Dangerous Mutations: the Continuous Emergence of SARS-CoV-2 Variants

Mary C. Vrtis, Ph.D., MSN, RN, OCN, NEA-BC, FCN

SARS-CoV-2, the virus that causes COVID-19, started as a single mutation in a critical location on a virus that may or may not have been infecting a particular type of animal, possibly a bat, see figure 1. That tiny mutation in a single, invisible, virus conferred the power to “jump species,” and infect human beings. The new virus was far more contagious from person-to-person than any previous type of Coronavirus the world had thus far seen.

Micro-organisms have one goal, and that is to reproduce. These organisms do not have any conscious motivation to do us harm, but over millions of years they have developed amazing skills that allow them not only to survive, but to thrive in all kinds of hostile environments. The human immune system automatically fights back, but until the anti-COVID-19 vaccines were available, the virus was clearly winning! We are the latecomers to this show and are no more than convenient hosts that assist the organisms in their quest to replicate while mutating and recombining to grow stronger.

Variants of Concern

Our battle with COVID-19 is not over. The SARS-CoV-2 virus is highly adaptable, as evidenced by the number of pathological variants that have emerged since December 2019 (discussed below).

GISAID, is an international private/ public partnership developed  developed by scientists in 2006 to share information on genetic sequences of influenza. When it was evident that the initial outbreak of COVID-19 was expanding, tracking of SARS-CoV-2 variants started.. As of October 1, 2023, there were 16,064,011 SARS-CoV-2 genomic sequences uploaded by scientists around the world. In the U.S. alone, 4,895,563 viral sequences have been uploaded to the database since January 10, 2020. Apps are available from the website that provide incredible amounts of information about SARS-CoV-2 variants for use by scientists, researchers, and public health teams worldwide (GISAID, 2023d, April 22). It is possible to identify when and where a given variant of concern emerged, how widespread it is across the globe, and exactly what the genetic changes are (GISAID, 2023e, April 22. Audacity instant app video). Though some of these may be duplicates of the exact genomic sequence from multiple sources and countries, there is no question that this is one of the most adaptable viruses that our world has faced (see figure 2).

New variants of SARS-CoV-2 emerge regularly. Some of the variants amount to nothing and disappear. Other mutations generate variants of concern as the changes in the genome bestow a competitive advantage over earlier versions of the virus. In other situations, two existing variants of the virus infecting one patient will combine, share genetic material, and create a new recombinant variant during the viral reproduction process. Recombination may produce dangerous variants that have the most threatening characteristics of the two variants that combine (CDC (n.d.). Summary of variant surveillance. Pango lineages. Lineages). The Pango lineage graph shows the SARS-CoV-2 family tree, see figure 2.

Some variants infect people more easily than others. Some variants cause more damage and destruction to the human body than others. Some variants are better able to evade the human immune system. Some variants are resistant to the prevailing vaccines. Variants of concern that have emerged recently have had 30 or more mutations that make the virus more transmissible and lethal. So far, those who are vaccinated have milder disease and are less likely to die than those who refused the vaccines (CDC, August 29).

Front Line Staff Nurses are an Invaluable Resource

The point of this discussion is not to strike fear, but to stress the need to be alerted to changes that we see in clinical and non-clinical settings. Nurses providing direct care to sick patients are very likely to notice changes in the clinical picture that herald the onset of a new variant. Mechanisms for rapid transmission of nurse observations to those who need to know and have the ability to investigate further are very important. For example, a method to communicate concern to the organization’s infection preventionist or infection control team may need to be developed. Communication to public health professionals in a timely manner is still important.

Why? Just imagine what could have happened if the clinicians in that one hospital in China had not reported that small cluster of patients with an acute respiratory infection to the local public health office. No doubt that the COVID-19 pandemic would have been far more devastating than was the case. 

Knowledge-based, comprehensive nursing assessment skills save lives. Understanding how to prevent infections saves lives. Timely implementation of transmission-based precautions to prevent cross-patient transmission saves lives.

When a nurse sees early signs and symptoms of infection from COVID-19 or any other type of infection, the nurse needs to be free to act immediately. No matter what our practice setting is, we need to be prepared to isolate and quarantine our sick patients, and ourselves, if necessary, until all the facts are in, or the recommended quarantine period is over.

If a nurse puts a patient on transmission-based precautions and it turns out they do not have the suspected infection, harm is unlikely. However, the actual harm that results from failure to contain a highly transmissible infection is clear in COVID-19 cases and deaths. If there are obstacles that prevent a nurse initiated intervention to stop the chain of cross infection, such as a need to obtain a physician order to implement precautions, the obstacles need to be removed from the organization’s policies and procedures.

Regardless of the type of outbreak organism under discussion (virus, bacteria, or fungus), the astute, well-informed staff nurse will likely see patterns before anyone else does. A nurse’s eyes, ears, and nose can detect a potential disaster before it happens. Be alert for sudden increases in patients admitted to your workplace who have evidence of infection, similar symptoms, more severe symptoms than expected for a given infection, a higher rate of death, or anything else that appears to be different. Clusters of infection from a given neighborhood, referral source, or a specific unit in a facility provide important epidemiological data for an investigation. These kinds of changes may well signal the emergence of a variant that could be even more dangerous than the circulating versions of an organism.

