“It Ain't Over ‘til It's Over”

For most of the past year, we have had neither vaccines nor effective therapies to treat SARS-CoV-2. Our only defense has been nonpharmaceutical interventions (e.g., public health interventions). Two opposing strategies emerged. China adopted a strategy of elimination, implementing exceptionally strict measures, including shutting down transportation, closing cities, isolating people in their homes, and quarantining individuals (seemingly without consent) to stop the spread of infection. The strategy worked exceptionally well, but few countries would tolerate Chinese-style government-imposed measures. Four Asian countries – Japan, South Korea, Vietnam, and Thailand – imposed measures nearly as strict as China but seemingly with more voluntary compliance. For most of the past year, the per capita rate of cases and deaths was 1/100th in these four Asian countries compared to the U.S. and Western Europe.

In contrast, most countries adopted a strategy of mitigation, not elimination. Mitigation public health measures sought to “flatten the curve.” SARS-CoV-2 would continue to spread, but at rates that prevented COVID-19 from overwhelming local health care resources. Even these far less strict measures were met with public resistance, sentiments stoked in many countries for partisan gain (Science Advances 2021;7:eabd7204).

With the benefit of hindsight, epidemiologists recently evaluated elimination versus mitigation strategies (Lancet April 2021). The title of the paper states the conclusion: “SARS-CoV-2 elimination, not mitigation, creates best outcomes for health, the economy, and civil liberties.” The authors compared the outcomes in countries that pursued elimination (Australia, Iceland, Japan, New Zealand, and South Korea) with those that pursued mitigation (Canada, Mexico, Israel, and a majority of European countries). Mitigation strategies yielded 25 times as many COVID-19 deaths per million population, as well as similar increases in the burden of long-term morbidities from COVID-19. At almost all time-points, the five nations that pursued an elimination strategy outperformed the 32 countries with the mitigation strategy. The authors noted “GDP growth returned to pre-pandemic levels in early 2021 in the five countries that opted for elimination, whereas growth is still negative for the other 32 Organisation for Economic Co-operation and Development (OECD) countries.” Finally, the authors address the elephant in the room: civil liberties. The authors note that elimination strategies, such as those used by China, are considered anathema to civil liberties. The authors challenge this assertion using an index developed by University of Oxford researchers assessing the strictness of lockdown policies (Nat Hum Behav 2021;5:529-38). This index comprises eight containment/closure policy indicators, eight system policy indicators, and a public information campaign indicator. Using this index, liberties were negatively impacted the most in those countries choosing a mitigation strategy compared to those opting for elimination. The reason is that elimination strategies start quickly, are effective, and ultimately become “less strict and of shorter duration.” In addition, countries that used elimination (other than China) appealed to common cause (e.g., civic duty) as part of the elimination strategy, a strategy that was generally not used in countries with mitigation strategies.

The authors conclude that “the consequences of varying government COVID-19 responses will be long-lasting and extend beyond the end of the pandemic.... Early economic and political gains made by countries aiming to eliminate SARS-CoV-2 will probably pay off in the long run.”

Given these findings, what are we to make of the surging cases in Japan, South Korea, Thailand, and Vietnam (Figure 2)? Since the paper was published, it is clear that seemingly successful “elimination” strategies must adapt to more infectious variants, and these countries aren't adapting fast enough. In other words, it ain't over ‘til it's over.

The New England Journal of Medicine reported the cases of two women who developed COVID-19 after receiving the Pfizer or Moderna SARS-CoV-2 vaccine (N Engl J Med 2021;384:1952-4). Both women were infected with a SARS-CoV-2 variant after receiving both doses of vaccine. The viruses shared three alterations (D614G, T95I, and del144). One patient displayed the E484K escape mutation. This patient had neutralizing antibodies that recognized both E484K-mutant and B.1.526 variant SARS-CoV-2, but she nevertheless became infected. Neither viral sequence “precisely fit any known clade,” demonstrating ongoing evolution of variants.

An article in MMWR detailed the epidemiologic characteristics of the B.1.526 variant SARS-CoV-2 (MMWR Weekly 2021;70:712-6). This variant has been shown to have two distinct subclades, one of which has the E484K escape mutation. As of April 5, 2021, approximately 40% of the samples from COVID-19 cases in New York City were of this variant. Of these, more than half (56%) displayed the E484K mutation. Eleven individuals in these analyses were fully vaccinated and had been infected with the B.1.526 variant 14 days or after the second injection. Eight of these bore E484K-mutant lineages, while three did not.

The New England Journal of Medicine also published a report from Qatar on effectiveness of the Pfizer BNT162b2 vaccine against the B.1.1.7 and B.1.351 variants (N Engl J Med May 2021). The Pfizer vaccine was 89.5% effective against PCR-confirmed infection from the B.1.1.7 variant and 75% effective against the B.1.351 variant at 14 days after the second dose. Most importantly, there were no cases of severe, critical, or fatal disease arising from infection with either the B.1.1.7 or B.1.351 variants 14 days or more after the second injection. Clearly, this is good news for those who received the mRNA vaccines.

Two recent articles provided efficacy assessments from South Africa of the Oxford-AstraZeneca and Novavax vaccines (N Engl J Med 2021;384:1885-98; N Engl J Med 2021;384:1899-909). The Oxford-AstraZeneca vaccine demonstrated an efficacy of just 21.9% against the development of mild-to-moderate COVID-19, nearly all of which were the B.1.351 lineage. The investigators concluded that the “two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant.” The Novavax vaccine (NVX-CoV2373), which consists of 5 μg of recombinant spike protein and 50 μg of an adjuvant (Matrix-M1), demonstrated 49.4% efficacy among all patients, and 60.1% efficacy among HIV-negative patients. The investigators concluded that the vaccine was “efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants.” The overwhelming majority of SARS-CoV-2 infections were of the B.1.351 variant.

Returning to the paper in The Lancet, the authors note that that “history shows that vaccination alone can neither single-handedly nor rapidly control a virus and that a combination of public health measures are needed for containment” (Science Advances 2021;7:eabd7204). Both vaccine-based and non-pharmaceutical measures will need to defeat this tenacious virus. Since SARS-CoV-2 is global in nature, the pandemic won't be over without concerted international cooperation. Nations able to afford vaccination must assist nations that cannot afford mass vaccination to bring the pandemic to an end.

The authors point out that in addition to the obvious moral argument that vaccines should be globally available, there is also a strong self-interest argument. Continued viral evolution in unvaccinated populations may give rise to variants for which existing vaccines would be ineffective. We know that the P.1 variant in South America blew past “herd immunity” in Manaus, Brazil, and Iquitos, Peru (Lancet 2021;397:452-5; Science 2021;372:815-21; Lancet Glob Health May 2021). The rise of variants in unvaccinated individuals gives additional urgency to vaccinate the world, as “herd immunity is unlikely to be reached through natural exposure alone (Lancet Glob Health May 2021).

It ain't over ‘til it's over.

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.