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SARS-CoV-2 Immunity

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This page undergoes regular review and was last comprehensively reviewed on December 8, 2022. Some sections may reflect more recent updates.

Overview

Information continues to emerge about the immune response to SARS-CoV-2 infection and vaccination, and protection from subsequent SARS-CoV-2 infection. We provide a focused review of current knowledge and key literature pertaining to common questions about immunity to SARS-CoV-2 and highlight knowledge gaps.

Summary

  • The degree of infection-induced immunity varies by disease severity, patient age and underlying medical conditions, among other factors. Reinfection with SARS-CoV-2 can occur after primary infection; our knowledge of the risk of reinfection continues to evolve as new data emerges and as new variants emerge.
  • Vaccine effectiveness against infection with SARS-CoV-2 may wane over time, while vaccine effectiveness against severe outcomes (e.g., hospitalization, death) is more durable over time.
  • The proportion of vaccinated individuals who develop severe infection is lower than the proportion of unvaccinated, previously uninfected individuals who develop severe infection.

FAQs

Q: What is the difference between “infection” and “disease”?

A: There are small but important nuances in the definitions of the terms “infection” and “disease.” In most of the studies described in this immunity FAQ, “infection” is described as testing positive for SARS-CoV-2 and does not necessarily relate directly to symptoms (i.e., asymptomatic infection is possible). Conversely, “disease” implies the presence of at least some symptoms of COVID-19. When assessing information about vaccine effectiveness, specific outcomes described may or may not relate to symptomatic illness.

Q: What is “infection-induced immunity”?

A: Infection-induced immunity, often referred to as natural immunity, is the immune response mounted against a specific pathogen. Depending on the pathogen and the immune response, “infection-induced immunity” (protective effect against reinfection due to that same pathogen) may subsequently be developed. There has been intense interest in understanding infection-induced immunity to SARS-CoV-2, given its implications for disease epidemiology and vaccine policy.

Q: What does the humoral and cell-mediated immune response to SARS-CoV-2 infection look like?

A: Multiple studies have demonstrated durable humoral (Rodda, January 2021; Dan, February 2021; Sokal, March 2021; Turner, May 2021; Anand, June 2021; Cohen, July 2021) and cell-mediated (Rodda, January 2021; Dan, February 2021; Kang, March 2021; Breton, April 2021; Cohen, July 2021) immune responses to SARS-CoV-2 in individuals several months after infection. These immune responses vary based on the severity of the initial infection. For example, severe COVID-19 (i.e., hospitalization, intensive care unit admission, mechanical ventilation) is associated with more robust increases in immunoglobulin M and immunoglobulin G, as well as more robust T cell responses (Lynch, January 2021; Kang, March 2021; Betton, April 2021). However, although infection with the ancestral strain of SARS-CoV-2 appears to elicit robust and durable immunological protection against the ancestral strain, there appears to be substantially reduced (Wang, November 2022) but not zero (Holmer, November 2022) cross-immunological protection to Omicron variants or subvariants. Importantly, the relationship between durability of these responses and protection from clinical disease, especially as it relates to protection between different SARS-CoV-2 variants and subvariants, remains an area of active investigation.

Q: What is known about the impact of prior SARS-CoV-2 infection and the risk of reinfection? 

A: There is compelling evidence that SARS-CoV-2 infection can decrease the risk of reinfection with SARS-CoV-2. In large observational cohort studies in the U.S. (Sheehan, March 2021; Letizia, April 2021; Harvey, May 2021; Rennert, May 2021; Bozio, November 2021; Kim, December 2021; Shrestha, January 2022; León, January 2022), U.K. (Lumley, February 2021; Hall, May 2021; Lumley, July 2021; Hall, February 2022), Denmark (Hansen, March 2021), Italy (Vitale, May 2021; Manica, July 2021), France (Dimeglio, January 2021), Switzerland (Leidi, July 2021), and Qatar (Abu-Raddad, December 2020; Bertollini, June 2021; Altarawneh, February 2022), prior documented infection with SARS-CoV-2 (based on a PCR test or antibody result) was associated with a decreased rate of subsequent infection in the ensuing months, including up to 13 months after the initial infection (Kim, December 2021). In general, reinfections tended to be milder (Qureshi, April 2021; Abu Raddad, May 2021) but severe and fatal cases of reinfection have been reported (Tillet, January 2021; Cavanaugh, February 2021; Qureshi, April 2021). Importantly, a large proportion of these studies were conducted in the context of the ancestral SARS-CoV-2 strain; additional information about reinfection risk for different variants of concern is found below.