Whatever the setting, school, critical care, infection prevention, prison, home care, skilled nursing facility, assisted living, etc., use of the nursing process to assess and analyze the situation is an extremely important intervention. Reporting up the chain of command within the organization and to the Infection Prevention Practitioner or person filling this role needs to be easy and uncomplicated. Communication between public health departments and agencies/ facilities will need to be collaborative forever.

Emerging Variants Change Everything

Much has been learned about how fast the situation worldwide became disastrous when new and more toxic variants emerged, resulting in increased death and disability. With mitigation strategies such as vaccinations, at home testing, self-isolation, and widespread, voluntary application of public health measures, the situation has been improving. The Omicron variants are extremely contagious and capable of infecting vaccinated and unvaccinated people. However, those who are vaccinated tend to have less severe disease and are significantly less likely to die from the infection.

The U.S. CDC, World Health Organization, and most countries are closely monitoring variant proportions, so as to plan for manufacture, distribution, and administration of up-to-date vaccines based on ever changing variant characteristics. With a virus that mutates as often as SARS-CoV-2 does, this is a continuous challenge. There are currently 32 circulating variants and subvariants, of Omicron being monitored, https://covid.cdc.gov/covid-data-tracker/#variant-proportions. As described above, genetic sequencing is continuous, so that new variants of concern can be identified quickly.

We urge nurse leaders who also serve as Infection Preventionist (IP) professionals to pay attention to emerging variants and their characteristics. Emerging COVID-19 mutations will continue to impact patient care needs in the future as has been in the past, especially if the variants become more capable of resisting the effects of vaccine-induced immunity. Waiting until the data was available retrospectively has not worked out very well. We need to proactively have real time systems place in our practice settings so we can immediately implement effective strategies to protect staff from illness, disability, and death.

SARS-CoV-2 Variants and the Impact on Nurses and the U.S. Healthcare System: Looking Back so we can Move Forward

Each SARS-CoV-2 mutation of concern had an effect on the volume of patients, acuity-based staffing needs, death rates, and long-term consequences for those who recovered. The SARS-CoV-2 virus variants discussed here have essentially disappeared because they were superseded by new mutant or recombinant variants that were better able to compete for human hosts. Though these variants no longer pose a problem, critically analyzing what has happened in the past provides an opportunity to plan for a better future. As the reader will see, emerging variants are at this moment much more contagious than the earlier variants, but somewhat less virulent, especially in vaccinated people. Still, we need to be prepared to battle extremely contagious variants that are even better able to cause great harm to humans than was the case in the past.

Basic Concepts

Reproduction Number and Transmission

The letter R is used to represent the viral reproduction number and refers to the average number of people that a single infected person successfully transmits the disease to. Secondary contacts are the people infected by the first person that infect others (Leung, 2021).

The basic reproduction number, R naught, abbreviated as R0, is calculated at the beginning of an epidemic, when the population is still highly susceptible. For COVID-19 calculations of R0 have also been made as the populations of additional countries were newly infected or as new strains of concern have emerged worldwide (Leung, 2021). Calculations were made for the ancestral (original) strain of COVID-19 initially in China and then in other parts of the world as SARS-CoV-2 invaded more countries (GISAID, 2023a).

The basic reproduction number, R0, for the virus is the number of people infected by a single patient with the “primary” (first) infection.  R0 for SARS-CoV-2 was initially calculated to be 2.2 for the ancestral variant (Li, et al. 2020 January 29). As COVID-19 spread rapidly across China, Zhao, et al. (2021) estimated that R0 was 2.75 outside the epicenter in a mid-size city approximately 900 km (560 miles) from Wuhan (Zhao, et al, 2021).

Transmission rates for viruses change over time for several reasons. As a population becomes less susceptible to the infection, as more people become vaccinated, the rate will decrease. With some viruses the rate of transmission will drop if people develop at least temporary immunity after being infected. Superspreader events increase the number of people infected at a single event – which drastically alters the transmission rate. In addition, some competing variants of the virus will decrease the ability of other variants to cause infection if the emerging variants are:

  • More virulent (capable of causing harm), and/ or
  • Able to form a stronger bond between the spike protein and the ACE2 receptor on the human cell, and/ or
  • Better at evading the immune system, and/ or
  • Have a longer period during which they can cause infection or asymptomatic transmission.

Efforts to limit transmission by educating the population on basic prevention activities such as frequent hand hygiene, respiratory masks, eye protection, and social distancing does reduce transmission rates if they are implemented by enough individuals within the population.

Rt, the effective reproduction number, or number of people infected by one person, can be calculated at any time. The Rt in a particular area will change over time and is dependent on the multiple external and virus-specific variables. When population immunity reaches a point where the Rt is less than 1, viruses (or variants) generally start to die out. When vaccination is able to prevent active infection, then the Rt measured at various time points will decrease as the number of people vaccinated increases. If another variant of a virus is more contagious than the circulating variant being measured, the Rt for the circulating variant will likely decrease.

When a reproductive number R is less than 1, it means that one infected person is on average infecting less than one additional person. The virus (or variant of a virus that mutates rapidly) is likely to start to die out. The larger the R number, the more people who will be infected by one person. When the R is larger than 1, then the epidemic or pandemic will continue to grow and infect more and more people.

As shown in figure 3, each of the variants that emerged and became dominant was better able to reproduce and infect more people than the previous version. 

