Will SARS-CoV-2 become endemic?

From the Halloran lab, Biostatistics, Bioinformatics, and Epidemiology Program, Vaccine and Infectious Disease Division

As we near the third year of the SARS-CoV-2 pandemic, thoughts of eliminating the virus are instead shifting to how to best live with it. Many questions, including whether SARS-CoV-2 will ever be eliminated or instead become endemic in the population, must be answered with complex epidemiologic models that consider factors relating to the population and immunity. In a recent Immunity review, Profs. Rustom Antia (Emory University) and M. Elizabeth Halloran (Fred Hutch Vaccine and Infectious Disease Division, Biostatistics, Bioinformatics, and Epidemiology Program) explored this topic. They explain concepts behind the transition from an epidemic to an endemic state and discuss the implications of this phenomenon for the SARS-CoV-2 pandemic.

An infectious agent such as a virus can cause an epidemic (or pandemic, when spread globally) when the pathogen rapidly spreads through a population. At the beginning of an epidemic, most people are not yet immune to the infection, allowing for exponential spread through susceptible hosts, where each infected person causes at least 1 secondary infection.  As more and more people become at least temporarily immune and the pool of susceptible people declines, the exponential spread ceases, causing a drop in the infection prevalence within a population. At this stage, the epidemic can take one of two paths: go extinct, or become endemic. Complete eradication can occur when the population is small and no susceptible individuals remain, or if complete immunity by infection or immunization can be obtained. However, in a large population and with imperfect immunity, an infection is likely to become endemic.

Unlike the rapid spread of a virus during an epidemic or pandemic, an endemic state refers to the stable maintenance of a pathogen within a population at a relatively lower prevalence. Although many people at this point may be immune by either natural infection or vaccination, new susceptible individuals arise by birth, immigration, or by the waning of protective immunity. These new targets for the pathogen can sustain the endemic state for an extended and indefinite period of time. With these concepts established, the authors explore endemic human coronaviruses (hCoVs) and apply what is known about these viruses to the SARS-CoV-2 epidemic. While some infections or vaccinations generate lifelong protection, immunity to hCoVs gradually wanes over time, complicating the model of immune efficacy. Immunity can work in three ways: by reducing susceptibility to infection (IES), reducing infectiousness (IEI), or reducing pathology and death in infected people (IEP). The magnitude of these components is affected by the levels of antibodies and T cells generated within a person. Although a high level of immunity is required to completely prevent infection, moderate immunity can lower transmissibility and pathology within infected people. Collectively, immune efficacy influences how a pathogen is maintained or eradicated.

Relationship between infection fatality and age distribution.
Relationship between infection fatality and age distribution. Figure provided by Dr. Jennie Lavine.

Four hCoVs are currently endemic in the population. Infection with an hCoV initially provides high IEs, but this protection is transient. Later, previously immune people can become re-infected and transmit virus (suggesting only a moderate IEI), but experience mild disease. However, IEP is not well defined for hCoVs, as it is not known if hCoVs are inherently mild, or if preexisting immunity from childhood infection with hCoVs provides protection from severe disease. In SARS-CoV2, infection or vaccination provides strong but transient immunity to infection. After some time, previously protected individuals can become re-infected, although generally with much less severe disease. This suggests that immunity to infection (IES) wanes faster than immunity to pathology (IEP). These and other factors will affect both how prevalent SARS-CoV-2 is during the endemic phase and the severity of the disease burden in the population.

During the endemic state, most primary infections will occur in children who, unlike adults, are not already immune to infection. However, in SARS-CoV-2, infections in children are usually mild, suggesting that primary infections will not drive severe disease during the endemic phase. In contrast, an infection that does cause severe disease in children, such as Middle East Respiratory Syndrome (MERS)—another hCoV— would increase the number of severe cases in an endemic setting. Likewise, if primary infection in children causes mild disease but provides strong IEP, reinfections in the endemic phase will also be mild. This is an optimistic scenario for SARS-CoV-2 endemicity, although more research is needed on the long-term levels of IEP. In this case, reinfections would be common, but cause only mild disease. However, if IEP and IES wane at similar rates, reinfections could become severe. For example, if the window of IEP is shorter than the time in between reinfections, secondary infections could cause high pathology. This would cause a scenario where infections are less frequent but more severe.

Going forward, it is important to understand how to best manage the SARS-CoV-2 endemic phase. Vaccines are the most effective tool to control the spread of viruses, including SARS-CoV-2; vaccination during the epidemic phase is crucial to reduce disease, but also influences transmission dynamics. Because natural infection and vaccination provide transient immunity, endemicity, and not eradication, is likely. Although currently vaccination should be prioritized in older people, who experience more severe disease than younger people, many questions remain about how immune efficacy components are individually affected by overall immunity waning and by new viral variants. Most importantly, high IEP is necessary to facilitate a benign endemic phase, so understanding how to best generate long-lasting protection from disease is a priority.

This work was supported by the National Institute of Allergy and Infectious Diseases.

Antia R, Halloran ME. Transition to endemicity: Understanding COVID-19. Immunity. 2021 Oct 12;54(10):2172-2176. doi: 10.1016/j.immuni.2021.09.019.