Previous studies of infection-induced immunity demonstrated a protective effect of prior infection against the Alpha (Lumley, July 2021) and Delta (Bozio, November 2021; Kim, December 2021) variants of SARS-CoV-2. Existing data on Omicron suggests that infection with a pre-Omicron strain of SARS-CoV-2 confers limited, if any, protection against infection with Omicron (Rossler, January 2022; Altarawhneh, February 2022). An observational test-negative study from Qatar suggested that previous infection (more than 90 days prior) protected against infection with Alpha (effectiveness: 90.2%; 95% CI: 60.2%- 97.6%) and Beta (effectiveness: 92.0%; 95% CI: 87.9%-94.7%), but was less protective against Omicron (effectiveness: 56.0%; 95% CI: 50.6%-0.9%) (Altarawhneh, March 2022). An observational analysis of administrative data from South Africa identified an increase in the risk of reinfection associated with increases in Omicron circulation (Pulliam, March 2022). Another observational analysis of an individual-level population-wide dataset from the Czech Republic identified substantially reduced post-infection protection against Omicron hospitalization (declining from 68%, 95% CI: 68%-69% within 6 months of infection to 13%, 95% CI: 11%-14% at more than 6 months post-infection) (Šmíd, April 2022). Additionally, a report from the MRC Centre for Global Infectious Disease Analysis at Imperial College London noted a 5.41-fold higher risk of reinfection caused by Omicron, compared to reinfection caused by Delta, in the U.K. Finally, preliminary evidence from Danish COVID-19 surveillance mechanisms suggests that although Omicron BA.2 infection after Omicron BA.1 infection is possible, it is rare (Stegger, February 2022 - pre-print, not peer-reviewed).

Taken together, existing evidence suggests that infection with a pre-Omicron strain of SARS-CoV-2 may provide some protection against infection with an Omicron lineage/sublineage of SARS-CoV-2 (Holmer, November 2022), though the risk of infection is increased compared to risk of reinfection with a pre-Omicron strain (Wang, November 2022). Additional information about reinfection risk during the Omicron era is found below, in sections titled “What does COVID-19 breakthrough infection look like?” and “What does COVID-19 hybrid immunity look like in the Omicron period?

Q: How do age, comorbidities and other factors affect the immune response to SARS-CoV-2 infection?

A: Investigations assessing the effect of age, comorbidities, immune status and severity of the primary SARS-CoV-2 infection on the magnitude and durability of the protective effect that may be mounted after infection are still ongoing. In two separate studies in different populations, the protective effect of prior infection observed among individuals aged >65 years was significantly lower than that observed for the entire cohort (Hansen, March 2021; Kim, December 2021). However, in a small (N=91) cohort study in France, long-term care patients aged ≥ 70 years with SARS-CoV-2 infection from March to May 2020 exhibited persistent antibodies lasting for at least 12 months (Collarino, November 2022). Protection conferred by infection is not identical across important sub-populations, including those with immunocompromising conditions and other patient populations at higher risk of morbidity and mortality secondary to COVID-19 illness (Slezak, December 2021; Murillo-Zamora, September 2021). In a large-scale serological study in Switzerland after the first Omicron wave, children <12 years were less likely to have Omicron-specific neutralizing antibody compared to adolescents and adults, despite children 0-5 years having high seroprevalence of SARS-CoV-2 antibodies (Zaballa, December 2022).

Q: How does COVID-19 infection-induced immunity compare with vaccine-induced immunity?

A: There are limited data directly comparing infection-induced and vaccine-induced immunity following SARS-CoV-2 infection. Observational studies of rates of reinfection among seropositive or previously SARS-CoV-2 PCR-positive individuals cannot be directly compared with data from vaccine clinical trials or post-authorization studies of vaccine recipients. These studies were conducted in different populations during a variety of phases of the pandemic (with varying control measures and diverse variants circulating) and using different methods of case ascertainment. Furthermore, in most observational studies that have examined rates of reinfection among previously infected individuals (or breakthrough cases among vaccinated individuals), the period of observation for ascertaining cases was typically less than one year (and in some cases, just a few months) after initial infection or vaccination, which limits any conclusions about the long-term durability of protection.