The more infectious Alpha (B.1.1.7) replaced the ancestral variant and an unidentified variant. Alpha was replaced by the more virulent and highly transmissible Delta (B.1.617) variant. Then the Omicron variants started to emerge and mutate. Omicron has many variants that have become dominant, only to be replaced by even more highly infectious versions of Omicron that are better able to adapt and survive.

What we learned from the emergence of the Alpha, Delta and Omicron variants of SARS-CoV-2 that have already burned through the human population and have been extinguished provides excellent opportunities for learning how to be proactive with future outbreaks.

The Omicron variants were extremely contagious compared to the ancestral and other circulating strains, and the numbers have changed over time as more and more Omicron variants emerged. Reproduction numbers and transmission rates are captured at one moment in time, and a measurement made a month later or in a different country will likely be different than the baseline. Changes in transmission rates are seen with superspreader events, such as holiday parties, increased or decreased vaccination effectiveness, and viral competitors (Auwaerter, P. G., 2022, July 12; Davies, et al., 2021; Esterman, 2022, July 4; Leung, 2021; Scheuber & van Elsland, 2020, December; Thye, et al., 2021).

Each of these variants has left immense human suffering in its wake. It is evident by looking retrospectively that each variant that became dominant was better equipped to cause infection than the variant it replaced. As shown in figure 4, with SARS-CoV-2, as new dominant variants arise, the proportion of older variants in circulation eventually disappeared. Secondary analysis: CDC (updated 2023, September 15). SARS CoV-2 Variant Proportions. https://data.cdc.gov/Laboratory-Surveillance/SARS-CoV-2-Variant-Proportions/jr58-6ysp/. We did not have adequate information to include the ancestral variant or any variants that may have been circulating in the U.S. prior to Alpha on this graph.

As noted above, we compiled data from several sources in order to determine how emergence of the major variants that reached the highest levels of circulating dominance affected prevalence, the number of patients with COVID-19 infections (cases), and outcomes. For outcomes we used COVID-19 death counts and hospitalizations as a measure of illness severity, and case fatality rates. We compiled healthcare worker and skilled nursing staff cases and deaths from the two separate databases where this information was contained and added the numbers to reflect the total number of healthcare workers who became ill or died.

Due to the wide variation in number of days that any given variant of concern stayed in the proportion mix, we used outcomes per day to facilitate comparisons. We used the end of week date when each variant was at or greater than 10% of circulating variants as the criteria for the start date and when it dropped near 10% as the end date of the time period during which the outcomes were measured. The is overlap with dates, so needless to say, these are approximations not absolutes. As shown above, the time periods for the first two Omicron variants B.1.1.529 and its subvariant BA.1.1 overlapped, so we combined data from both for this analysis. We also completed extensive literature searches and review in order to obtain variant specific information on characteristics, reproduction and transmission data, and documented case fatality rates. We used basic statistics to facilitate readability. This research was not intended to be a comprehensive, quantitative study, but rather a starting point to help understand how the situation deteriorated so fast.

Secondary analysis: CDC, updated 2023, September 15. SARS CoV-2 Variant Proportions. https://data.cdc.gov/Laboratory-Surveillance/SARS-CoV-2-Variant-Proportions/jr58-6ysp/. CDC, downloaded 2023, July 22. COVID-19 data tracker – cases and deaths among health care personnel. https://covid.cdc.gov/covid-data-tracker/#health-care-personnel_healthcare-cases; CDC, downloaded 2023 July 31. COVID-19 nursing home data – weekly death graph. https://data.cms.gov/covid-19/covid-19-nursing-home-data. CDC data tracker, cases, and deaths https://covid.cdc.gov/covid-data-tracker/

The Ancestral Wuhan SARS-CoV-2 Variant

Figure 5 depicts the number of secondary infections generated by the primary infected person. At the beginning of this pandemic this was a novel virus to which no human beings had any type of resistance (Leung, 2021). The primary infected person transmitted the disease to 2 to 3 people and each of those 2 to 3 people infected 2 to 3 more, and on and on. It is very easy to see why COVID-19 became a pandemic so fast. As pre-symptomatic patients who develop signs and symptoms of infection later and people who remain totally asymptomatic throughout the course of their infection do not appear ill, exposures can occur without either party knowing transmission happened.

Figure 6 demonstrates how each person infected by someone goes on to infect others.

Case Fatality Rates/ Mortality Rates for the Ancestral Variant

The case fatality rate, the percentage of people who died, was 2.3% for the ancestral variant in China, but there were certainly variations in different countries. There are also likely to be variations in the case fatality rate by care setting within specific locations. For example, it would be expected that patients with very severe infection requiring critical care admission would have a higher case fatality rate than those in a home care setting.

Was there an Unnamed Variant October 31, 2020, to February 27, 2021?   

