A conquering virus has bested its variant brethren and covered the land. The delta variant of COVID-19 has spread exponentially in the United States, with 96% of counties reporting high (90%) or substantial (6%) transmission as of Oct. 8, 2021.

In ongoing genomic surveillance, prior variants have reached zero or near undetectable levels; delta is being found in 99.8% of sequenced SARS-CoV-2 in the United States, according to the Centers for Disease Control and Prevention (CDC).1,2

The variant has such a high degree of transmissibility that, if it continues its current pace, those unvaccinated are likely to acquire it, said Gregory Poland, MD, director of the Vaccine Research Group at the Mayo Clinic in Rochester, MN. “Frankly, if you’re not immune, you will become infected, it’s just a matter of time,” Poland said at the IDWeek 2021 virtual meeting, held Sept. 29-Oct. 4, 2021.

The initial Alpha variant is about 50% more transmissible than the original strain, and the delta variant is about 60% more transmissible than the Alpha, he noted. That seems understandable enough, but it “leads to a concept that’s hard for people to grasp, and that is exponentiality,” he said.

Noting that the beginning of an exponential surge is commonly missed in outbreaks, Poland gave two different scenarios that underscore how quickly the delta variant spread because of its high R-naught number, a measure of transmissibility from an infected case to susceptible people.

“Let’s just take that as baseline [of the pandemic], when the R-naught was 2.5. Now after 10 cycles of transmission in a naive population, that would lead to about 9,500 infections,” he said. “To give you a sense of exponentiality, let’s look at scenario B, where the R-naught now increases to 6. And with delta, people have proposed that it’s in the 6 to 8 range. That same 10 cycles of transmission through a naive population doesn’t lead to 9,500 infections, rather it leads to over 60 million infections.”  

1 in 500 dead

On Oct. 5, 2021, there were 101,668 cases of COVID-19, 73,020 people hospitalized and 1,808 deaths. Since the beginning of the pandemic, some 705,000 Americans have died.3 As this report was filed, COVID-19 cases were on a downswing from early September, but don’t expect the CDC to make the mistake again of suggesting the vaccinated can unmask. Millions of people remain unvaccinated.

“I think it surprises people to realize that about one out of every 500 Americans has died of COVID-19 — a very sobering statistic,” Poland said. “And yet no one modality in and of itself is sufficient to end this pandemic. It is much like an onion where there are layers of mitigation that we can put one atop of another in order to control this. Certainly, the primary one has to be vaccine.”

A susceptible population allows further infections, which in turn could lead to mutations and the emergence of other variants. We must hope, for example, that a variant more transmissible or virulent than delta does not evolve, but SARS-CoV-2 will continue to mutate as it circulates in humans around the globe. 

“We’re going to continue to see the evolution of viral variance,” Poland says. “In fact, this is one of the most condensed time periods in which we’ve watched, in living color if you will, the evolution of these viruses. And this includes the ability, the potential, to evade in part or in whole, vaccine-induced and convalescent immunity.”

The vaccines are holding against severe outcomes, but after much debate, the Pfizer booster shot was not approved for the general public as the Biden administration hoped. (See “Booster Options for HCWs Approved as CDC Overrules Advisory Panel.”) One of the central points was that you can’t boost your way out of a pandemic; only immunizing the unvaccinated will move the needle on that.

“You get diminishing returns if you are giving additional doses of vaccine to people who have already been vaccinated,” Celine Grounder, MD, ScM, FIDSA, of New York University said at IDWeek. “In order to control the spread, the transmission of the disease, we do not need to prevent all infections, we don’t need to induce sterilizing immunity with the vaccines. We simply need to reduce the effective reproductive rate, so the R-naught goes below 1.”

Given the intransigence of some of the unvaccinated, this is unlikely to happen unless attitudes change over time, and immunization becomes the price of admission to both work and social venues.

“I often ask people, which risk do you want?” Poland said. “The first is COVID-19 infection. And then if you risk it and survive it, [the risk] of post-acute sequalae — long COVID. The other choice you get to make is to get vaccinated, which may have some limited efficacy for immune-compromised individuals. As a vaccinologist for almost 40 years now, I can tell you, no vaccine has ever been studied with this degree of scrutiny prior to release. And yet I would be among the first to admit that we don’t know all that we would wish to know. The science always continues to evolve. The point is that every decision that you must make, whether by default or actively, has risks and benefits.”

With multiple millions now vaccinated in the United States, the risks associated with acquiring COVID-19 clearly are higher than the rare side effects of immunization for the vast majority of people. Yet many are blinded to reason by a kind of “cognitive dissonance” response, as social scientists term it.

In this case, the thought of being vaccinated causes unease and conflicts with the thought of remaining unvaccinated, so the latter is reinforced through confirmation by like-minded others and misinformation that supports the decision to refuse the shot. There is no shortage of false anti-vaccine information being amplified on social media, where it is consumed and rationalized as truth by some.

