Potential COVID-19 Endgame Scenarios: Eradication, Elimination, Cohabitation, or Conflagration?

High vaccination rates of the adult US population have given rise to the hope that a return to prepandemic life may be in the offing. However, differential vaccine access, persistent vaccine hesitancy, emerging viral variants, and deadly global disease waves may well stand in the way. In that volatility has heretofore been the invariant attribute of SARS-CoV-2, envisioning a future steady state can be inherently problematic. This Viewpoint describes 4 potential scenarios—eradication, elimination, cohabitation, and conflagration—comprising a spectrum of “endgames” that may constitute the resolution of the COVID-19 pandemic; however, other scenarios also may be possible.

What would it take to eradicate SARS-CoV-2? By definition, eradication would require the permanent global reduction of the prevalence of SARS-CoV-2–mediated disease to zero. To realize such an outcome, sufficient herd immunity would have to be achieved through vaccination and prior infection. Both vaccine- and infection-derived immunity would have to be highly effective, long-lasting, adept at preventing secondary transmission and reinfection, and protective against all manner of present and future viral variants.

Given these relatively astringent requirements, eradication may prove to be too aspirational a goal even as a thought experiment, let alone as a public health strategy. However, smallpox, yet another highly contagious respiratory infection, was irreversibly eradicated, an outcome once considered unimaginable. Other vaccine-preventable airborne diseases such as measles and rubella have been the subject of elimination, that is, the regional, rather than global reduction of disease prevalence to zero. Elimination may well constitute a more realistic near-term goal for SARS-CoV-2 especially if slow-to-distribute booster vaccines become necessary to target emerging viral variants. Evidence of the successful elimination of SARS-CoV-2 is rapidly accumulating. Elimination may be close-at-hand in Israel, a model of vaccination efficiency wherein incident SARS-CoV-2 cases are presently at 0.7% of their all-time high.¹ Similar successes could be realized in other nations wherein sufficiently high vaccination rates have been achieved. Temporary elimination of SARS-CoV-2 absent the advent of vaccines may well prove feasible as well as demonstrated by New Zealand in early August of 2020.

Were eradication or elimination to be achieved in the US or elsewhere, ongoing vaccination against SARS-CoV-2 and its variants would be required to counter the ongoing risk of suspected zoonotic transfer from bats, farmed minks, or yet-to-be uncovered animal reservoirs.² In this regard, SARS-CoV-2 stands out relative to smallpox for which no known animal reservoir has been identified. It follows that absent indefinite future vaccination efforts against SARS-CoV-2, durable elimination, let alone eradication, may prove infeasible.

Alternatively, might a more civil cohabitation be achieved with SARS-CoV-2, an outcome short of all-out eradication or substantial elimination? In this scenario, vaccine-mediated protection would go so far as to prevent the most severe manifestations of COVID-19, interrupt the chain of viral transmission, and counter the majority of emergent viral variants. Evidence in support of the realization of such scenario is likely to include, but not be limited to, the documentation of sparse reinfections, rare vaccine breakthroughs, and negligible secondary transmission even in the face of most viral variants.^3-5

In a world with a state of immunologic cohabitation, distinct viral-free pockets of infection may well exist wherein vaccine uptake is high. Whereas most incident infections would slow down significantly, some may well persist at either low levels or in the form of sporadic outbreaks outside of the viral-free pockets in question. Such new infections would be expected to occur predominantly among the undervaccinated. Rare breakthrough infections among vaccinated people may come to pass due to limited vaccine efficacy, immunocompromised states, sporadic vaccine supply or quality control issues, or future viral variants. Overall, however, despite occasional new infections, a more tolerable endemicity may well replace the volatility of the pandemic phase.

As vaccine accessibility expands globally, as vaccine hesitancy and access challenges subside, and as viral replication and variant generation are reduced, the number of viral-free pockets may well grow. Although vaccination may well continue to provide high levels of immunity against viral variants, boosters may be required to maintain the status quo. Where and when vaccination rates sputter and infections reoccur, new localized outbreaks may be seeded. In these instances, the implementation of and adherence to preventive public health measures may still be required. However, for those who are either vaccinated or who reside in geographic areas with low case prevalence, with limited selection of viral variants, or both, the risk of infection is likely to be manageably low. Over the long-term, however, as global immunity due to exposure or vaccination becomes commonplace, the disease symptoms experienced may come to resemble those of the common cold, which is brought about by seasonal coronaviruses.

Absent a cohabitation option, the endgame may well come to resemble a conflagration, that is, a steady state characterized by moderate-level endemicity of SARS-CoV-2. With large segments of the population undervaccinated due to access constraints, hesitancy, or immunocompromised states, the circulation of SARS-CoV-2 is bound to remain robust. This would afford the virus with continuous opportunities to replicate and adapt so as to evade host-mediated and vaccine-derived immune responses. Among vaccinated populations, infections could still arise periodically due to incomplete vaccine-derived immunity, the waning of vaccine efficacy, evasion by new viral variants, or transmission from the unvaccinated. Two recent breakthrough cases of variant SARS-CoV-2 serve as an important reminder of such a possibility.⁶

The degree of conflagration may come to depend substantially on the efficacy and acceptance of vaccines by geography. Potential coverage gaps against specific variants have been noted for several vaccines. The utility of the AstraZeneca vaccine against the B.1.351 variant is one such example.⁷ Similar gaps in the coverage of worrisome variants may exist for other vaccines for which publicly available data have heretofore been either absent, sparse, or limited to in vitro studies. Assuming a state of conflagration, with much of the world subject to limited availability of vaccines or to less-effective ones, ongoing outbreaks on a wider scale are to be expected.

Only a year ago, much of the world was united in lockdown in the midst of the first outbreak of COVID-19. Today, the global experience is widely divergent. Israel, New Zealand, Vietnam, and Brunei may well be approaching elimination. The United Kingdom, the United States, and China, for their part, appear to exist in a state of cohabitation. In contrast, India, other parts of Southeast Asia, and much of South America appear to be weighed down by a conflagration-like state. Reversing the fortunes of nations in the grip of a conflagration-like state will require the buildup of population-level immunity via vaccines capable of neutralizing new viral variants. Breakthroughs in the development of highly effective therapeutics, should they occur, stand to further disrupt the global status quo with an eye toward accelerating recovery, especially in the conflagration context. Ultimately, where on the endgame spectrum individual countries end up will depend on both the collective choices and realities of the global community and the oft-inscrutable and perhaps unpredictable dynamics of SARS-CoV-2.

Corresponding Author: Eli Y. Adashi, MD, MS, Brown University, 222 Richmond St, Providence, RI 02903 (eli_adashi@brown.edu).

Published Online: July 8, 2021. doi:10.1001/jama.2021.11042

Conflict of Interest Disclosures: Dr Kantor reported being coprimary investigator on a research grant from Gilead Sciences unrelated to this article. No other disclosures were reported.

Funding/Support: Dr Kantor is supported by grant K24AI134359 from the National Institutes of Health (NIH).

Role of the Funder/Sponsor: NIH had no role in the preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.