The ancestral Wuhan variant was likely replaced by an unnamed, more toxic variant that caused a marked escalation in the number of people ill with COVID-19, hospitalizations, and deaths from approximately October 31, 2020, to February 27, 2021. On October 28, 2020, the total, cumulative COVID-19 case count was 8,863,408. During this 120-day period, over 20 million (20,065,957) NEW cases of COVID-19 were identified in the U.S., at a rate of approximately 167,216 cases per day. In that 120-day period, 1.4 million (1,448,438) people needed to be hospitalized, 7.2% of those who contracted the disease, at a rate of 12,070 NEW patients per day. During that same 120-day period, 311,045 people died from the infection, at a rate of 2,592 per day. The case fatality rate was 1.6%

During this same time period, 454,685 healthcare workers and nursing home staff became ill with COVID-19 infections at a rate of 3,789/ day. Another 947 healthcare providers died at a rate of 8 per day, and the overall healthcare case fatality rate was 0.21%. The only positive about this situation was that the case fatality rate for providers at 0.21% was markedly lower than that for the general population, 1.6% (secondary analysis: CDC, updated 2023, September 15. SARS CoV-2 Variant Proportions. https://data.cdc.gov/Laboratory-Surveillance/SARS-CoV-2-Variant-Proportions/jr58-6ysp/. CDC, downloaded 2023, July 22. COVID-19 data tracker – cases and deaths among health care personnel. https://covid.cdc.gov/covid-data-tracker/#health-care-personnel_healthcare-cases; CDC, downloaded 2023 July 31. COVID-19 nursing home data – weekly death graph. https://data.cms.gov/covid-19/covid-19-nursing-home-data. CDC data tracker, cases, and deaths https://covid.cdc.gov/covid-data-tracker/). See table 1.

NO ONE WAS PREPARED FOR THIS SURGE, and it literally changed everything that affected practicing nurses and other healthcare workers. It is likely that the variant that caused these dramatic changes in outcomes is among the 16,012,947 SARS-CoV-2 variant genetic sequences uploaded to the https://GISAID.org database by scientists worldwide. There were several variants circulating in the U.S. around this time, but we have not been able to locate further information that identifies it.

The Alpha B.1.1.7 SARS-CoV-2 Variant, February 27 to July 3, 2021

The COVID-19 Alpha variant provides an excellent example of how viral mutation affected the entire U.S. health care system, see figure 6. The Alpha variant was identified in the U.S. in November 2020 and became the dominant variant. We used the time period from when it reached a 10% proportion of circulating variants to when it dropped to 10% as the time during which it influenced outcomes, February 27, 2021, to July 3, 2021, see table 1.

During this 126-day time period, 5.9 million (5,859,544) people in the U.S. developed a COVID-19 infection at a rate of 46,504 patients per day. 

This variant had mutations that gave it an advantage over the ancestral variant. Alpha, also known as B.1.1.7, is transmitted easily from person to person. It was initially found in England, and rapidly spread everywhere. Monoclonal antibodies that had become a mainstream treatment for ancestral SARS-CoV-2 did not work as well for this variant. There were approximately 17 mutations that provided a competitive advantage over earlier SARS-CoV-2 variants of concern. Alpha produced a higher viral load than did previous variants, which contributed to how contagious it was and how many people one person was likely to infect. Other mutations made it easier for the virus to attach to and enter human cells (Davies, et al., 2021). A specific deletion mutation caused one of the main PCR tests to fail to identify the virus, and that caused false negative results in patients who were infected – patients who then thought there was no need to isolate or quarantine (Davies, et al., 2021; Galloway, et al., 2021).

Reproduction Number and Transmission for Alpha

By mid-April of 2021 up to 66% of U.S. COVID-19 infections were caused by the lethal Alpha variant (Tabatabai, et al., 2023).  Alpha was a very toxic virus, highly transmissible, and it was estimated to have an R0 of 4.5 to 5.5 (Technical Advisory Group, 2021 June). Transmission was estimated at 43 to 90% greater than the circulating variants that existed at that time (Davies, et al., 2021), see figure 7. As noted above R0 for the ancestral Wuhan variant was 2.2 to 2.75%. As it was much more contagious, Alpha had a competitive advantage over circulating variants at the time.

Case Fatality Rates/ Mortality Rates for Alpha

Case fatality rates are calculated by dividing the number of infection related deaths by the number of confirmed cases of a disease to determine the percentage of patients that died. The formula is:

(number of deaths/ number of confirmed cases of the disease) x 100.

The formula is modified as needed when the researcher limits to a specific time frame. In general, the case fatality rate and mortality rate are used interchangeably.

The Alpha variant caused high mortality worldwide. Tabatabai, et al. (2023) used data from the CDC COVID-19 Case surveillance public use data, and information from death certificates to estimate a U.S. case fatality rate of 5.35% for the Alpha variant. Patients were excluded unless the COVID-19 was lab confirmed. Deaths were excluded from the analysis unless a COVID-19 cause of death was documented on the death certificate. Deaths during that time period were attributed to Alpha as it accounted for the highest proportion of circulating variants, but the specific lab analysis for cases was not available to these researchers (Tabatabai, et al., 2023).

The case fatality rate for Alpha reported above was consistent with reports from other countries. Cetin, et al. (2021) reported that the arrival of the Alpha variant in Turkey increased the COVID-19 case fatality rate from a baseline of 0.84% for those who were not infected with the Alpha variant in that country to 5.3% for those with a confirmed Alpha infection. For patients over 70, the fatality rate was 13.6% for the other circulating variants, but for patients 70 and older with a confirmed Alpha variant infection, 31.5% of patients died (Cetin, et al., 2021). 

Using the compilation of data described above, we calculated a case fatality rate for Alpha to be 9.3% for the U.S. general population. Over 76,863 people lost their lives during this 126-day period of time at a rate of 3,903 per day.

