Immunity Against the Omicron Variant From Vaccination, Recovery, or Both

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Data comparing the protective immunity from coronavirus disease 2019 (COVID-19) recovery versus 2-dose vaccination are limited in the Omicron variant era. During the Delta variant surge in the United States, an analysis performed by the Centers for Disease Control and Prevention (CDC) showed that previous infection was more than 2.5 times more protective against subsequent COVID-19 infection and hospitalizations than a standard 2-dose vaccine schedule [1]. However, vaccination after recovery (“hybrid immunity”) [2] conferred slightly more protection than recovery immunity alone in the CDC study.

Data from the Cleveland Clinic had previously shown that recovery immunity was as protective against reinfection as 2-dose vaccination during the Delta wave [3]. In this edition of Clinical Infectious Diseases, Shrestha et al [4], again from the Cleveland Clinic, extend their analysis to compare the protection from vaccination versus recovery immunity against infection and severe disease during the Omicron variant surge. Specifically, of the 52 238 Cleveland Clinic employees included in the study, 4718 (9%) had prior COVID-19 infection and 36 922 (71%) were recipients of 2 doses of mRNA vaccine. Before and through the Delta wave in the United States, the cumulative incidence of symptomatic COVID-19 was not significantly different between those vaccinated and previously infected, even at almost 1 year of follow-up. However, during the Omicron surge, the risk of symptomatic COVID-19 increased substantially in both groups, with vaccination after recovery reducing the incidence of symptomatic COVID-19. However, both the previously infected and vaccinated cohorts had substantial protection against COVID-19–related hospitalization compared with the unvaccinated group.

The protective effects of immunity resulting from recovery have been reported in multiple earlier studies, with a systematic review published prior to the Omicron wave estimating roughly equal protection from both infection and vaccination [5]. However, during the Omicron variant era, protection from infection is reduced with either vaccination or previous infection, necessitating recommendations for booster shots in the United States. A study from Qatar showed that protection from reinfection after natural infection declined from approximately 90% with the Alpha, Beta, and Delta variants to 56% against the Omicron variant [6]. The protection from infection after 2-dose vaccines declined from 89% against Delta to 36% against Omicron in a Canadian study [7]. This is likely due to the ability of the Omicron variant to evade antibodies [8]. In both studies, however, protection against severe disease persisted, likely mediated by cellular immunity.

Neutralizing antibodies generated by both COVID-19 vaccines or natural infection will wane over time [7, 9, 10]. However, memory B and T cells are both generated by either infection or vaccination. Memory B cells triggered by either the vaccines [11] or prior infection [12] should be durable [13, 14], with no apparent half-life in 1 study [14], and have been shown to recognize different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as they emerge [15, 16]. Although we do not know how long memory B cells from SARS-CoV-2 vaccination or infection will persist, survivors of the 1918 influenza pandemic were able to produce antibodies from memory B cells when stimulated by the same strain 9 decades later [17]. The need for boosting neutralizing antibodies with further vaccine doses, instead of relying on production of antibodies from memory B cells, will likely be impacted by the prevalence of the virus and its variants in circulation, as well as the age and comorbidities of the host.

Both vaccines [18] or prior infection [14] also trigger the production of T cells, which amplify the immune response to a virus and recruit cells to attack the pathogen directly. SARS-CoV-2–specific T cells help protect individuals from severe disease with COVID-19 [19, 20]. Despite mutations across the spike protein that may influence antibody binding, like with the Omicron variant [21], COVID-19–specific T cells from the vaccines or infection maintain their protective immune response against variants [22, 23]. Although we do not know how long memory T cells to SARS-CoV-2 will last, the estimated half-life of memory T cells generated by COVID-19 infection was as long as that generated by yellow fever vaccination in a study that examined participants with varying degrees of initial disease severity [14]. Moreover, memory T cells generated in individuals who survived SARS-CoV infection in 2003 (another coronavirus that caused severe disease) have been shown to be durable to at least 17 years later in a recent paper [19].

Vaccination is a much safer way to acquire immunity to a pathogen than enduring the natural infection. However, natural immunity has controlled disease in prior infectious disease pandemics. The 1918 influenza pandemic was by far the deadliest respiratory virus pandemic recorded in recent human history, but the fatal consequences of this highly transmissible virus slowed only after enough of the population had acquired immunity [24], since the first vaccine for influenza was not developed until 1942 [25]. Prior to vaccination, measles was a highly transmissible respiratory virus with deaths each year among the nonimmune until a vaccine was developed in 1963 [26]. Smallpox and multiple other infections prior to vaccine development led to natural immunity [27], but often with concomitant severe disease and death.

This study in Clinical Infectious Diseases and several other recent studies demonstrate the benefit of at least 1 dose of the mRNA (or adenoviral DNA vaccines) after recovery or a booster after 2-dose vaccination to protect against Omicron. Indeed, “hybrid immunity” or a combination of natural infection plus vaccination or vaccination followed by infection seems to be stronger than either recovery immunity or vaccination alone [2]. A preprint study by Shrestha et al published subsequent to this current report verifies that 1 booster dose of the vaccine after either 2-dose vaccination or natural infection protects against subsequent reinfection with Omicron [28]. This analysis confirms, like other studies [29], that only 1 dose (not 2) of the vaccine after recovery is adequate to achieve the enhanced protection against reinfection. Two recent studies in the New England Journal of Medicine verify the benefits of vaccination after recovery [30, 31]. The first study showed that a single dose of the Pfizer COVID-19 vaccine after recovery protected against reinfection by at least 3-fold, with 2 doses conferring no additional benefit [30]. The second study showed that infection-acquired immunity waned after a year but remained consistently higher than 90% in those with subsequent vaccination (out to 18 months and counting) [31].

Finally, although the increase in antibodies from a vaccine boost may only last a short period (~4 months according to a CDC study) [32], this boost is required for certain groups to maintain protection against severe disease. The need for further booster doses of vaccine will depend on the degree of viral transmission during the respiratory pathogen season, the emergence of new variants, and clinical characteristics of the individual predisposing to severe breakthrough infections (eg, immunocompromise, older age with multiple comorbidities) [33]. Inactivated whole-virus vaccines with an effective adjuvant [34, 35] may be more protective against variants with multiple mutations in the spike protein in the future. Nasal vaccines may also boost immunity at mucosal surfaces, which could potentially impact viral transmission [36]. Finally, the durable protection against severe disease from vaccines among younger, immunocompetent individuals to date gives hope for the longevity of memory cell immunity against SARS-CoV-2 [37].

Although not a substitute for vaccination by itself, recovery from infection generates SARS-CoV-2 immunity and protects against severe disease for many individuals. The US Supreme Court has agreed that most healthcare workers should be subject to mandatory vaccination [38]. As suggested in an earlier editorial in The Lancet, a history of recovery immunity should be considered in mandatory vaccination requirements among healthcare workers [39]. Requiring only 1 vaccine dose after recovery should provide short-term protection and might serve to increase trust in public health and heal divisiveness. This study adds to the growing database that recovery from infection generates SARS-CoV-2 immunity and protects against severe disease for many individuals, with policy implications for the United States.

Notes

Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) grant R01AI158013 (Principal Investigator: Monica Gandhi).

Potential conflicts of interest. The author: No reported conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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