Some observational studies have compared the level of immunological protection from infection-induced immunity alone to the level of immunological protection from vaccine-induced immunity alone. Two studies, one in Qatar (Bertollini, June 2021) and one in the U.K. (Lumley, July 2021), concluded that the risk of reinfection was similarly low in those who had been previously infected or vaccinated. In a third study in the U.S., investigators identified a stronger protective effect of vaccination (Bozio, November 2021) compared to prior infection.

Other observational studies have compared the level of immunological protection from infection-induced immunity alone to the level of immunological protection from prior infection plus vaccination. A study in Qatar during the Omicron period identified a stronger protective effect of prior infection and vaccination with three doses of Pfizer-BioNTech (effectiveness: 77.3%, 95% CI: 72.4%-81.4%) compared to vaccination alone (effectiveness of three doses of Pfizer-BioNTech with no prior infection: 52.2%, 95% CI: 48.1%-55.9%) (Altarawneh, July 2022). Similarly, a study in the Czech Republic identified a higher vaccine effectiveness against Omicron for individuals with a prior infection history, compared to vaccinated individuals without a prior infection history (Šmíd, April 2022). A study in the long-term congregate care population and the general population in Rhode Island identified a statistically significant protective effect of vaccination for individuals with prior infection (effectiveness against reinfection for general population: 62%, 95% CI: 58%-68%; effectiveness for long-term congregate care population: 49%, 95% CI: 27%-65%) (Lewis, July 2022).

Finally, there are emerging data that immune responses following infection — especially mild infections — may not be as robust as compared with vaccine-induced responses, including against variants of concern such as Alpha and Beta (Marot, May 2021); and Beta, Gamma, Delta, Epsilon and Iota (Greaney, June 2021). Conversely, in a small-scale study of individuals either previously hospitalized with SARS-CoV-2 or who had previously received COVID-19 mRNA vaccine, a higher proportion of hospitalized individuals maintained neutralizing antibody titers against Alpha, Beta and Gamma, compared to vaccine recipients (Caniels, September 2021).

Q: What is waning immunity?

A: Waning immunity refers to a phenomenon where an individual’s initial immune response (i.e., antibody response) to a vaccine decreases. There is now extensive evidence that COVID-19 vaccine-induced antibodies decrease over time. However, emerging evidence indicates that the T-cell response to COVID-19 remains durable over longer periods of time (Bonifacius, February 2021, Venet, April 2022), although others have found waning of SARS-CoV-2 T-memory-cell populations with a half-life of 3-5 months (Dan, January 2021). Additionally, T-cell responses may be challenging to disentangle from neutralizing antibody responses, as neutralizing antibody responses rely on T-cell activation (Kent, April 2022). As a result, these findings may have varying implications for the duration of clinical protection against symptomatic SARS-CoV-2 infection and severe COVID-19.

Q: Does waning immunity equate to waning protection against infection?

A: Evidence for whether waning immunity results in “waning protection” is almost always indirect, because there are many immune system factors and many external, immune system-independent factors that can influence immunological protection and vaccine effectiveness over time. In fact, observations of waning protection, which may be suggested by lower population-level vaccine effectiveness estimates over time or rates of breakthrough infection, need not be solely attributable to waning immune responses.

Other factors that can contribute to time-dependent estimates of vaccine effectiveness include:

  • Changes in masking and distancing behavior, policy or local disease epidemiology that influence the “force of infection” (likelihood of being exposed/infected and burden of virus with each exposure) over time. This means that vaccine efficacy estimates determined in clinical trials are context-dependent, and caution is warranted when extrapolating to new settings and circumstances.
  • Evolution of the pathogen that results in diminished protection conferred by vaccine-induced immune responses, such as novel variants. Vaccine-induced immunity may be preserved but may be less effective against a new SARS-CoV-2 variant.
  • Differences in the comparison groups used to estimate vaccine effectiveness. For example, the unvaccinated population may experience fewer cases because it has a higher level of immunity due to an accumulation of infections not captured by testing; alternatively, individuals who were vaccinated earlier in the pandemic may differ from more recent vaccinees in their likelihood to have a poor initial response to the vaccine or to be exposed to SARS-CoV-2.