COVID-19 became a leading cause of death during the Alpha time period. On October 3, 2020, COVID-19 infections accounted for 7.1% of all deaths in the U.S., and by January 9, 2021, 30% of all U.S. deaths were due to COVID-19. Secondary analysis: CDC (downloaded 2023, March 10) CDC, 2023). COVID-19 data tracker – U.S. data table for total cases. https://covid.cdc.gov/covid-data-tracker/#datatracker-home; CDC (downloaded 2023, July 10). COVID-19 data tracker – U.S. data table for cumulative death trends, United States. https://covid.cdc.gov/covid-data-tracker/#datatracker-home).

We used data from the CDC public use data tracker to estimate the overall U.S. case fatality rate (secondary analysis CDC data tracker, cases, and deaths https://covid.cdc.gov/covid-data-tracker/). During the time that Alpha was dominant, there were a total of 19,354,096 new cases of COVID-19 infections in the general population with 323,999 deaths. From mid-November 2020 through May 9, 2021, the overall case fatality rate in the U.S. was 1.7%.

Variants were not identified, and diagnoses on death certificates were not available in the database we used. The case fatality rate documented here includes all COVID-19 deaths reported by CDC that occurred during the time that Alpha was dominant. It was not possible to identify deaths due specifically to Alpha or other circulating variants that may have been less or more lethal. Thus, we can only indicate that these findings occurred during the Alpha period.

Nurse and Other Healthcare Worker Deaths during Alpha

This variant rose to dominance in the U.S. from approximately February of 2021 to July of 2021 and caused an increase in healthcare worker and nursing home staff deaths.

There were 82,693 new cases of healthcare workers/ nursing home staff illness with COVID-19 during the Alpha dominant time period, and 246 died from the infection. On a positive note, the health care and skilled nursing staff case fatality rate during Alpha dominance was only 0.30% (secondary analysis: CDC, downloaded 2023, July 22. COVID-19 data tracker – cases and deaths among health care personnel. https://covid.cdc.gov/covid-data-tracker/#health-care-personnel_healthcare-cases;  CDC, downloaded 2023 July 31. COVID-19 nursing home data – weekly death graph. https://data.cms.gov/covid-19/covid-19-nursing-home-data).

The number of healthcare worker deaths began to drop as the vaccine rollout began in mid-December. Supplies were limited so healthcare and essential workers were prioritized. Increasing numbers of healthcare providers were vaccinated with the first and in some cases second dose of Moderna or Pfizer vaccines. The Alpha variant did demonstrate immune evasion and was able to cause infection in vaccinated people, but the course of the infection was less severe. So, large numbers of nursing and other healthcare workers who were vaccinated got sick, but few died.

Hospitalizations/ Severity of Illness during Alpha

Hospitalization rates for the Alpha variant were higher than for the previous variants of concern, and ICU care was also needed more often. European studies found that those under the age of 60 were more likely to be hospitalized than was the case with previous strains (Thye, et al., 2021).

We used hospitalization as an indicator of severity of the infections during the reign of Alpha. From February 27 to July 3, 2021, there were 547,631 patients hospitalized at a rate of 4,346 patients per day. A total of 9.3% of patients experienced disease severity that required hospitalization (secondary analysis CDC (downloaded 2023, September 8). Data table for weekly covid19 hospital admissions – the United States. https://covid.cdc.gov/covid-data-tracker/#hospitalizations-landing). See table 1 for a comparison of variants.

Mitigation Strategies February 2021 to January 2022

During this time period risk was mitigated by the segment of the population that followed public health advice by social distancing, wearing masks as indicated, regularly performing hand hygiene and surface disinfection, and self-isolating to protect others when sick. Pre-travel requirements for testing, mask mandates on public transportation, and remote work options also helped reduce transmission.

Rising vaccination rates, fueled by armies of volunteers who helped to administer the vaccines had a major impact on reducing risk of life-threatening effects of the infection. Starting early in January 2021, COVID-19 vaccines were administered in the U.S. at an initial rate of approximately one million per day (Galloway, et al., 2021).

The Delta B.1.617.2 Variant, June 5, 2021, to January 1, 2022   

Delta was another deadly variant that emerged in the U.S. in May of 2021 and was ultimately replaced by the highly contagious Omicron SARS-COV-2 variant in November of 2021. We used the time period from June 5, 2021, to January 1, 2022, for outcome analysis.

Delta was first identified in India in November 2020 and then traveled all over the world. Delta caused massive loss of life in India in two waves. In India for both waves the number of pediatric cases was 10 to 15%. Densely populated cities in India were hit very hard by the Delta variant (Thye, et al., 2021).

Delta had approximately 10 mutations. The viral load was higher than with previously circulating variants, and it attached more firmly to the ACE receptor on the human cell, making it easier to enter the cell and reproduce itself. This variant was also better equipped to evade the human immune response. In addition, the Delta variant was not as well controlled by the existing vaccines as it was able to infect people who were vaccinated. As with Alpha, severity of illness was lessened for those who had received vaccinations (Aleem, et al., 2023; Thye, 2021).      

Reproduction Number and Transmission for Delta

Figure 8 refers to the Delta variant B.1.617.2 that rose to dominance in the U.S. from June 5, 2021, to January 1, 2022. The reproduction number (R0) estimated when the Delta variant arrived as a variant of concern in several countries ranged from 3.2 to 8, with a mean of 5.08. Thus, one infected person would transmit the infection to 3.2 to 8 other people. This variant caused large numbers of deaths in India, where it was first identified (Liu & Rocklov. 2021; Tabatabai, et al., 2023).

England was also overwhelmed with Delta cases. Over time the proportion of infections caused by the Delta variant increased while the proportion for Alpha decreased. In England, the reproduction number for Delta was estimated to be 40 to 80% higher than was the case for Alpha (Technical Advisory Group, 2021).

In the U.S., Delta (B.1.617.2) began to rise to dominance in May of 2021. On May 1, 2021, the Delta variant accounted for 1% of variants circulating in the U.S., and by June 26, 2021, the proportion of U.S. variants that were B.1.617.2 was at 50%. Delta continued to be the highest proportion variant through to December 2021, until it was replaced by the first Omicron variant in December of 2021 (Lambrou, et al., 2022).

From June 5, 2021, to January 1, 2022, while the Delta variant remained above 10% of all circulating SARS-CoV-2 variants, a period of 210 days, over 20 million (20,379,776) NEW cases of COVID-19 infections were recorded in the U.S. The rate of new infections rose by nearly 100,000 (97,047) per day (secondary analysis CDC data tracker, cases, and deaths https://covid.cdc.gov/covid-data-tracker/).

Case Fatality Rates/ Mortality Rates for Delta

The same team of researchers that estimated a U.S. case fatality rate of 5.35% for the Alpha variant recorded a rate of 7.5% while Delta was the predominant variant from May 20, 2021, to November 30, 2021. For this study, individuals were included if COVID-19 was confirmed by labs, and if a COVID-19 cause of death was on the death certificate. The researchers were not able to confirm the infection was Delta rather than another circulating variant, as that information was not available. Information from the CDC COVID-19 case surveillance public use data, for the Delta dates was analyzed to generate the case fatality rate (Tabatabai, et al., 2023).

Advanced age affected the Delta case fatality rate. In South Africa, 2.60% of those infected of all ages died, but the case fatality rate was 11.71% for those at or over the age of 60. In Italy, 12.8% of those aged 70 to 79 died, and mortality for individuals over 80 was 20.2%. A similar pattern was seen in China with an 8.0% case fatality rate for those people who were 70 to 79 and mortality increased to 14.8% for infected individuals over the age of 80. Vaccination status and comorbidities also contributed to the wide variations (Liu, et al., 2023).

Johnson, et al. found that the average weekly incidence of deaths in the U.S. during the period when Delta was dominant was 11.4 for unvaccinated persons and 0.7 per 100,000 population for those who were fully vaccinated (Johnson, et al., 2022). Overall, infection with Delta caused more severe disease in the unvaccinated than was the case with prior variants. Post vaccination breakthrough infections were not uncommon with Delta due to the immune evasion properties conferred by mutations, but the viral load decreased more quickly in those who were vaccinated (CDC, 2021, August 6).      

During the time period specified while cases proliferated in the U.S., Delta claimed 253,880 American lives at a rate of 1,209 deaths per day. The case fatality rate we calculated was markedly lower than reported in other countries at 1.3%. The lower rate may have been due to the rapid rollout of the vaccination program in the U.S., which was likely a major factor in mitigating severity of illness.

Nurse and Other Healthcare Worker Deaths During Delta

We used data from the CDC COVID-19 tracker for healthcare personnel and nursing home data to calculate rates. As noted previously healthcare personnel cases and death information and nursing home staff data were maintained separately by the CDC. It was necessary to combine this data for more accurate totals.

A total of 253,880 nurses and other healthcare providers were infected, at the rate of 1,209 per day, during the Delta period. There were 5 healthcare/ nursing home staff deaths for a case fatality rate of 0.24% during this time period, see table 1. (Secondary analysis: CDC, downloaded 2023, July 22. COVID-19 data tracker – cases and deaths among health care personnel. https://covid.cdc.gov/covid-data-tracker/#health-care-personnel_healthcare-cases;  CDC, downloaded 2023 July 31. COVID-19 nursing home data – weekly death graph. https://data.cms.gov/covid-19/covid-19-nursing-home-data).

Hospitalizations/ Severity of Illness – Delta

During the Delta variant wave, 1,499,570 people were hospitalized at a rate of 7,141 per day (compared with 10,182 per day with Alpha). During Delta 7.4% of individuals infected were hospitalized. These are, of course estimates, as while each wave of new variant increased, there were still other variants circulating, Delta became the dominant, but was not the sole variant.

Several factors mitigated the severity of this variant in the U.S., decreasing the case fatality rates. Once the vaccines became available in December of 2020, healthcare workers and first responders were prioritized. Public health education was still ignored by a segment of the U.S. population who believed that the pandemic was a hoax. But more people were listening to the advice of experts and were better able to protect themselves and their families.

Omicron Variants, Multiple Variants of Concern, December 2021

Omicron B.1.1.527 and BA.1, December 28, 2021, to April 2, 2022

Omicron arrived in the U.S. with variant B1.1.527 and the subvariant BA.1 near the end of November 2021, and they remained over 10% of circulating variants from December 18, 2021, to April 2, 2022, approximately 105 days. As shown in figure 9 there was a high degree of overlap, so we evaluated them together instead of separately.

Within the 105 days of circulation 30,675,560 new cases of COVID-19 infections were recorded. This translated to 292,148 new cases per day due to the first Omicron variants. 

B.1.1.527/ BA.1 had at least 30 mutations that provided competitive advantages over other circulating variants. Omicron was far more contagious and better able to bind to the ACE receptors on the outside of the human cell. The firm bond helped the virus to enter the cell and take over the cellular processes needed to reproduce itself. Monoclonal antibody medications were no longer effective with Omicron variants (Aleem, et al., 2023; Galloway, et al., 2021).  More than 30 Omicron variants and subvariants have been identified (Ma, et al., 2023). The original vaccines were not as effective at preventing infection but did reduce severity and risk of death. The bivalent Omicron booster vaccination received approval in January 2022.

Asymptomatic and pre-symptomatic viral shedding continue to be of concern with the Omicron variants because most people do not realize they are infected until (if) symptoms appear. For those who developed symptoms, they were contagious for at least 2 days before symptoms and for at least 2 to 6 days after. For those who never developed symptoms viral shedding still occurred and they were contagious (Auwaerter, 2022 July 12). Table 1 shows Omicron variants of concern that have gained dominance and then have been replaced.

Reproduction Number and Transmission

With the emergence of the Omicron B.1.1.529 and its subvariant BA.1 a single sick individual could infect from 5.5 to 24 other people. The average basic reproduction number was 9.5). Given the ability to transmit from one person to another so easily, Omicron was responsible for widespread disease. One factor that increased R0 was the ability to avoid the human immune system, especially in unvaccinated people. Unfortunately, this variant was also able to evade the existing vaccines and infect fully vaccinated people as well. However, vaccinated people were far less likely to die (Liu & Rocklov, 2021; Tabatabai, et al., 2023).

Omicron B.1.1.529/ BA.1.1 caused 180,760 deaths with a case fatality rate of 0.59%. Tabatabai, et al. (2023) reported a case fatality rate for Omicron B.1.1.529/ BA.1 of 9.0%, see figure 9. As noted above, this team of researchers analyzed data from the CDC COVID-19 Case surveillance public use data,  for Omicron from December 1, 2021 to March 2022. The authors state that the publication did not cover Omicron BA subvariants. Patient cases were limited to those with lab confirmation of COVID-19 infection and a COVID-19 diagnosis on the death certificate (Tabatabai, et al., 2023). The much higher rates reported by these researchers was likely due to differences in dates used, and more restrictive criteria in that they required a COVID-19 diagnosis on the death certificate and a lab confirmed diagnosis.

We estimated that a total of 1,091,707 people required hospitalization during the 105-day wave when Omicron B.1.1.527/ BA.1 was over 10% of variants circulating, from December 18, 2021, to April 2, 2022. Of those infected, 3.6% required hospitalization, at a rate of 10,397 admissions per day. The sheer volume of patients requiring hospital care placed a back-breaking burden on the nurses and then entire U.S. healthcare system, see table 1.

Nurses and other health care providers were still getting sick with a total of 368,127 infected with SARS-CoV-2 at a rate of 3,505 per day. Almost a thousand workers died (3,505), 9 per day, with a case fatality rate of 0.27%. Most of staff who died during this time worked in nursing homes.

Omicron BA.5 June 4, 2022, to December 31, 2022

As of January 22, 2022, 99.2% of variants were Omicron subvariants (Lambrou, et al., 2022) and most of them have died out.

The second major wave for Omicron began when variant BA.5 reached 10% of the circulating variants in the U.S. June 4, 2022, and dropped to 10% December 31, 2023. The mutations in BA.5 resulted in a reproduction rate, R0 of 18.5. With transmission rates this high, each infected person – symptomatic or asymptomatic was capable of creating superspreader events. Figure 10 illustrates the average number of primary infections caused by one infected person. Each of the 18 people infected in the first round were capable of infecting 18 more people, and so on (Auwaerter, 2022 July 12).

During this 210-day period during which Omicron BA.5 emerged as dominant, another 82,996 people died at a rate of 395 per day, case fatality 0.49%. Hospitalizations continued to be high at 4,816 per day for a total of 1,011,434 patients. Whereas Omicron B.1.1.528/ BA.1.1 had the lowest hospitalization rate at 3.6%, the percentage hospitalized while BA.5 rose and fell from dominance was at 6.0%.

Healthcare providers continued to become infected at a rate of 2,397 per day to a total of 503,316. On a positive note, healthcare provider deaths were down to an average of 3 per day and the number of staff who died was down to 627 during this 210-day time period. The staff case fatality rate was 0.13%, see table 1.

Mitigation Strategies: Vaccinations and Omicron

Bivalent booster vaccines that targeted ancestral and Omicron variants were introduced in 2022 (Abbasi, 2023). “Fully vaccinated” at that time included a booster injection that was designed to include Omicron. In the U.S. the updated version based on currently circulating variants was approved at the end of September 2023 and the terminology has changed from “fully vaccinated” to “vaccinated.”

