rate as high as 25-35% in at-risk individuals, yet only causes a mild clinical illness in children and immunocompetent adults. Similar to other common coronaviruses, presenting clinical manifestations include cough and respiratory symptoms, which frequently are accompanied by fever, chills, dyspnea, and the gastrointestinal manifestations of diarrhea and vomiting. Unique laboratory features are thrombocytopenia and elevated lactate dehydrogenase (LDH).

An outbreak occurred in South Korea in 2015 that was related to an infected emigrant, but most other cases since then have been reported in travelers to the Middle East. 

Infection begins as an acute respiratory illness that progresses to pneumonia. In adults with comorbidity factors or who are elderly, disease may progress to multi-organ system failure. MERS-CoV is spread from person to person after close contact, but transmissibility is relatively low. Secondary cases are highest in healthcare workers, caregivers, and close contacts of infected individuals.

Variants of Concern

Many viruses mutate over time. The best examples are influenza and human immunodeficiency viruses, which constantly change, and these mutations sometimes result in a new variant of the virus causing disease that eludes previous control and treatment methods. Some variants emerge and disappear, whereas others persist. It now is apparent that new COVID-19 variants and omicron subvariants will continue to emerge. ^{[1, 2, 5, 6]}  CDC and other public health organizations are responsible for monitoring all variants of these coronaviruses and rapidly advising healthcare workers of any new developments.

Viruses, such as SARS-CoV-2, constantly are changing. Among the hundreds of variants detected in the first year of the pandemic, the most worrying are variants of concern (VOCs). Tracking VOCs is vital to assess evidence of:

• Impact on diagnostics, treatments (eg, monoclonal antibodies, antiviral agents), or vaccines 
• Increased transmissibility
• Increased disease severity

Infections with the original variant increased early in the pandemic, but soon new variants and subvariants were identified (Table 1), each with a different severity and communicability profile. ^[7]  The proportion of VOCs circulating in the United States and regions is monitored by the CDC.

COVID-19 Alpha VOC

Alpha was the first of the highly publicized VOCs, initially reported in Great Britain in November 2020. ^[6]  Infections surged in December of that year. The Alpha variant soon surfaced around the world and became the dominant variant in the United States, where the CDC classified it as a VOC. Symptoms were flulike, and included fever with chills, congestion, cough, sore throat, shortness of breath or difficulty breathing, fatigue, myalgia, headache, new loss of taste or smell, nausea, vomiting, and diarrhea. Alpha rapidly faded away with the rise of the more aggressive Delta variant.

COVID-19 Beta VOC

The COVID-19 Beta variant was identified at about the same time as the Alpha variant in late 2020, first in South Africa, where many investigators thought it would spread and spark a second pandemic. ^[6]  People infected with Beta were 25% more likely than those infected with Alpha to develop severe disease; around 50% more likely to require intensive care; and 57% more likely to die. Beta surged in Qatar, acute care admissions doubled, and ICU admissions and deaths quadrupled.

Severe cases of COVID-19 were more common during South Africa’s second wave, which was caused by the Beta variant, than during its first wave, caused by the initial SARS-CoV-2 strain. Limited data from Qatar and South Africa in early 2021 supported the more severe illness with this COVID-19 variant.

In studies from South Africa, infected individuals were 30% more likely to die after hospitalization during its second wave than during its first outbreak. Beta infection also appeared to be less severe in vaccinated individuals or those who had been infected with the earlier strains. The focus on the COVID-19 Beta variant soon was superseded by concerns with the emerging Delta variant, which was more transmissible and rapidly replaced Beta.

COVID-19 Lambda VOC

The Lambda COVID-19 VOC was observed to be more infectious than the original COVID-19 (SARS-CoV-2), and it also was more resistant to available vaccines. The first case in the United States was reported in Houston, Texas in November 2020. This variant, too, soon was replaced by Delta because of Delta’s greater transmissibility, so little information is available relevant to its clinical course and prevention with current vaccines. ^[8]

COVID-19 Delta VOC

Delta is the VOC that continues to receive the most attention because of its severe manifestations and rapid spread, including among patients who have received the available COVID-19 vaccines; it has more than a dozen mutations. First identified in India in November 2020, it soon spread throughout the world, becoming the predominant variant of coronavirus, until Omicron surfaced in December 2021 and replaced Delta.

COVID-19 Gamma VOC 

Gamma emerged in July 2021 as a cluster outbreak in French Guiana with a high attack rate even in fully vaccinated persons. ^[5]  This was anticipated based on in vitro studies of antibody production against the variant in vaccine recipients. Some of the vaccine failure may have been related to improper administration of vaccines since storage of vaccines at appropriate cold temperatures could be documented. However, vaccination did appear to protect from severe manifestations of disease, requiring less hospitalization and intensive care support among immunized individuals than was seen in unvaccinated patients. When Gamma became the predominant variant in French Guiana, essentially causing an epidemic wave, it threatened to overload hospital capacity and overwhelm healthcare personnel.

