Winter of Omicron—The Evolving COVID-19 Pandemic

Nearly 2 years into the coronavirus pandemic, COVID-19 cases, hospitalizations, and deaths are rising in the US and in many other countries. Despite widespread availability of effective vaccines and novel therapeutics, health systems in many US regions are again being overwhelmed with largely unvaccinated or medically vulnerable patients filling emergency departments and intensive care units. Although most of these severe cases have been due to the Delta variant that has been dominant since May 2021,¹ the recently identified Omicron variant is rapidly displacing Delta as the most common SARS-CoV-2 variant. The lack of universal uptake of COVID-19 vaccination and the emergence of the Omicron variant of SARS-CoV-2 are critical factors in the ongoing pandemic.

Vaccines remain the most important tool for controlling COVID-19 and helping to shift the pandemic to the next phase. Yet in the US suboptimal vaccine acceptance, at least partly associated with misinformation and political division, continues to be a major barrier. As of December 20, 2021, nearly 500 million doses of COVID-19 vaccines have been administered in the US, enough to fully vaccinate approximately 62% of the population.² In addition, approximately 30% of the population has received a booster dose. Vaccination rates, however, vary geographically, with 9 states and Puerto Rico having more than 70% of the population fully vaccinated, whereas in 4 states, the proportion is less than 50%.²

Given the high transmissibility of the Delta and Omicron variants, increasing vaccination coverage to more than 80% to 85% for the entire US population should be the goal. However, this is unlikely to happen without widely implemented mandates, especially by employers and educational institutions. While mandates are effective means of increasing vaccination rates, the future of vaccine mandates in the US is now in the courts and remains uncertain. On December 17, 2021, an appeals court panel in Cincinnati, Ohio, allowed President Biden’s vaccine mandate for larger private employers to move ahead, reversing a previous decision on a requirement that could affect millions of US workers.³ It is expected that the federal private employer–based vaccine mandates will be eventually adjudicated by the US Supreme Court. For the foreseeable future it is likely that highly vaccinated communities will fare better than those with low vaccination rates, with clinically severe infections occurring mostly in unvaccinated persons.

In late November 2021 the identification of the Omicron variant of SARS-CoV-2 in South Africa and Botswana, quickly classified by the World Health Organization as a Variant of Concern, has again changed the trajectory of the pandemic. While there is still much to be learned about the epidemiology of Omicron, available data suggest that this variant is substantially more transmissible than the Delta variant and is capable of significant immune evasion (ie, evades the immune protection provided by antibodies from vaccines or prior SARS-CoV-2 infection). Since initially identified, Omicron has been detected in more than 90 countries and 46 US states. However, as opposed to South Africa and Botswana, where very few cases of COVID-19 were reported when Omicron emerged, there was an ongoing surge due to the Delta variant in the US.

As of December 20, 2021, in the US, approximately 70 000 individuals are hospitalized and an average of 1300 deaths per day are attributed to COVID-19. Nationwide, in less than 3 weeks, Omicron has become the dominant variant, present now in 73% of the samples for the week ending December 18, 2021. Given the experience from South Africa and Europe and now in the US, Omicron will likely displace Delta as the dominant variant in much of the world.

Most current hospitalizations and deaths are among unvaccinated individuals; however, so-called breakthrough infections are increasingly being diagnosed among individuals who have been fully vaccinated and even among those who have received booster doses. To date, most of these infections have not resulted in clinically severe disease. While vaccination does not prevent all infections, thus far vaccination has provided protection against severe illness, hospitalization, and death.⁴ The degree to which current vaccines will be protective against severe illness related to the Omicron variant will require careful monitoring.

Omicron exhibits multiple mutations in the receptor-binding domain (RBD) and the N-terminal domain (NTD) that are associated with more efficient cell entry, immune evasion, and increased infectivity. Although information is still emerging, it now appears certain that Omicron may be 2 to 3 times more transmissible than Delta, and vaccination effectiveness against Omicron is also likely diminished. Still, 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine provides 70% protection against severe complications from COVID-19 requiring hospitalization but only 33% protection against SARS-CoV-2 laboratory-confirmed symptomatic infection (based on data from a non–peer-reviewed report of 581 symptomatic Omicron cases, 56 439 Delta cases, and 130 867 test-negative controls).⁵ Giving a booster increases the protection against symptomatic infection with Omicron to about 75%. Another non–peer-reviewed report based on 30 individuals who had previous SARS-CoV-2 infection suggests that prior infection-induced immunity offers no protection, but people who previously had COVID-19 and received at least a dose of an mRNA vaccine are also protected against Omicron.⁶