COVID-19 now is an annual vaccine. Getting vaccinated is VERY important! Results from three studies conducted during periods when three different Omicron variants were predominant are as follows:

  • Omicron BA.5, September 18 to November 5, 2022 (n=1,717) – the mortality rate for those with the bivalent booster was 0.8% compared to 13.5% for unvaccinated persons.
  • Omicron BQ.1/ BQ1.1, November 6, 2022, to January 21, 2023 (n=4,537) – mortality was 1.6 to 1.8% for individuals who had the bivalent booster and 18.8% for the unvaccinated.
  • Omicron XBB.1.5, January 22 to April 1, 2023 (n=1907) – mortality rates for those vaccinated with the bivalent vaccine were 0.9 to 1.0% compared to 7.3% for unvaccinated people (Johnson, A. G., et al., 2023).

Omicron XBB.1.5, December 24, 2022 to August 5, 2023

            Omicron XBB.1.5 rose to dominance during a 223-day period stretching from December of 2022 to August of 2023. Like the other mutations that came before, this variant rose to dominance quickly and then became essentially obsolete. The U.S. has stopped reporting the number of cases of COVID-19, so it was not possible to calculate case fatality rates for XBB from this data.

During this time period, there were 580,881 people hospitalized at a rate of 2,605 per day. People were still dying at a rate of 234 per day for a total of 52,187. Most of those deaths could have been avoided with vaccination, as noted above, 7.3% of unvaccinated people died, whereas only 1.0% of those who received the vaccine lost their lives. Another 369 healthcare professionals died as a result of COVID-19 infections at a rate of 2 per day and with a case fatality rate of 0.15%, see table 1.

Omicron EG.5 (Eris) and Omicron FL.1.5.1 and Omicron HV.1, September/ October 2023

As of September 30, 2023, three new Omicron variants are rapidly replacing all the others. Omicron EG.5 (Eris) was first identified in the U.S. in late May 2023 and currently accounts for 29.4% of all circulating variants (see orange block on the diagram below). As shown, the proportion of this circulating variant has been increasing.

EG.5 was first detected in February of 2023, and the World Health Organization started monitoring it in July of 2023. This variant is a descendant of XBB.1.9.2 and has characteristics that allow it to escape the immune system, and it has a growth advantage over other variants, such as XBB.1.16 and XBB.1.5. The good news so far is that EG.5 appears to have a lower risk for severe disease than some of the other variants and has not increased hospitalization rates (World Health Organization, 2023, August 9. EG.5 initial risk evaluation. https://www.who.int/docs/default-source/coronaviruse/09082023eg.5_ire_final.pdf?sfvrsn=2aa2daee_3)

Omicron FL.1.5.1 (so far unnamed), was identified in the U.S. toward the end of June 2023 is at 13.7% (CDC., accessed 2023, October 1. National and regional variant proportions. https://covid.cdc.gov/covid-data-tracker/#variant-proportions). FL.1.5 is depicted by the light green block on the graph. Note that the percentage of circulating variants identified as FL.1.5 is increasing.

A new competitor, Omicron HV.1, see the darker gray color on the graph, rose to 12.9% of the circulating variants as of September 30, 2023. As shown, this variant was identified in the U.S. around August 5 to 19, 2023 and is increasing rapidly.

Note that the Omicron XBB variants are beginning to disappear from circulation. At the time of this writing, an easy way to stay on top of emerging variants is to periodically go to the CDC variant proportion page https://covid.cdc.gov/covid-data-tracker/#variant-proportions. See figure 11. These graphs provide a quick visualization of the changing variant environment. If an emerging variant is more transmissible and extremely virulent, patient acuity and staffing needs are likely to increase dramatically.


The first COVID-19 vaccine administered outside of a clinical trial on was given on December 14, 2020, and by December 24, 2020, over 1 million doses of COVID-19 vaccines were administered to U.S. healthcare workers and older adults living in long term care facilities. A total of 2.8 million received the vaccine by December 31, 2020 (CDC, 2023, March 15).

SARS-CoV2, and its countless variants, have not disappeared, but the threat of serious disease has been lessened due to the availability of vaccines. The first doses of COVID-19 vaccines became available in some countries, including the U.S. in December of 2020, a full year after the SARS-CoV-2 virus was discovered, but in some developing countries, the vaccine was not available until July of 2021 (World Health Organization Coronavirus (COVID-19) dashboard, vaccination data. Limited supplies in each country required that the vaccine be provided to those who were at highest risk for several months, so priority was given to first responders and healthcare providers.

Over 13,474,185,140 doses of COVID-19 vaccines were administered worldwide as of July 9, 2023 (WHO Coronavirus (COVID-19) dashboard (https://covid19.who.int/). As of May 10, 2023, the last date rates were reported, the U.S. has administered at least 676,728,782 vaccine doses, see figure 12. (CDC data tracker, https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status).

COVID-19: The Public Health Emergency Has Ended, COVID-19 Has Not

The United Nations World Health Organization announced that the COVID-19 public health emergency ended May 5, 2023 (WHO, 2023, May 5). The U.S. Centers for Disease Control and Prevention ended the public health emergency on May 11, 2023 (CDC, 2023, September 12). Do NOT get comfortable or complacent. The “public health emergency” may be declared over, but the virus that caused the disaster is alive and well and continuously mutating. SARS-CoV2 continues to cause morbidity and mortality worldwide.

The World Health Organization COVID-19 situation report dated August 3, 2023, indicated that in the 28 days ending July 30, 2023, there were over 1 million new cases of COVID-19 and 3,100 deaths worldwide.

It will continue to be very important for global citizens to be vaccinated at the recommended frequency with vaccines updated for the predominant variants indefinitely to keep this virus in check!

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