From Pandemic to Endemic? Plus, What’s Up with the Delta Variant?

While the world watches, the viral agent that causes COVID-19 is morphing from the driver of a pandemic to one that may become endemic in humans. This is truly one for the history books.

More than a year-and-a-half since the pandemic began, country after country has proven unable to stop the original SARS-CoV-2 virus that causes COVID-19 from spreading—not to mention successive waves of its genetic variants. Reasons the virus continues to spread stretch well beyond its high transmissibility rates and infectious disease dynamics[i] to include more complex factors such as:

  • Varying degrees of local conformance to basic mitigation strategies such as wearing face masks and social distancing[ii]
  • A lack of coordination on mitigation strategies between local, regional, national, and international public health authorities and governments,[iii]
  • Fewer people accepting commercially available vaccines than are needed to significantly drive transmission down to make R-naught less than 1[iv]
  • Unequal global access to COVID-19 vaccines[v]

Although vaccines against COVID-19 have been available in the US since December 2020,[vi] nine months later only 51% of the country is fully vaccinated and only 60% is partially vaccinated.[vii] The US vaccine rollout began when the alpha variant was dominant in the US. Meanwhile, scientist catalogued a parade of successive genetic variants with ever changing names:[viii]

  • Alpha (B.1.1.7)
  • Beta (B.1.351, B.1.351.2, B.1.351.3)
  • Delta (B.1.617.2, AY.1, AY.2, AY.3)
  • Gamma (P.1, P.1.1, P.1.2) 1.617.2
  • Iota (B.1.526), B.1.427, B.1.429
  • Kappa (B.1.617.1)

Who could have predicted that estoeric arguments over viral phylogeny and nomenclature conventions would command global headlines last winter?[ix] For the record, the greek letters in use today are intended as a unifying shorthand to discourage attaching stigma to regional places from which the genetic variants were first identified; while the system of ordered letters and numbers denote nested subgroups with each subsequent character documenting a new change from the prior one that begat it.[x] The changes are identified using genomic sequencing techniques, and tracked in global data repositories, such as GISAID[xi] which hit its 1 million coronavirus sequences milestone last spring.[xii]

Each named variant represents a distinguishable genetic lineage where some of the 30,000 nucleotides that comprise the SARS-CoV-2 RNA genome became rearranged due to mutations. Most mutations fail to significantly change viral function. But others are important, such as ones that allow the virus easier entry into a host cell, increase its ability to cause disease, or speed its ability to replicate and infect new hosts.[xiii]

The delta variant first began finding a foothold in America’s susceptibles this summer. It is defined by a diverse set of mutations in the N-terminal domain and the receptor-binding domain of the SARS-CoV-2 spike protein.[xiv] It quickly spread from the midwest throughout the Southeast, with Louisiana and Florida jockeying for position as the country’s most infected states. Hospitals began filling up again,[xv] mask mandates were resurrected in some areas,[xvi] and some who dawdled over getting a vaccine rolled up their sleeve.

Those who were paying attention had watched the same events unfold in the United Kingdom and India earlier this year when the delta variant tore through their populations. Initial studies indicated that it was more infectious than the original alpha variant[xvii] and—more troubling—that it can better evade our immunity, possibly due to the mutations noted above.[xviii]

But how often do coronaviruses mutate? In general, their rate of change is slow despite being an RNA virus, which tend to have higher rates of mutation than DNA viruses. This is because they have a special enzyme that acts as an editor to correct some of the mistakes that arise naturally during replication. But adaptation wins the day, and if a mutation tends to confer an advantage, it will likely be retained.[xix]

And yet, this one has been mutating all along. The sheer number of hosts it now occupies drives the emergence of new strains. It’s just that until recently, not many of the new strains did anything all that different clinically.[xx]

Teasing apart such nuances is exactly why there is a strong argument for increased genomic surveillance monitoring of SARS-CoV-2 in the populace. The premise is to have a system for collecting and processing samples from infected individuals with the goal of keeping track of what variants are where and quickly identifying new variants as they emerge or move into new geographic areas.[xxi] It’s not all that different than the national flu network — and it may be our public health future.

Given the steady march of new genetic variants that have emerged, many have questioned the efficacy of our current vaccines. Up until the delta variant burst onto the global stage, the answer was that most commercially available vaccines were highly effective with a pooled vaccine efficacy of 85% against infection, and close to 100% against severe disease, hospitalization, or death.[xxii]

But the situation is rapidly changing. First, there is newly emerging evidence that all adults—not just the immunocompromised and elderly—will need booster shots due to potential natural decay of immunity over time that was acquired from the first full dose.[xxiii] Second, the delta variant may have evolved an adaptation that allows it to better evade the immune system of people who were naturally immunized by prior infection with COVID-19.[xxiv]

But while vaccines receive the lion’s share of attention, some researchers are looking for answers to the pandemic by studying the human coronavirus known as HCoV-OC43, which causes common seasonal cold symptoms. It is in the same betacoronavirus family as comparatively more pathogenic agents such as SARS-CoV-2, MERS-CoV, which causes Middle East Respiratory Syndrome, and SARS-CoV which fueled the first SARS outbreak in Asia.[xxv] By investigating factors that influence virulence—asking why some betacoronaviruses cause only mild illness while others produce high fatality rates—researchers hope to pinpoint draggable targets that can be used to develop antiviral therapies.[xxvi]

More research is needed on the durability of immune responses to the COVID-19 vaccines, the feasibility of developing a pancoronavirus vaccine, and antiviral therapies. Antivirals in particular would be a welcome tool for healthcare providers, especially in community settings where low vaccination rates fuel transmission, or for use in patients who can’t receive a vaccine.