The experience in the United States was somewhat different. Of 555 COVID-19 vaccine breakthrough infections in the United States during January 2021 to April 2021 in which sequencing was performed, only 28 were caused by the Gamma variant. This contrasted with observations of the Beta variant, which shares a similar mutation with Gamma and had an estimated 75.0% attack rate in vaccinated individuals. The Gamma variant no longer is circulating.           

Omicron variants and subvariants

Omicron BA.1 VOC       

New variants of COVID-19 were reported in November 2021, with the first in the United States identified in December and named Omicron (BA.1). In early January 2022, Omicron was estimated to account for 95.4% of novel coronavirus infections, surpassing the COVID-19 Delta variant as the most common of the novel coronaviruses worldwide. This highly contagious variant causes less severe disease than the Delta strain but is more transmissible. A South African study showed that vaccinated individuals are less prone to severe illness associated with Omicron, and unvaccinated patients also are less likely to have severe manifestations of the disease when compared with the experience with the earlier COVID-19 strains.

Omicron XE

Omicron XE is a recombinant variant of Omicron BA.1, the original Omicron strain, and BA.2; it is a consequence of BA.1 and BA.2 cocirculating widely. XE also has 3 mutations that aren’t present in all BA.1 or BA.2 strains.

Omicron XE is a hybrid of the 2 earlier strains; it acquired properties from each strain that account for their virulence. The World Health Organization (WHO) reported Omicron XE may be 10% more transmissible than BA.2, but the number of studied cases is relatively low. The lack of spread in countries that identified this variant in late January 2022 suggested it did not represent a major threat for rapid or extensive outbreaks. Recombinant strains are well described for many other viruses and rarely have been associated with more severe disease.

The first identified cases of XE occurred in England in late January 2022, and subsequently more than 600 cases of XE were identified there. However, XE accounted for less than 1% of cases in this region as BA.2 remained the major variant of SARS-CoV-2 both in the United Kingdom and throughout the world. XE also was identified in Thailand and India, with a single case reported on April 6, 2022, in Mumbai, India.

Since BA.1 and BA.2 each were resistant to some monoclonal antibody therapies, these drugs were found to be ineffective against XE. Again, following our experience with BA.1 and BA.2, ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir should be effective against the XE strain for outpatient therapy.

Omicron subvariant BA.3

Two more subvariants, designated Omicron BA.3 and BA.4, were identified with different mutations.

The novel Omicron subvariant BA.3 with 13 mutations was first identified in South Africa late in 2021 and subsequently confirmed in 9 patients globally, including 3 airline passengers arriving in the United States from South Africa in December 2021. ^[9]

Omicron subvariants BA.4 and BA.5

The Omicron BA.5 subvariant of SARS-CoV-2 is less susceptible to antibody and cellular immune responses induced by current vaccines than any earlier variants. ^{[10, 11]}  However, clinical data show that previous infection with an older variant (such as Alpha, Beta or Delta) offers significant protection against reinfection with the newer BA.4 and now BA.5 subvariants.16 More importantly, while BA.5 spreads more rapidly than any others, ^[10]  it has not caused more severe disease in infected individuals, including those with partial or no immunization. ^[12]

BA.5, the highly contagious Omicron subvariant that caused most reinfections or first infections in people who hadn't had COVID-19 the summer and fall of 2022, has steadily decreased since late August 2022. BA.5 was extremely contagious and caused more reinfections in individuals who had already been infected with COVID-19.

The potential for combined infection with the newest Omicron variants and influenza is worrisome, particularly after the 2022 winter holidays and increased travel. Coinfection with the two viruses is more severe, and influenza rates are high. ^[13]

The highly contagious Omicron subvariants that emerged in April 2022 appeared to reduce the protection offered by the Pfizer-BioNTech and Moderna vaccines against COVID hospitalizations, with more vaccinated people hospitalized with COVID than during the earlier winter Omicron wave. Still, booster shots have raised levels of protection even though the incidence of infection has increased. BA.4 and BA.5 appear to be 20-fold more resistant than BA.2 to tixagevimab and cilgavimab (Evusheld), the monoclonal antibody treatment that has been providing preemptive protection for immunocompromised patients. 

BQ.1 and BQ.1.1

More than 68% of COVID-19 cases in the United States are caused by the Omicron variants BQ.1 (Typhon) and BQ.1.1 (Cerberus) in late December 2022. ^[14] These variants first began circulating during winter 2022 ^{[15, 16, 32, 33]}  and caused a marked increase in COVID-19 infections. As of the week ending December 16, 2022, BQ.1 was responsible for 30.7% of COVID-19 cases, down from 31.1% the week before; BQ.1.1 caused 38.4% of new cases, up from 36.8% the week before.

This Omicron variant is highly transmissible and is spreading faster than any previous variant, but it may cause less severe symptoms than previous strains. These Omicron variants can escape the immune system's defenses, and COVID-19 vaccines are less effective against them. ^{[17, 18]} However, early careful preventive steps, particularly vaccination, remain the best option for suppression of these Omicron variants. In August 2022, unvaccinated adults were more than five times more likely to die from COVID-19 compared with adults aged 18 years and older who had completed immunization and booster doses. ^[18]

According to the World Health Organization, BQ.1 is specifically mutated from BA.5 and carries a few additional changes. BQ.1.1 has another key mutation, which makes it potentially more virulent.

Monoclonal antibody treatments, including Evusheld, are unlikely to benefit immunocompromised patients infected with BQ.1 and BQ.1.1, according to the National Institutes of Health. Bebtelovimab (Eli Lilly) is ineffective against the now-dominant subvariants of COVID-19, and the FDA revoked its authorization in the United States on November 30, 2022. Other monoclonal antibody treatments were removed from the US market earlier in the pandemic as the mutated viruses were highly resistant, rendering these agents ineffective.

There is no indication that Paxlovid, an antiviral for higher risk patients in the first few days of their illness, will not work against the newer forms of Omicron.

Table 1. Omicron subvariants circulating in late December 2022 (Open Table in a new window)

COVID-19 Variants and subvariants that are no longer circulating as of late December 2022

• November 2020: COVID-19  Alpha  VOC first reported in Great Britain. ^[6]  Alpha then rapidly faded away with the rise of the more aggressive Delta variant.
• November 2020:  Beta  variant was first identified at about the same time as the Alpha variant in late 2020, initially in South Africa, where many investigators thought it would spread and spark a second pandemic. ^[6]  In South Africa, studies concluded that infected individuals were 30% more likely to die after hospitalization during South Africa’s second wave than during its first outbreak. Beta infection also appeared to be less severe in individuals who had received the available COVID-19 vaccines or who had been infected with the earlier strains. Was rapidly replaced by the Delta VOC, which was more transmissible.
• November 2020: The  Lambda COVID-19 VOC first emerged in the United States in Houston, Texas. Lambda was observed to be more infectious than the original COVID-19 (SARS-CoV-2), and it also was more resistant to available vaccines. Was also quickly replaced by the Delta VOC.
• December 2020: The  Delta VOC was first identified in India and soon spread throughout the world, becoming the predominant variant of coronavirus until December 2021, when Omicron surfaced. Delta is the VOC that continues to receive the most attention because of its severe manifestations and rapid spread, including among patients who have received the available COVID-19 vaccines; it has more than a dozen mutations.
• July 2021: The  Gamma  VOC emerged as a cluster outbreak in French Guiana with a high attack rate even in fully vaccinated persons. ^[5]  Vaccination appeared to protect from severe manifestations of disease, requiring less hospitalization and intensive care support among immunized individuals than was seen in unvaccinated patients. In the United States, of 555 COVID-19 vaccine breakthrough infections during January 2021 to April 2021 in which sequencing was performed, only 28 were caused by the Gamma variant.
• As the Omicron subvariants became even more dominant in August 2022, an offshoot called BA.4.6  increased in some Midwestern states with the highest BA.4.6 reported cases coming from Iowa, Kansas, Missouri, and Nebraska. ^{[19, 20]}   As of early December 2022, BA.4.6 was no longer circulating.

Table 2. Variants and subvariants no longer circulating as of late December 2022 (Open Table in a new window)

Although acquired immunity, vaccination, and newer treatment options have been very helpful in decreasing disease severity and hospitalizations, it is imperative to be vigilant. Combined with waning vaccine protection and lower booster vaccine compliance among the elderly, the virus’s accelerating evolution is resulting in strains (eg, BA.4, BA.5), that have greater transmissibility, evasiveness, and possibly pathogenicity.

Vaccines available against COVID-19 remain protective against severe disease.

Please see Coronavirus Disease 2019 (COVID-19) in Children.

The need to develop new COVID-19 vaccines is urgent. Existing vaccines based on the version of the SARS-CoV-2 virus that emerged in Wuhan, China in late 2019 clearly are less effective against Omicron strains in July 2022. As a result, current vaccines only offer brief protection from infection caused by newer variants and subvariants.

BA.1 sublineage (including BA.1.1) caused a large surge in COVID-19 cases. ^{[8, 21]}  Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases. The VISION Network examined 214,487 emergency department/urgent care visits and 58,782 hospitalizations with a COVID-19–like illness diagnosis among 10 states during December 18, 2021–June 10, 2022, to evaluate vaccine efficacy (VE) of 2, 3, and 4 doses of mRNA COVID-19 vaccines compared with no vaccination among immunocompetent adults. VE during the BA.2/BA.2.12.2 period was lower than that during the BA.1 period. A third vaccine dose provided additional protection against moderate and severe COVID-19–associated illness in all age groups, and a fourth dose provided additional protection in eligible adults aged 50 years and older. ^[22]   

Analysis of neutralizing antibody responses to the most recent omicron lineages circulating during summer 2022 (ie, BA.2.12.1, BA.4, BA.5) was published. The researchers found neutralizing antibody titers against the BA.4 or BA.5 subvariant and (to a lesser extent) against the BA.2.12.1 subvariant were lower than titers against the BA.1 and BA.2 subvariants, suggesting the SARS-CoV-2 omicron variant has continued to evolve with increasing neutralization escape. ^{[23, 24, 25, 26]}

It will be challenging to keep vaccines current, as antigenic differences in emerging strains are difficult to predict. Decisions directing the composition of vaccines are based on an understanding of how those viruses evolve, something researchers have not achieved for SARS-CoV-2. Even if new vaccines are effective against BA.4 and BA.5, by the time they are available, other circulating Omicron strains may have emerged.

The FDA authorized Moderna and Pfizer bivalent COVID-19 vaccines for booster doses in August 2022 for adolescents and adults, and for children as young as 5 years in October 2022. The bivalent vaccines contain original (wild-type spike protein) plus an omicron BA.4/BA.5 subvariants spike protein. These vaccines replace the use of the original monovalent vaccines for booster doses. ^[10]  

On October 19, 2022, was authorized NVX-CoV2373 to be used as a first booster (3rd dose) in adults at least 6 months after completion of primary vaccination. Use as a booster is specifically for situations when an mRNA bivalent COVID-19 booster vaccine is not accessible or clinically appropriate, or for those who elect this vaccine, because they would otherwise not receive a booster dose. 

Studies from the University of Texas Health Science Center at Houston have indicated that children aged 5-19 years have persistent protective antibody concentrations for at least 6 months following infection or vaccination. ^[27]  Although the numbers were low there was no evidence that vaccination reduced antibody responses to potential subsequent infection in contrast to an earlier study in adults suggesting that SARS-CoV-2 vaccination blunted the development of antibodies to the nucleocapsid viral component after natural infection. ^[28]

In a study of vaccinated veterans published May 25, 2022, one third who had subsequent breakthrough infections developed long COVID. ^[29] However, breakthrough infections were seen in only 1% of vaccinated study patients. A 4% higher incidence of long COVID was seen in unvaccinated veterans who became infected. Similarly, in a report from the Centers for Disease Control and Prevention, 1 in 4 adults aged 65 and older had signs of long COVID following infection as compared to 1 in 5 of younger adults.

Most of these infections were from the BA.2.21.1 subvariant. The risk for long COVID from the new BA.4 and BA.5 subvariants is not yet known. Thus it is clear that older adults have a higher risk for long term illness with COVID-19 infection.

Please see Long COVID-19 and Coronavirus 2019 (COVID-19) Reinfections.

Will COVID-19 become endemic?

It is unlikely that COVID-19 will be eradicated as was SARS-1. Similar to the original coronaviruses, COVID-19 likely will become endemic in most countries, requiring similar management as that used to control many other endemic pathogens. Most importantly, major control of infectious agents has been achieved with the development of safe and effective vaccines. Smallpox was totally eradicated because of the administration of vaccine worldwide. Polio has been eliminated in the United States and most developed countries, and diphtheria and tetanus almost completely controlled. The major reduction of some other viruses such as measles, rubella, and mumps are further examples of vaccine success.

Our decades-long experiences with influenza viruses offer the best guidance for our future efforts if COVID-19 becomes endemic. Similar to the novel coronaviruses, influenza strains change at least yearly, requiring identification of new antigenic components and adjustments in the content of vaccine. As with our approach to influenza, COVID-19 vaccines likely will be given yearly and modified based on the characterization of circulating virus strains. Just as masks have been shown to be effective in controlling the spread of influenza, consideration should be given to recommending their use during identified outbreaks of COVID-19. Whether COVID-19 infections will become a winter disease like the older coronavirus strains remains to be seen; they have not demonstrated the clear seasonal incidence shown by most viral respiratory pathogens. 

Please see Coronavirus 2019 (COVID-19).