“This is the way the world ends

This is the way the world ends

This is the way the world ends

Not with a bang but a whimper.”

T.S. Eliot

In January 2021, Public Health England initiated a comprehensive strategy to monitor vaccination efficacy and safety (asamonitor.pub/3vnt0G9). Since then, Public Health England has monitored vaccination, serology (collected from blood doners), and outcomes (hospitalization and death). The serological analysis involved testing 250 samples every week from blood donors for antibodies.

According to the most recent COVID-19 Vaccine Surveillance Report (as of this writing), published on October 14, 2021, 65% of the U.K. population had received one dose of vaccine and 60% had received two doses (asamonitor.pub/30rkWc3). Serological surveillance indicates that 95% of the entire U.K. population has antibodies to the spike protein, including 99% of U.K. adults over the age of 60 (asamonitor.pub/2YYZYk6). The U.K. is now in the “end game,” where most adults have antibodies. What does it look like? What does it mean for the United States?

The first observation is that high levels of seropositivity don't bring either cases or deaths to an end. Figure 1 shows the COVID-19 time series for England as of this writing (October 17, 2021). Since August, cases and deaths have been remarkably constant. Deaths are averaging about 1,000 per week. That's almost an order of magnitude less than the number of deaths in December and January, but still horrific. Cases are running about 300,000 per week, which is a considerable health care burden.

“Even though cases and deaths are declining, and immunity is rising, the U.S. picture remains grim. We are still seeing about 1,000 deaths per week.”

As discussed in the October “In the Know” column, the high case numbers in the U.K. reflect offsetting effects of increased infectiousness of the Delta variant and increased resistance to infection conferred by vaccination (ASA Monitor 2021;85:1-13). Every week, the U.K. Health Security Agency publishes the efficacy of the three available vaccines. As shown in Table 1, the Pfizer BNT162b2 vaccine is more efficacious than the AstraZeneca vaccine. The primary utility of the vaccines is not in preventing cases but in preventing hospitalization and death.

Since adults were vaccinated earlier than adolescents and children in the U.K., it isn't surprising that most of the current infections are in children and teenagers, as shown in Figure 2. As expected, most of these cases are in unvaccinated kids, as shown in Figure 3.

Figure 3 suggests that vaccination is increasing the rate of infection in those over age 40. Wow – is that possible? Are vaccinations increasing the rate of infection in those over 40?

The answer, of course, is that vaccinations are not raising the rate of infections. As the U.K. Vaccine Surveillance Report suggests, “even with a highly effective vaccine, it is expected that a large proportion of cases, hospitalisations and deaths would occur in vaccinated individuals, simply because a larger proportion of the population are vaccinated than unvaccinated and no vaccine is 100% effective.”

As shown in Figure 4, vaccination provides excellent protection against death. Additionally, nearly all hospitalizations and deaths in vaccinated individuals reflect comorbidities (Clin Microbiol Infect July 2021). These observations are consistent with the vaccine efficacy reported in Table 1.

As noted by William Haseltine, vaccination is the cornerstone of controlling the pandemic (asamonitor.pub/2Z45MsR). With 95%-99% seropositivity in adults, depending on age, the U.K. provides guidance to what 2022 will look like when (and if) we are able to reach similar vaccination rates in the U.S.

Figure 5 shows the current time series for the U.S. We are getting through the Delta surge. As discussed in the ASA Monitor, if you don't get vaccinated, you are likely to be infected with COVID (ASA Monitor 2021;85:1,7). That is exactly what happened in the U.K., accounting for 95%-99% seropositivity in their adult population. This is happening in the U.S. Quoting the September 9 policy briefing from the Institute for Health Metrics and Evaluation at the University of Washington, cases in the U.S. are now declining “likely due to running out of susceptible individuals rather than policy interventions,” (asamonitor.pub/3ASoWyW). Cases may be declining in the U.S. more rapidly than in the U.K. because the Pfizer and Moderna vaccines are more effective than the AstraZeneca vaccine received by most of the U.K. population.

Even though cases and deaths are declining, and immunity is rising, the U.S. picture remains grim. We are still seeing about 1,000 deaths per week. The Institute for Health Metrics and Evaluation expects this death toll to remain nearly constant through the end of 2021.

A recent paper in Scientific Reports explored the linked dynamics of viral evolution and vaccinations during the COVID-19 pandemic (Sci Rep 2021;11:15729). The evolutionary advantage of a resistant strain increases sharply as vaccination approaches 100%. The authors show that once a large fraction of the population is vaccinated, the resistant variant has a significant evolutionary advantage relative to the wild type. The authors conclude that it is exceptionally important to maintain non-pharmaceutical interventions (e.g., masks, social distancing) throughout the entire vaccination period to prevent establishing more resistant strains.

This suggests it would be wise to wear masks and follow social distancing for a substantial portion of 2022 as immunity rises to 99%. However, it is worth noting that despite >95% seropositivity, and despite sequencing over 1 million SARS-CoV-2 genomes, the U.K. has not seen the emergence of a variant more infectious than Delta (asamonitor.pub/3vpmpv9).

The U.K. Scientific Advisory Group for Emergencies reviewed evolutionary scenarios for SARS-CoV-2 (asamonitor.pub/3vrPtSv). One scenario was an increase in lethality, similar to SARS-CoV-1 (10% mortality) or MERS (35% mortality). The authors concluded there was a realistic possibility for the emergence a more lethal variant and suggested increased emphasis on booster vaccinations combined with improved therapeutics (e.g., molnupiravir).

Another scenario was a variant evades current vaccines based on the original SARS-CoV-2 spike protein. The authors suggest the possibility of developing “universal” vaccines that target highly conserved regions of the spike protein (Science 2021;373:818-23). It is also possible that “universal” oral therapeutics that target highly conserved SARS-CoV-2 proteins, such as the Mpro protease, will be effective against future variants (medRxiv July 2021).

The Delta variant is as infectious as smallpox, which is about as infectious as viruses get. Our existing vaccines are effective in preventing serious illness and death from the Delta variant (Table 1). While there will be new variants, it appears our vaccines will likely remain effective. Thus, it seems unlikely that future variants will extend the pandemic.

SARS-CoV-2 is never going away. Two years ago, we had four endemic coronaviruses: HCoV-HKU1, HCoV-OC43, HCoV-50NL63, and HCoV-229E. These viruses infect children without serious sequelae. Re-infections from these coronaviruses occur throughout life roughly every 12 months (Nat Mede 2020;26:1691-3). We now have five endemic coronaviruses. SARS-CoV-2 will likely behave like the others: infecting young children without consequence and then re-infecting everyone roughly yearly. The effect will be to boost immunity and minimize the complications of future infections.

Over the next year, immunity will rise to nearly 100% and be further boosted by vaccination or re-infection. As our immunity becomes increasingly robust, we will get to the point where we may still catch SARS-CoV-2, but it will just be another cold.

That is likely at least a year away. The Institute for Health Metrics and Evaluation projects that we will start 2022 with about 1,000 deaths per week. We know how to minimize this toll: 1) increase vaccination, 2) maintain non-pharmaceutical interventions, 3) develop improved therapeutics, and 4) work globally to end the pandemic. These are exactly the four recommendations from William Haseltine to finally get control over the SARS-CoV-2 pandemic (asamonitor.pub/2Z45MsR).

Richard Simoneaux is a freelance writer with an MS in organic chemistry from Indiana University. He has more than 15 years of experience covering the pharmaceutical industry and an additional seven years as a laboratory-based medicinal chemist.