“[These] distorting factors have had a major impact on how this pandemic has played out, human behavior primary among them,” Poland says. “[There is] the false presupposition of the democratization of expertise, as if everybody’s scientific opinion were equal. We live in the West, in a place of cultural narcissism, where we think about ‘me’ and not the greater ‘we.’”

‘I’d rather die than take the vaccine’

Striking examples of this effect were provided recently by a Michigan physician, who posted the dying denialism of COVID-19 patients on his Facebook page. Many healthcare workers have heard such words themselves, which reveal a startling rejection of science and a zealous commitment to remain unvaccinated. Matthew Trunsky, MD, who works in hospice and pulmonary care in Royal Oak, MI, posted the following on September 11, 2021.3 The parenthetical comments are his. 

“In my last two days of work I have heard the following,” Trunsky wrote. 

  • “You’re wrong doctor. I’m too healthy. I don’t have COVID. I’m fine.” (In reality, he’s fighting for his life.)
  • “I demand ivermectin or you’ll hear from my lawyer.”
  • “I demand hydroxychloroquine.”
  • “I don’t care what you say. I’m going to leave.” (Response: “That is your prerogative, but you’ll be dead before you get to your car.”)
  • “I’d rather die than take the vaccine.” (You may get your wish.)
  • “I didn’t take it because my son told me it would kill me.” (The patient is currently fighting for his life — in fact it was the son’s advice that may kill him.)
  • “I want a different doctor. I don’t believe you.”
  • From a woman whose husband died of COVID: “I would never feel comfortable recommending the vaccine for family and friends.”

“This is not to mention the anger the people have towards the physicians and the nurses who are really doing our best — and who are delivering exceptionally excellent care,” Trunsky concluded. “Of course, the answer was to have been vaccinated — but they were not and now they’re angry at the medical community for their failure. Numbers are on the rise. Get your vaccine.” 

Kathryn Ivey, RN, a critical care nurse at a hospital in Nashville, shared similar sentiments on Twitter: “I don't know what to say that will make people listen,” Ivey tweeted.5 “I wish I could snap so many people out of their selfish stupor, but I can't, so I get to watch instead as people learn the hard way; with a tube down your throat. With a ‘code blue, code blue!’ and the crack of a sternum.”

Here is just one set of facts from the Pennsylvania Department of Health, which reviewed state data and records recently and reported that 94% of SARS-CoV-2 infections, 95% of hospitalizations, and 97% of deaths occurred in the unvaccinated.6 Many states are reporting these kinds of numbers, which are startling at first and then disheartening when they seem to have no effect on the unvaccinated. Likewise, it was thought that full licensure of the Pfizer vaccine would be a tipping point toward vaccination, but it appears only mandates will change the status quo.

“The issue is not data, the issue is not licensure, it has to do with fear and misinformation and a false epistemology,” Poland said. “There are certainly legitimate concerns and questions that come up, but all of those should be answered by now. What we’re dealing with is misinformation, conspiratorial-type thinking, limited scientific literacy, bandwagoning — which you can kind of think of as peer pressure — and magical thinking, perhaps best exemplified by that famous statement, ‘We’re going to wake up one morning and this will all be gone.’”

To paraphrase George Bernard Shaw’s observation, “What we learn from history is that we learn nothing from history.” Poland cited this quote in recalling the 1918 influenza pandemic, saying, “In many ways, we learned nothing from that history.” Although there was no vaccine for that virulent strain of H1N1 influenza A, similar themes to the COVID-19 pandemic were its unknown origin, national disputes over mask wearing, and that people in crowds were more likely to be infected in cities that held large parades for returning soldiers.

“[Now] we see vaccine hesitancy and rejection, anti-masking, political and economic conflicts of interest, lack of leadership, and fear,” Poland said. “Epistemology is the interpretive lens that one uses for determining truth. I would put forward that for a scientific medical problem like SARS-CoV-2, the epistemological lens must be that of science.”

The Science of Vaccine Efficacy

To put science in the lead, we must decide what we are trying to accomplish when looking at, for example, COVID-19 vaccine efficacy, Grounder said.

“Are we measuring vaccine effectiveness against infection, against symptomatic infection — so that would include mild to moderate disease — against severe disease, against hospitalization, or against death?” she said. “Are we trying to protect our healthcare system — which is really about flattening the curve, trying to slow the spread — so that the burden of severe disease is something that our hospitals can absorb and handle?”

After breakthrough infections — and subsequent transmission — were reported in the large outbreak in Provincetown, MA, in July 2021, the default efficacy measure seems to have become preventing hospitalization and death. There has been uncertainty and differing opinions on whether we are seeing the effects of waning immunity, the rise of the more transmissible delta variant, or some combination of both. 

Grounder broke it down to the basics, using the analogy of “a race” when the variant starts incubating and the memory immune system is triggered.

“Going back to sort of immunology 101, when you’re first exposed to a pathogen, a virus, or for that matter when you’re first vaccinated, you develop an antibody response,” she said. “You also develop an [immune] memory response, which takes a little bit longer to develop. That is the part of the immune response that is longer lasting, even after your neutralizing antibodies wane, declining over time. And then if you’re re-challenged with that same pathogen, be it a virus or perhaps it’s a second dose of vaccination, you get another bump in your neutralizing antibodies and also further maturation of your memory response. In particular, the memory B cells are undergoing a process of becoming better and better at recognizing the antigen — the virus.”

As the antibody response wanes, this immune memory may remain protective for an indefinite period, she said. “It’s the memory response that persists, and then if you’re re-challenged with an exposure or a vaccination, your memory B cells, your long-lived plasma cells will secrete, will produce neutralizing antibodies again,” Grounder explained.

 The memory B cells take about four days to ramp up antibodies, which is roughly akin to the incubation period to infection by the delta variant. At that point, “it’s a race between your immune system and the infecting virus as to which one wins out,” Grounder said. “Right at around the time that your immune system memory response is revving up, the infection is also taking off, so the timing means that it’s very difficult to beat the virus — at least at the level of a breakthrough infection.”

However, a breakthrough infection in the vaccinated is less important if the stated goal of vaccine efficacy is to prevent hospitalization and death. The problem, which research now is addressing, is that there are no mucosal or intranasal vaccines that could elicit an immune response in the upper airway.

There is a “spillover” effect right after vaccination, but when neutralizing antibodies wane, the immune memory response is not as protective in the upper airway, Grounder said.

“[We need to] find another way to elicit a mucosal response to complement the systemic immune response that you get with a parenteral vaccination,” she said.

Although the current vaccines do not prevent all breakthrough infections, “the protection against hospitalization from the COVID vaccines remains very high over time,” Grounder says. “It remains quite robust at 95%.”

Still, people age 65 years and older are more at risk of breakthroughs and were an important group to be targeted for booster shots, she said.

There is also a rare but real risk of developing long COVID after a breakthrough infection in fully vaccinated people. In a small Israeli study of some 1,500 fully vaccinated healthcare workers, 39 had SARS-CoV-2 breakthrough infections. Of those, seven had persistent symptoms of more than six weeks.7

It is one study with small numbers, the lead author emphasizes, but concedes it was disturbing to see.

“They had severe fatigue. They continued to have loss of taste and smell,” said Gili Regev-Yochay, MD, of Sheba Medical Center. “It's very concerning.”8

It’s important to emphasize that those unvaccinated are much more likely to develop long COVID after infection than those immunized.

A United Kingdom study reported recently that vaccination — compared to the unvaccinated — was associated with a 50% reduced likelihood of long COVID with more than 28 days of symptoms.9 This is if a breakthrough infection occurs in the first place, which may not happen at all if one is fully vaccinated.

However, both of the aforementioned studies involved the Alpha variant before the delta variant was predominate. 

“Still, this [United Kingdom study] is quite promising, showing that your risk of long COVID is much reduced if you have been vaccinated and have a breakthrough infection vs. having an infection as an unvaccinated person,” Grounder said.


  1. Centers for Disease Control and Prevention. COVID Data Tracker. COVID-19 Integrated County View. https://covid.cdc.gov/covid-data-tracker/#county-view
  2. Centers for Disease Control and Prevention. COVID Data Tracker. Variant Proportions. Updated Oct. 7, 2021. https://covid.cdc.gov/covid-data-tracker/#variant-proportions
  3. The New York Times. Coronavirus in the U.S.: Latest Map and Case Count. Updated Oct. 12, 2021. https://www.nytimes.com/interactive/2021/us/covid-cases.html
  4. Erb R. A Michigan doctor goes to Facebook over dying, unvaccinated COVID patients. Bridge Michigan. Published Sept. 15, 2021. https://www.bridgemi.com/michigan-health-watch/michigan-doctor-goes-facebook-over-dying-unvaccinated-covid-patients
  5. Ivey K. Twitter. Aug. 1, 2021. https://twitter.com/kathryniveyy/status/1421815491400716297
  6. Pennsylvania Pressroom. Vaccines work: 97% Of COVID deaths, 95% of hospitalizations and 94% of cases are among unvaccinated Pennsylvanians. Published Sept. 14, 2021. https://www.media.pa.gov/pages/health-details.aspx?newsid=1595
  7. Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 breakthrough infections in vaccinated health care workers. N Engl J Med 2021; Jul 28:NEJMoa2109072. doi: 10.1056/NEJMoa2109072. [Online ahead of print].
  8. National Public Radio. COVID symptoms may linger in some vaccinated people who get infected, study finds. Published July 28, 2021. https://www.npr.org/transcripts/1021888033
  9. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: A prospective, community-based, nested, case-control study. Lancet Infect Dis 2021; Sep 1:S1473-3099(21)00460-6. doi: 10.1016/S1473-3099(21)00460-6. [Online ahead of print].