COVID-19 Variants 

Updated: Aug 26, 2022
  • Author: Russell W Steele, MD; Chief Editor: Michael Stuart Bronze, MD  more...
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Coronavirus-2019 (COVID-19)

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]

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 a large number of 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.

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Human Coronaviruses, 1965-Present

Human coronaviruses from 1965 to the present

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 were first 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. 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 are frequently 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.

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COVID-19 Variants and Subvariants

Omicron subvariants spreading rapidly

As of June 15, 2022, the dominant strain is BA.2.21.1, which replaced BA.2 soon after replacing BA.1.1. The spread of new omicron subvariants has always been rapid. The first omicron case in the United States was detected on December 1, 2021, and just 4 weeks later, the subvariant BA.1.1 replaced the Delta variant as the dominant strain. The newer omicron subvariants all have the property of being more transmissible than the early COVID-19 viruses; however, none of these omicron subvariants have been found to cause more severe disease than the original omicron strain. And while omicron has been reported to cause less severe illness than Delta, it has still conferred a significant incidence of severe infection due to its extreme transmissibility leading to more infected individuals. [4]

Omicron BA.1 VOC                        

New variants of COVID-19 were reported in November, 2021, with the first in the United States identified the next month and named Omicron. Only a month later, 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 it 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. In summary, the substitution of Omicron for the Delta variant was a welcome event.

Omicron subvariant BA.2 (Stealth)

A subvariant of the Omicron strain of COVID-19, designated BA.2 and named “Stealth” because of its ability to make it more difficult to detect with COVID-19 testing, was identified in December 2021. [5, 6]  It appears that although it is more transmissible than Omicron BA.1, it does not cause more severe illness than the original variants. BA.2 appears to have an additional 20 mutations on its spike protein compared with the original Omicron variant.

Each week during the month of May 2022, the United States identified 100,000 COVID-19 cases, a 60% increase attributable to the Omicron subvariant BA.2 and its BA.2.12.1 strain. The current decreased use of masks and social distancing along with the increased contagiousness of these COVID variants likely account for this surge. This was evident from the reported increased cases attributable to attendance at the Jazz and Heritage Festival in New Orleans April 28th- May 8, 2022. However, hospitalizations and deaths have not increased likely due to immunizations and previous infection.  

The Centers for Disease Control and Prevention has determined that the BA.2.12.1 subvariant of omicron accounts for about 42.6% of current coronavirus cases for the week ending on May 7, 2022 whereas the BA.2 omicron variant accounts for about 56.4% of current cases. The BA.2.12.1 subvariant may become the dominant strain in the next few weeks as it is about 25% more transmissible than the original Omicron that caused a sharp rise in cases in the winter of 2021. [7]

The primary property of the virus to account for its rapid increase in prevalence is its increased transmissibility as compared with BA.1 and earlier COVID-19 Omicron strains.

Because infection with the original Omicron wave has decreased, BA.2 is now the likely strain to become predominant.

Despite BA.2’s transmissibility, we should not be greatly concerned for two reasons. One is that BA.2 causes less severe disease as compared with the original Omicron variant strain, known as BA.1, which itself is a variant producing much milder clinical illness than the Delta strain. The other reassuring factor is that BA.2 is not substantially different from BA.1, which has been documented to be prevented by current vaccines and prior infection. Those who are vaccinated and boosted remain well-protected from severe illness. Recent data indicate that people with booster doses produced equally effective antibodies against BA.1 as BA.2 and patient data from England and Qatar have confirmed that vaccines provide excellent protection against severe illness due BA.2. [8]

Secondly, patients who were previously infected with other Omicron strains are unlikely to be infected with BA.2. An estimated 45 percent have already contracted Omicron and therefore, are unlikely to be infected with this new strain. A study from Denmark found only 47 instances of BA.2 reinfection following infection of the original Omicron strain, out of more than 1.8 million recent cases of COVID-19. [9]

In population studies, those individuals who had previous Omicron infection and/or vaccination demonstrated high antibody concentrations against BA.2. [10]  It is estimated that as many as 80 percent of Americans have some immunity that will protect them against a BA.2 as well as future strain variants. These data are reassuring that there will not be a significant rise in hospitalizations as we have seen in the past that overwhelm personnel resources and hospitals.

In conclusion, it is unlikely that we shall have to alter our relaxed recommendations for wearing masks and social distancing because of the increased infection and colonization with BA.2, but vigilance and careful following of disease incidence are still essential. However, for those who are at high risk because of immune compromise or other comorbidity, continued precautions are certainly appropriate. This includes social distancing, avoiding crowds, and wearing an N95 mask in indoor settings.

Omicron XE

Omicron XE is a recombinant variant of Omicron BA.1, the original Omicron strain, and BA.2, the more communicable strain that is now the most prevalent in the United States and most countries. This recombinant strain 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.