While there won’t be a single path to end the pandemic, a combination of equitable vaccine distribution, antiviral therapies, and public health campaigns to combat vaccine hesitancy and increase mitigation strategies could bend the arc of the current trajectory more toward endemicism instead of the extended pandemic phase the world has endured so far.



[i] Linka K, Peirlinck M, Kuhl E. The reproduction number of COVID-19 and its correlation with public health interventions. Preprint. medRxiv. 2020;2020.05.01.20088047. Published 2020 Jul 7. doi:10.1101/2020.05.01.20088047

[ii] Eikenberry SE, Mancuso M, Iboi E, et al. To mask or not to mask: Modeling the potential for face mask use by the general public to curtail the COVID-19 pandemic. Infect Dis Model. 2020;5:293-308. Published 2020 Apr 21. doi:10.1016/j.idm.2020.04.001

[iii] Kortessis N, Simon MW, Barfield M, Glass GE, Singer BH, Holt RD. The interplay of movement and spatiotemporal variation in transmission degrades pandemic control. Proc Natl Acad Sci U S A. 2020;117(48):30104-30106. doi:10.1073/pnas.2018286117

[iv] Bates, V. What is R. Available at Accessed on 8/18/2021.

[v] Stephenson J. Unequal Access to COVID-19 Vaccines Leaves Less-Wealthy Countries More Vulnerable, Poses Threat to Global Immunity. JAMA Health Forum. 2021;2(3):e210505. doi:10.1001/jamahealthforum.2021.0505

[vi] Centers for Disease Control and Prevention. How CDC is making COVID-19 vaccine recommendations. Available at Accessed 08/18/2021.

[vii] See how vaccinations are going in your county and state. New York Times. Available at Updated 08/18/2021. Accessed 08/18/2021

[viii] Centers for Disease Control and Prevent. SARS-CoV-2 variant classifications and definitions. Available at Updated 08/17/2021. Accessed 08/18/2021.

[ix] Callaway E. ‘A bloody mess’: Confusion reigns over naming of new COVID variants. Nature. 2021;589(7842):339. doi:10.1038/d41586-021-00097-w

[x] Callaway E. ‘A bloody mess’: Confusion reigns over naming of new COVID variants. Nature. 2021;589(7842):339. doi:10.1038/d41586-021-00097-w

[xi] GISAID. Available at . Accessed on 08/18/2021.

[xii] Maxmen A. One million coronavirus sequences: popular genome site hits mega milestone. Nature. 2021;593(7857):21. doi:10.1038/d41586-021-01069-w

[xiii] Sunderman A, Harrison L, Cooper V. Genomic surveillance: What it is and why we need more of it to track coronavirus variants and help end the COVID-19 pandemic. The Conversation. Available at Accessed 08/18/2021.

[xiv] Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280. doi:10.1038/s41586-021-03777-9

[xv] Hawkins, D. The delta variant is putting America’s hospitals back in crisis mode. Washington Post. Available at Accessed 08/18/2021.

[xvi] Solender, A. Pandemic of the unvaccinated: CDC says delta variant may warrant local mask mandates. Forbes. Available at Accessed 08/18/2021.

[xvii] Callaway E. Delta coronavirus variant: scientists brace for impact. Nature. 2021;595(7865):17-18. doi:10.1038/d41586-021-01696-3

[xviii] Adam D. What scientists know about new, fast-spreading coronavirus variants. Nature. 2021;594(7861):19-20. doi:10.1038/d41586-021-01390-4

[xix] Lauring AS, Hodcroft EB. Genetic Variants of SARS-CoV-2-What Do They Mean?. JAMA. 2021;325(6):529-531. doi:10.1001/jama.2020.27124

[xx] Resnick B. 4 reasons we’re seeing these worrying coronavirus variants now. Vox, 01/27/2021. Available at Accessed 08/18/2021.

[xxi] Sunderman A, Harrison L, Cooper V. Genomic surveillance: What it is and why we need more of it to track coronavirus variants and help end the COVID-19 pandemic. The Conversation. Available at Accessed 08/18/2021.

[xxii] Shapiro J, Dean N, Madewell Z, Yang Y, Hallorhan E, and Longini I. Efficacy estimate for various COVID-19 vaccines: What we know from the literature and reports. medRxiv, 05/21/2021. Available at Accessed 08/18/2021.

[xxiii] Firth S. US adults to be offered COVID booster shots in September. MedPage Today, 8/18/2021. Available at Accessed 08/18/2021

[xxiv] Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280. doi:10.1038/s41586-021-03777-9

[xxv] Cuffari, B. What is OC43? Medical Life Sciences News. Available at Accessed 08/18/2021.

[xxvi] Grodzki M, et al. Genome-scale CRISPR screens identify host factors that promote human coronavirus infection. bioRxiv. 06/04/2021, doi: