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SARS-CoV-2 Immunity

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The content below is current as of August 2022. This page will be updated with additional information and FAQs as information about SARS-CoV-2 immunity continues to emerge.

 

Overview

A patient’s degree of infection-induced SARS-CoV-2 immunity varies by disease severity, age and underlying medical conditions, among other factors. Reinfection with SARS-CoV-2 can occur after primary infection. Knowledge about the risk of reinfection continues to evolve as new data emerges.

Vaccine-induced immunity plays an important role in immune response to SARS-CoV-2. 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.

Information continues to emerge about immune response to SARS-CoV-2 infection and vaccination, hybrid immunity and protection from subsequent SARS-CoV-2 infection. Here we provide background about immunology and virology as well as a focused review of current knowledge and key literature to answer common questions about SARS-CoV-2 immunity and highlight knowledge gaps.

Background on Immunology

Immune responses to pathogens and vaccines are complex and can be broadly categorized into humoral responses (including antibodies and the complement cascade) and cell-mediated responses (including macrophages and T cells). Immune responses can also be categorized as innate responses (immediate responses that do not require immune system learning or memory, such as the inflammatory response) and adaptive responses (B- and T-cell-mediated responses, which are stimulated by and specific to the type of pathogen). Both innate and adaptive immunity contain humoral and cell-mediated components.

Although the development and evaluation of vaccines often focuses on eliciting a robust antibody response, other components of the immune system (B cells, T helper cells and cytotoxic T cells) are also crucial for the immune system to respond to and protect against pathogens (Plotkin, July 2010). Further information about vaccine immunology can be found here.

Background on Virology

One method to approximate the amount of virus in respiratory samples is with nucleic acid amplification tests, including polymerase chain reaction. PCR reports a cycle threshold, which correlates with the number of cycles required for a replication signal to cross the threshold for detection by the assay. Ct values are inversely proportional to the amount of target nucleic acid in the sample (i.e., the lower the Ct value, the greater the amount of target nucleic acid in the sample). Many additional factors are known to affect the amount of viral genetic material present, including sample quality, specimen type, dilution of the sample in transport media, and specimen transport and storage conditions (Walker, July 2021), which impacts the interpretability of Ct values in measuring viral load.

There are small but important nuances in the definitions of the terms “infection” and “disease.” In most of the studies described below, “infection” is described as testing positive for SARS-CoV-2 and does not 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.

Infection-Induced Immunity

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.

What is known about immune responses to SARS-CoV-2 infection?

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 initial infection. For example, severe COVID-19 (i.e., hospitalization, intensive care unit admission, mechanical ventilation) is associated with more robust increases in IgM and IgG, as well as more robust T-cell responses (Lynch, January 2021; Kang, March 2021; Betton, April 2021). Importantly, the relationship between durability of these responses and protection from clinical disease remains an area of active investigation.

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

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, April 2021; Lumley, July 2021; Hall, February 2022), Denmark (Hansen, March 2021), Italy (Vitale, May 2021; Manica, July 2021), France (Dimeglio, January 2021), Switzerland (Leidi, May 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 during the pre-Omicron era; additional information about reinfection risk during the Omicron era is found below. 

Information is still being gathered on how the effect of age, comorbidities, immune status and severity of the primary SARS-CoV-2 infection may affect the magnitude and durability of the protective effect that may be mounted after infection. For example, 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). 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).

Finally, 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, although limited by its relatively recent emergence and the emergence of Omicron subvariants, 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%-60.9%) (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 UK. 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 - preprint, not peer-reviewed).

How does infection-induced immunity compare with vaccine-induced immunity?

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, March 2022 – preprint, not peer-reviewed). 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 (Daniels, September 2021).

 

Vaccine-Induced Immunity

“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 relies 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.

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 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.

Some of the key studies that contribute to our current understanding of waning immunity, and their limitations, are summarized here.

Antibody responses to SARS-CoV-2 vaccines wane over time.

There is now extensive evidence that COVID-19 vaccine-induced antibodies decrease over time. One study compared the kinetics of humoral and cellular responses between recipients of the Pfizer-BioNTech, Moderna and Johnson & Johnson/Janssen COVID-19 vaccines. In this study, the mRNA COVID-19 vaccines elicited robust neutralizing antibody responses shortly after vaccination that then decayed significantly over 8 months, with relative maintenance of CD4 and CD8 T-cell responses over the same time frame (Collier, October 2021).

In another prospective 6-month longitudinal immunogenicity study of nearly 5,000 health care workers aged 18 years and older at Sheba Medical Center in Israel who received two doses of the Pfizer-BioNTech COVID-19 vaccine, anti–SARS-CoV-2 spike antibody titers reached their peak between days 4 and 30 after the second dose of vaccine, then consistently declined over the entire study period, ultimately decreasing by a factor of 18.3 after 6 months. Antibody neutralization also decreased, but the rate of decline slowed after 3 months (Levin, October 2021).

COVID-19 vaccine effectiveness decreases over calendar time.

Several population-level observational studies have shown that COVID-19 vaccine effectiveness against infection decreases over time (or that the incidence rate of SARS-CoV-2 infections in vaccinated individuals increases over time) in the first year after vaccination (Rosenberg, September 2021; Scobie, September 2021; Fowlkes, August 2021; Nanduri, August 2021; Keehner, September 2021). Importantly, many of these same studies (and others) also found that vaccine effectiveness against severe COVID-19 disease remained stable (Bajema, September 2021; Tenforde, August 2021) when the predominant circulating variants remained susceptible to vaccine-induced antibodies. Given that the follow-up period for these studies spanned the time period when the Delta variant emerged, several of these studies stratified their analysis by time period, calculating vaccine effectiveness before and after Delta became predominant. In these analyses, vaccine effectiveness was essentially preserved (compared with vaccine efficacy estimates from clinical trials) before the emergence of Delta but decreased following the emergence of Delta.

Vaccine effectiveness decreases by time since vaccination.

Some studies have specifically evaluated the potential role of waning immunity by stratifying VE calculations by time since vaccination at the individual level. Studies from the U.S. (Self, September 2021; Fowlkes, August 2021; Tartof, October 2021), U.K. (Pouwels, October 2021; Public Health England report, September 2021), Israel (Mizrahi, November 2021; Goldberg, December 2021; Israel, November 2021), Canada (Nasreen, February 2022; Skowronski, November 2021 – preprint, not peer-reviewed) and Qatar (Chemaitelly, December 2021) all found that a longer time period since the second dose of an mRNA COVID-19 vaccine was associated with decreased VE against symptomatic infection. Similar results were seen for viral vector vaccines (Katikireddi, January 2022 [Oxford-AstraZeneca] and Lin, March 2022 [Johnson & Johnson/Janssen]). Notably, VE against severe disease was essentially preserved when the predominant circulating variants remained susceptible to neutralization by vaccine-induced antibodies for both mRNA and viral vector vaccines, though mRNA vaccine effectiveness stayed higher (Lin, March 2022; Risk, February 2022). In addition, in a 6-month follow-up study of participants in the multinational Phase 3 trial of the Pfizer-BioNTech COVID-19 vaccine before the emergence of the Delta variant, VE against infection had decreased to 84% by 6 months, but VE against severe disease remained >90% (Thomas, September 2021).

Important considerations for interpreting the literature

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).

Not all of these studies computed SARS-CoV-2 variant-specific VE estimates. Furthermore, the follow-up period for most of these studies also coincided with a relaxation of control measures (e.g., masking, social distancing, etc.), and there may have been important differences between the groups who were vaccinated at different times that influenced their likelihood of infection. Finally, limited current evidence suggests that extended intervals between the two primary doses of mRNA vaccines may partially mitigate waning (Payne, November 2021). This suggestion is supported by observational data from Canada, where most individuals received mRNA primary doses more than 3 weeks apart, and where waning VE has been observed to a lesser extent than in the United States (Nasreen, February 2022). However, the direct effect of extended dosing intervals is challenging to investigate in observational studies because there are few environments where dosing intervals vary independently of other important characteristics influencing vaccine immunogenicity and response.

Breakthrough Infection

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: 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: When an individual’s initial immune response to a vaccine, which may have been robust, diminishes over time (see waning immunity above) making them vulnerable to infection. An example of this would be an individual who develops SARS-CoV-2 infection 8 months after their second dose of an mRNA COVID-19 vaccine.
  • Immune escape: When changes in SARS-CoV-2 over time, i.e., emergence of novel variants, allow the virus to escape vaccine-induced immune responses (for example, infection due to the Omicron variant in a recently fully vaccinated, healthy individual).

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 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.

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).

Below are critical summaries of selected reports of breakthrough SARS-CoV-2 infections in the published literature.

Breakthrough infections are milder than infections in unvaccinated individuals.

In an analysis of breakthrough SARS-CoV-2 infections reported to CDC through April 30, 2021, investigators described 10,262 cases, of which 27% (N=2,725) were asymptomatic, 10% (N=995) were hospitalized at the time of their infection, and 2% (N=160) died. Notably, 29% of hospitalized patients with a reported breakthrough infection were asymptomatic or hospitalized for another reason, and 18% of the deaths were asymptomatic at the time their breakthrough infection was identified or died from another cause. Only 5% (n=555) of the breakthrough infections had sequencing data available, and nearly two-thirds (64%, n=356) were identified as variants of concern (CDC, May 2021).

Investigators in Israel analyzed a cohort of 39 breakthrough cases (<1% of the 1,497 fully vaccinated health care workers that underwent PCR testing) and found that the majority (N=26, or 67%) were mild (and none required hospitalization) and the remainder were asymptomatic. Although 29 (74%) of the case patients had a cycle threshold value of <30 at some point during their infection, no secondary infections were documented. Of note, the time point of this low Ct value was not reported or compared with an unvaccinated cohort (Bergwerk, July 2021).

In a pre-Delta analysis of SARS-CoV-2 infections identified through the HEROES-RECOVER network in the U.S., an ongoing prospective cohort study of health care personnel, first responders, and other essential and frontline workers – investigators described 204 cases, of which five (2.5%) were fully vaccinated and 11 (5.4%) were partially vaccinated (the remaining >92% of cases were unvaccinated). Vaccinated or partially vaccinated individuals had fewer febrile symptoms and had fewer days of symptoms compared with unvaccinated individuals.

In an analysis of nearly 5,000 early post-vaccination infections in the Maccabi Healthcare Services in Israel, investigators determined Ct values for SARS-CoV-2 positive tests among fully vaccinated individuals, stratified them by time since vaccination and compared them to the Ct values of positive tests among unvaccinated individuals over the same time period. In this study, individuals vaccinated fewer than 12 days prior to the onset of their breakthrough infection had Ct values similar to unvaccinated case patients, whereas those who were vaccinated 12 or more days earlier had significantly higher Ct values (Levine-Tiefenbrun, March 2021). In a similar study of the longitudinal viral dynamics of SARS-CoV-2 breakthrough infections occurring at various time points after the first dose of mRNA COVID vaccine, investigators found that fully vaccinated individuals shed less infectious virus at a given genome load, had a shorter duration of viral shedding, and some had tissue restriction of viral replication in saliva (and not the nasal cavity) (Ke, April 2022). These findings are suggestive, but not definitive, that COVID-19 vaccination may impact SARS-CoV-2 viral loads and transmissibility of breakthrough infection. Conversely, a U.S.-based study found no difference in Ct values between vaccinated and unvaccinated cases of SARS-CoV-2 caused during the Delta period (Brown, August 2021). A key limitation of the studies above is that they were conducted prior to the emergence of the Omicron variant (see below). However, a seroepidemiological study identified high levels of COVID-19 IgG seropositivity in South Africa before the establishment of the Omicron variant; in this environment, Omicron severity was observed to be lower (Madhi, February 2022).

Older age, immunocompromised status and comorbidities are risk factors for severe disease in breakthrough infections.

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. 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).

Breakthrough infections may skew toward SARS-CoV-2 variants demonstrating high transmissibility or immune evasion.

In one of the largest case series of breakthrough infections reported to date, CDC investigators described a cluster of SARS-CoV-2 infections associated with large public gatherings in Barnstable County, Massachusetts (CDC, August 2021; Gharpure, January 2022). The initial investigation described 469 COVID-19 cases, of which 346 (74%) occurred in fully vaccinated individuals. The final investigation described a multistate outbreak totaling 1,098 primary cases as well as 30 secondary cases – of these, 918 (81%) were breakthrough cases. In the initial study the investigators reported Ct values as a surrogate for viral load and noted that the median Ct values in vaccinated individuals were similar to those who were unvaccinated, partially vaccinated or with unknown vaccination status. Notably, of the 371 infections for which genome sequencing data were available, 98% were due to the Delta variant.

Key limitations of this report included: incomplete data on the exposed population (which limited the ability to assess the relative incidence of infection in vaccinated and unvaccinated individuals); use of a surrogate measure of viral load (that does not distinguish between culturable virus, total RNA or subgenomic RNA); and no description of the approach to viral detection (specimen type, timing of specimen in course of illness, etc.).

A few small studies of breakthrough cases early after vaccine introduction were suggestive that infection after vaccination may skew toward SARS-CoV-2 variants possessing mutations that facilitate immune escape (Hacisuleyman, June 2021; Kustin, August 2021). Multiple studies have since also found higher viral loads and a longer duration of shedding of infectious virus associated with highly transmissible variants, such as Delta and Omicron, as compared with previous SARS-CoV-2 variants. In a careful analysis of 24 breakthrough cases – including 10 due to Delta and 14 due to non-Delta variants – individuals with infection due to Delta had slower decay of PCR and viral culture positivity, though all individuals were culture-negative by day 10 after symptom onset or 24 hours after symptom resolution (Siedner, December 2021). In another analysis of breakthrough infections within Maccabi Healthcare Services in Israel, investigators found that the impact of prior Pfizer-BioNTech COVID-19 vaccination on Ct values diminished by time since vaccination – by 6 months after vaccination, Ct values among breakthrough cases were no different than unvaccinated cases. Notably, this difference was restored after a booster dose of vaccine (Levine-Tiefenbrun, November 2021). In analyses of breakthrough infections caused by Delta versus caused by Omicron, existing evidence suggests that vaccinated individuals are at higher risk of Omicron breakthrough infections, compared to Delta breakthrough infections (Watson, April 2022; Plumb, April 2022; Shrestha, January 2022), and immunological evidence suggests that this increase in breakthrough infection risk associated with Omicron may further vary by Omicron sub-variant (Karaba, June 2022).

The differential viral dynamics of highly transmissible SARS-CoV-2 variants, such as Delta, have also been associated with increased transmission – to both vaccinated and unvaccinated individuals – in carefully conducted household contact studies. In a longitudinal household study in the U.K. (Singanayagam, October 2021), index cases with Delta infection had similar viral loads regardless of vaccination status and had slower viral load decline compared with data from pre-Delta variants. In this study, the secondary attack rate among fully vaccinated household contacts was 25%. In a similar analysis, investigators found a greater odds of household transmission if the index case was infected with Delta compared to Alpha (Allen, January 2022).

 

Hybrid Immunity

A number of observational studies have compared the level of immunological protection from infection-induced immunity alone to hybrid immunity obtained through prior infection plus vaccination.

Hybrid immunity during the Omicron period

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 VE 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).

Taken together, evidence during the Omicron period suggests that although both previous infection and vaccination may 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.

Hybrid immunity pre-Omicron

Studies in Israel (Gazit, February 2022; Gazit, August 2021 – preprint, not peer-reviewed; Hammerman, February 2022), the U.K. (Hall, December 2021), India (Murugesan, August 2021) and the U.S. (Cavanaugh, August 2021; León, January 2022), all conducted during the pre-Omicron period, noted higher protection for those with previous infection and vaccination, compared to individuals previously infected but not vaccinated. large-scale observational study in the U.S. of adults with previous SARS-CoV-2 infection conservatively estimated vaccine effectiveness at 57.8% (after two primary doses and a booster dose; 95% CI: 32.1%-73.8%) against subsequent hospitalization for COVID-19 during a period of Delta circulation (Plumb, April 2022). An additional observational study in U.S. health care workers noted that among previously infected individuals, the cumulative incidence of subsequent infection in the pre-Omicron period did not differ statistically significantly by vaccination status (Shrestha, January 2022). However, in the same study, vaccination reduced the risk of symptomatic COVID-19 among individuals with previous infection (HR: 0.60; 95% CI: 0.40-0.90). Taken together, evidence from the pre-Omicron period suggests that there is an additional protective benefit of vaccination for individuals with a prior COVID-19 infection.

Important considerations in interpreting research on SARS-CoV-2 hybrid immunity

These studies have key limitations. First, other than age and sex, many studies did not report baseline characteristics of previously infected individuals, such as comorbidities, immunocompromised status or severity of initial COVID-19 illness, which are factors known to influence the magnitude and durability of the immune response to infection. Second, the duration of follow-up in most of these studies is a few months; therefore, the relative durability of protection from infection versus vaccination over longer periods of time (i.e., years) requires further investigation. Third, the individual effects of prior infection and vaccination are hard to separate when occurring closely together, or when the time elapsed since infection vs. vaccination is not comparable. Most studies did not stratify based on time since vaccination and time since prior infection. Finally, most studies report on effects assessed before periods of Omicron circulation; therefore, there are limits to the generalizability of study results to the Omicron period.

Gaps in Current Knowledge

Current knowledge gaps about SARS-CoV-2 immunity include:

  • The durability, kinetics, and breadth of protective immunity following SARS-CoV-2 infection and how these factors may change over time and in the context of new circulating variants of concern.
  • The impact of age, immune status, comorbidities, and severity of initial SARS-CoV-2 infection on the magnitude and durability of infection-induced immunity.
  • Immune correlates of protection following infection-induced immunity (though investigation of this topic is ongoing - see Wei, May 2022).

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