Although XE is a hybrid of the 2 earlier strains, acquiring properties from each strain that account for their virulence, it is unlikely to be a greater danger for increased outbreaks nor greater morbidity. It is too early to clearly define its communicability and clinical characteristics as compared with other variants of SARS-CoV-2, but initial data indicated that the XE variant resembles BA.2 in its ability to spread. The World Health Organization (WHO) reports the variant may be 10% more transmissible than BA.2, but it should be emphasized that the number of studied cases is relatively low. The lack of spread in countries that have identified this variant since late January 2022 suggests it does 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 have been identified there. However, XE accounts for less than 1% of cases in this region as BA.2 remains the major variant of SARS-CoV-2 both in the United Kingdom and throughout the world. XE also has been identified in Thailand and India, with a single case reported on April 6, 2022 in Mumbai, India.

Early data indicate that current vaccines are protective particularly in otherwise healthy individuals. This is expected because the vaccines protect against symptomatic disease from both BA.1 and BA.2. On the other hand, since BA.1 and BA.2 each are resistant to some current monoclonal antibody therapies, these drugs are likely to be ineffective against XE. Again, following our experience with BA.1 and BA.2, Paxlovid and molnupiravir should be effective against the XE strain for outpatient therapy.

Those who are not vaccinated or who have comorbidities should exercise the usual protective measures of wearing high-quality masks and social distancing.

Omicron subvariant BA.3

Two more subvariants, designated Omicron BA.3 and BA.4, were identified with different mutations, but these have not yet been characterized for their communicability nor clinical severity.

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. [11]

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. [12, 13]  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. [13]  More importantly, while BA.5 spreads more rapidly than any others, [12]  it has not caused more severe disease in infected individuals. including those with partial or no immunization. [4]

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 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. 

As the Omicron subvariants became even more dominant in August, 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. [14, 15]  As of late August 2022, these states are seeing the highest BA.4.6 proportions, where it makes up 13.2% of sequenced specimens. [15]  This subvariant also has been reported in other US regions, especially in the east.

Healthcare providers anticipate increased activity when schools resume and people gather more indoors in the late fall and winter. Recent surveys suggest a decrease in vaccination, both in children and older adults, further contributing to the likelihood of increased cases.

In its weekly variant proportion updates, the Centers for Disease Control and Prevention (CDC) reported the proportion of BA.5 viruses in sequenced samples August 7th-13th rose from 84.5% to 87.1%, whereas BA.4 fell slightly, from 8.2% to 6.6%. However, the proportion of BA.4.6 viruses increased to 4.8% from 4.2% the week before.

Meanwhile, the number of COVID-19 cases in children in early August grew for the fourth consecutive week, the American Academy of Pediatrics reported in its latest weekly update. Nearly 97,000 cases were documented for the week ending Aug 4th. [16]  Thus, children’s illnesses are increasing even before the beginning of the school year.

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

Despite elevated numbers of total cases, there are fewer US patients with COVID in intensive care units than there were during previous phases of the pandemic, and the national death rate (300-400 per day) is near an all-time low. This likely is a result of acquired immunity, vaccination compliance, and newer treatment options. But combined with waning vaccine protection and lower booster vaccine compliance among the elderly, the virus’s accelerating evolution is resulting in strains, such as BA.4 and BA.5, that have greater transmissibility, evasiveness, and possibly pathogenicity.

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

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COVID-19 Variants, Subvariants, and Vaccines

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) is causing the largest surge in COVID-19 cases to date. 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. [17]  

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. [18]

It will not be easy 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, circulating Omicron strains likely will be different.

On August 15th Britain became the first country to authorize a coronavirus vaccine that targets BA.4 and BA.5, as well as offering coverage for the original virus and Omicron, the variant that became dominant over the winter of 2021. [19]  

A new vaccine developed by Moderna, an updated version of their original Covid vaccine, generates antibody concentrations to the virus that caused infection in 2020 as well as the BA.4 and BA.5 subvariants in adults. [12]  Half of each dose of this vaccine targets the original variant, and the other half targets Omicron. Moderna announced in late July that the United States government had secured 66 million doses of this vaccine. The Biden administration expects to begin a Covid-19 booster campaign in September with updated vaccines from Pfizer as well as Moderna targeting the new subvariants. [12]  Officials decided to delay expanded eligibility for second boosters of existing vaccines this summer because the new formulations were close to being ready. Currently, only Americans over 50 and those over 12 with certain immune deficiencies are eligible.

An entirely new variant likely will emerge from the original SARS-CoV-2, rather than from the Omicron major variant. As a result of such uncertainty, experts suggest the next COVID-19 vaccines need to provide broader protection, ideally eliciting an immune response that can recognize past variants as well as present and future ones.

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. [20]   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. [21]

Please see COVID-19 Vaccines.

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COVID-19 Variants, Subvariants, and Long COVID-19

In a study of vaccinated veterans published May 25, 2022, one third who had subsequent breakthrough infections developed long COVID. [22] 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.

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Endemicity

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).

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