These issues are relevant because the relative contribution of these factors informs the optimal use of vaccine “boosters” at a population level.

Q: How should we interpret declines in SARS-CoV-2 antibody concentrations over time?

A: Declines in antibody concentrations may not correlate with a decrease in immune memory responses, which may be more relevant for protection against severe disease. In a longitudinal study of humoral and cell-mediated immune responses to SARS-CoV-2 following mRNA COVID-19 vaccination (mostly the Pfizer-BioNTech COVID-19 vaccine), although anti-spike antibodies waned over 6 months, memory B- and T-cell responses were durable over the same time period (Goel, October 2021).

Furthermore, decreases in antibody responses demonstrate an imperfect correlation with waning clinical protection that also depends on the outcome being measured. As an example, in longitudinal immunogenicity and efficacy analyses of data from the Phase 1-3 clinical trials of the Pfizer-BioNTech COVID-19 vaccine, neutralizing antibody titers against wild type SARS-CoV-2 decreased 6- to 13-fold over the 8 months after the second dose of vaccine (Falsey, September 2021). Vaccine efficacy against symptomatic infection did decrease from 96% to 84% over the same time frame, but remained >96% against severe COVID-19 (Thomas, September 2021).

Q: What are COVID-19 breakthrough infections?

A: “Breakthrough infection” refers to a SARS-CoV-2 infection that occurs after completion of a recommended COVID-19 vaccine series. Breakthrough infections can occur for a variety of reasons, including:

  • Primary vaccine failure – This refers to the phenomenon when an individual does not mount an adequate immune response to the primary series of a recommended COVID-19 vaccine. An example of this would be an immunocompromised patient whose immune system does not respond to two doses of an mRNA COVID-19 vaccine.
  • Secondary vaccine failure – This refers to a phenomenon where an individual’s initial immune response to a vaccine, which may have been robust, diminishes over time (see “What is waning immunity?” above), making them vulnerable to infection. An example of this would be an individual who develops SARS-CoV-2 infection 14 months after completing a recommended COVID-19 vaccine series.
  • Immune escape – This refers to a phenomenon where changes in the SARS-CoV-2 virus over time (i.e., emergence of novel variants) allow the virus to escape vaccine-induced immune responses. An example of this would be infection due to an Omicron variant in an individual who was fully vaccinated against the ancestral strain of SARS-CoV-2 and did not receive a bivalent (Omicron-specific) booster.

Q: Do COVID-19 breakthrough infections mean that vaccines don’t work?

A: No. The observation that high numbers of breakthrough infections are occurring in vaccinated people does not necessarily indicate an ineffective vaccine, as vaccines are not expected to completely stop transmission. Rather, this observation is a natural consequence of having a large proportion of people vaccinated, which means that vaccinated persons could account for the same or a higher proportion of total infections than unvaccinated (Lipsitch, December 2021). However, breakthrough infections in vaccinated people occur at much lower rates than infections in the unvaccinated, and are less likely to result in severe disease (Johnson, January 2022; Danza, February 2022). Thus, the occurrence of breakthrough infections does not diminish the critical importance of vaccination against COVID-19.

Q: What do COVID-19 breakthrough infections look like?

A: To date, the data suggest that breakthrough infections are milder compared to primary illnesses in unvaccinated individuals. An observational study in the U.S. found that Delta breakthrough illnesses had reduced severity to incident illnesses for vaccinated individuals (an effect not seen for unvaccinated individuals with history of prior infection) (Kim, December 2021). Another large-scale observational study in the U.S. found that the cumulative incidence of COVID-19 hospitalization was lower for vaccinated compared to unvaccinated individuals (León, January 2022). A third observational U.S. study based at 21 hospitals in 18 states showed sustained effectiveness against COVID-19 hospitalization (Tenforde, August 2021). These studies were all conducted during the pre-Omicron era. However, limited research on the severity of breakthrough infections with Omicron also suggest that vaccination reduces the severity of illness caused by Omicron (Skarbinski, June 2022). Breakthrough infections can also be asymptomatic, with boosters further substantially reducing the risk of breakthrough infection in areas of Omicron circulation. There are also emerging variant-specific data on the virologic and immunologic aspects of breakthrough infections that have implications for risk assessment (for breakthrough infection) after vaccination and transmissibility of breakthrough infections (symptomatic or asymptomatic).

 

In cohort studies from the U.S. (Bosch, November 2021; Butt, December 2021; Yek, January 2022) and Israel (Brosh-Nissimov, November 2021), investigators analyzed breakthrough SARS-CoV-2 infections to identify risk factors associated with hospitalization and poor outcomes. Older age, immunocompromised status and multiple comorbidities (also risk factors for severe COVID-19) were associated with hospitalization, ICU admission, need for mechanical ventilation and death due to COVID-19. In a longitudinal analysis in Tunisian adults, underlying cardiovascular disease was associated with an increased risk of breakthrough infection that was severe (requiring oxygen support) or critical (requiring ICU admission and/or resulting in death) (Ben Fredj, November 2022). Importantly, even when vaccinated individuals are hospitalized with COVID-19, vaccination has been associated with a lower likelihood of progression to critical illness requiring mechanical ventilation and resulting in death, when compared to unvaccinated individuals (Tenforde, November 2021).

 

Q: What is “hybrid immunity”?

A: “Hybrid immunity” refers to a state of immunological protection that exists as a result of prior infection and prior vaccination together.

 

Q: What does COVID-19 hybrid immunity look like during the Omicron period?

A: Taken together, evidence during the Omicron period suggests that although both previous infection and vaccination may individually provide reduced protection compared to the pre-Omicron era, there still may be an additive effect of prior infection and vaccination against Omicron infection. The strongest evidence is for severe Omicron infection (requiring hospitalization) and for mortality outcomes.

A small study (N=30) conducted in Japan, which analyzed in vitro responses to Omicron from mRNA vaccinees and previously infected individuals, found increasing virus neutralization in individuals both vaccinated and previously infected (Miyamoto, April 2022). A large-scale observational study of U.S. adults with previous SARS-CoV-2 infection conservatively estimated vaccine effectiveness against hospitalization at 67.6% (after two primary doses and a booster dose; 95% CI: 61.4%-72.8%) during a period of Omicron circulation (Plumb, April 2022). The authors reported that vaccine effectiveness estimates were similar whether hospitalizations were <90 days or ≥ 90 days after the most recent vaccine dose but did not stratify VE according to time since prior infection. In another large-scale study in U.S. health care workers, the cumulative incidence of COVID-19 among previously infected individuals was not significantly different by vaccination status during the Omicron period, and vaccination among previously infected individuals was not associated with a lower risk of COVID-19 during the Omicron period (HR: 0.78; 95% CI: 0.31-1.96) (Shrestha, January 2022). Importantly, in the same study, the authors noted a statistically significant effect of vaccination in reducing the risk of symptomatic COVID-19 during the Omicron period (HR: 0.36; 95% CI: 0.23-0.57) for individuals with previous infection.

An additional cohort study of individuals in the U.K. found that among vaccinated individuals, prior infection did not provide additional protection against hospitalization with Delta or Omicron (HR: 0.96; 95% CI: 0.88-1.04) – but did provide additional protection against death (HR: 0.47; 95% CI: 0.32- 0.68) (Nyberg, April 2022). In a test-negative analysis of U.K. adolescents, hybrid immunity provided the highest protection against Omicron infection, compared to either vaccination or previous infection alone (Powell, November 2022).

In an Omicron-era cohort study of Norwegian adults with immunoinflammatory conditions who were on immunosuppressive therapy, hybrid immunity (three COVID-19 vaccine doses plus prior infection) was associated with higher anti-RBD antibody concentrations compared to vaccine-induced immunity alone (four COVID-19 vaccine doses) (Byørlykke, November 2022).

Finally, an analysis of individuals with at least one RT-PCR test for SARS-CoV-2 in Ontario, Canada before November 2021 identified that prior infection was associated with reduced risk of Omicron infection among vaccinated individuals (Wu, November 2022). This analysis found that prior infection reduced the risk of Omicron infection among individuals vaccinated with two doses of vaccine by 68% (95% CI: 61%-73%) but reduced the risk among individuals with three vaccine doses by 43% (95% CI: 27%-56%). Additionally, for individuals receiving two vaccine doses, the protective effect of prior infection decreased over time.

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