Data are more limited in terms of severity of illness but there is currently no clear evidence that Omicron causes more severe disease, with some reports from South Africa suggesting illness may be milder than that associated with the Delta variant.⁷ However, reports of decreased disease severity may be confounded by the younger age of early case patients as well as the lag between cases and an increase in hospitalization and deaths. A recent report from Denmark involving 785 cases with the SARS-CoV-2 Omicron variant suggests that Omicron may not be a less severe infection than that caused by Delta.⁸

Another concern is that most of the monoclonal antibodies currently authorized by the US Food and Drug Administration (with the possible exception of sotrovimab) have little or no in vitro activity against Omicron.⁹ Variant-specific data on the effectiveness of antiviral treatments including remdesivir, molnupiravir, and nirmatrelvir are not yet available, but because of the mechanism of action of these antivirals it is not expected that their activity will be affected.

In response to Omicron, the Biden administration has authorized boosters for anyone older than 16 years, has decreased the time a negative COVID-19 test result is required to board an international flight bound for the US from 72 hours to 24 hours, and is working to make rapid tests for SARS-CoV-2 readily available to all US residents free of charge. Increased efforts around surveillance and monitoring of vaccine effectiveness are additional aspects of the federal response.

As the number of breakthrough cases increases due to the spread of the Omicron variant, one consideration is whether to count an infection as a vaccine “dose.” While some evidence suggests a higher immune response with fewer doses among those who were previously infected with SARS-CoV-2,¹⁰ the current Centers for Disease Control and Prevention (CDC) recommendations do not support omitting a dose of vaccine in case of a breakthrough or prevaccination infection.

Questions also have been raised if the definition of “fully vaccinated” should be amended to include 3 doses of an mRNA vaccine (primary series plus a booster). How “fully vaccinated” is defined matters when vaccination status is required for international travel, dining, attending indoor events, or because of mandates. Currently the CDC indicates that fully vaccinated means 2 weeks after getting the Johnson & Johnson/Janssen single-dose vaccine or the second dose of an mRNA vaccine. However, increasingly many universities, sports organizations, and now the State of New Mexico are defining fully vaccinated as a primary series plus a booster.

Despite vaccines and advances in therapeutics, the US is entering what is potentially the most dangerous phase of the pandemic to date. The coming weeks may bring a triple respiratory virus threat: Delta, Omicron, and seasonal influenza. In addition to COVID-19, and unlike last year when influenza activity was uncharacteristically low, this winter could bring a significant influenza season. Outbreaks of influenza A(H3N2) have already been reported on several college campuses. Thus far national numbers of influenza cases are still low, although CDC surveillance indicates more than 2000 respiratory samples have already tested positive for influenza, more than the entire 2020-2021 season.

To mitigate the effects, especially strain on health care resources, robust efforts are needed to increase vaccination against both influenza and COVID-19, including booster doses. For unvaccinated individuals, the winter months will likely be a time of increased risk for severe illness and death. For vaccinated persons and especially for those who have been boosted, infections are more likely to be mild and not require medical attention.

While the origins of the Omicron variant are uncertain, the persistent global spread of SARS-CoV-2 increases the likelihood that additional variants will emerge. Hence, the success of domestic efforts to control COVID-19 also rely on effective surveillance for emerging variants and access to vaccines globally. Therefore, efforts to stabilize global vaccine supply as well as strengthen delivery and vaccine uptake will not only be essential for reducing morbidity and mortality (and helping preserve economies) in resource-limited countries but will also support the response in high-income countries. While the pandemic clearly is not over, the tools to control spread and continue essential activities are available and must be used with urgency now.

Corresponding Author: Carlos del Rio, MD, Emory University School of Medicine, 49 Jesse Hill Jr Dr, FOB Room 201, Atlanta, GA 30303 (cdelrio@emory.edu).

Published Online: December 22, 2021. doi:10.1001/jama.2021.24315

Conflict of Interest Disclosures: Dr del Rio reported receiving grants from the NIH/NIAID Emory Vaccine and Treatment Evaluation Unit. No other disclosures were reported.