CDC Science Brief: SARS-CoV-2 Infection-induced and Vaccine-induced Immunity (Excerpts)

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Excerpts from:

Science Brief: SARS-CoV-2 Infection-induced and Vaccine-induced Immunity

Updated Oct. 29, 2021 Print

This brief provides an overview of the current scientific evidence regarding infection-induced and vaccine-induced immunity, including both peer-reviewed and preprint publications, as well as unpublished CDC data. Although comprehensive, it is neither a formal systematic review nor meta-analysis. New data continue to emerge, and recommendations will be updated periodically, as needed.

Recovery from many viral infectious diseases is followed by a period of infection-induced immunologic protection against reinfection. This phenomenon is widely observed with many respiratory viral infections, including both influenza and the endemic coronaviruses, for which acquired immunity also wanes over time making individuals susceptible to reinfection.

CDC continues to recommend COVID-19 vaccination for all eligible persons, including those who have been previously infected with SARS-CoV-2.

Executive Summary

Key findings and considerations for this brief are as follows:

  • Available evidence shows that fully vaccinated individuals and those previously infected with SARS-CoV-2 each have a low risk of subsequent infection for at least 6 months. Data are presently insufficient to determine an antibody titer threshold that indicates when an individual is protected from infection. At this time, there is no FDA-authorized or approved test that providers or the public can use to reliably determine whether a person is protected from infection.
    • The immunity provided by vaccine and prior infection are both high but not complete (i.e., not 100%).
    • Multiple studies have shown that antibody titers correlate with protection at a population level, but protective titers at the individual level remain unknown.
    • Whereas there is a wide range in antibody titers in response to infection with SARS-CoV-2, completion of a primary vaccine series, especially with mRNA vaccines, typically leads to a more consistent and higher-titer initial antibody response.
    • For certain populations, such as the elderly and immunocompromised, the levels of protection may be decreased following both vaccination and infection.
    • Current evidence indicates that the level of protection may not be the same for all viral variants.
    • The body of evidence for infection-induced immunity is more limited than that for vaccine-induced immunity in terms of the quality of evidence (e.g., probable bias towards symptomatic or medically-attended infections) and types of studies (e.g., observational cohort studies, mostly retrospective versus a mix of randomized controlled trials, case-control studies, and cohort studies for vaccine-induced immunity). There are insufficient data to extend the findings related to infection-induced immunity at this time to persons with very mild or asymptomatic infection or children.
  • Substantial immunologic evidence and a growing body of epidemiologic evidence indicate that vaccination after infection significantly enhances protection and further reduces risk of reinfection, which lays the foundation for CDC recommendations.

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Background

CDC recommends COVID-19 vaccination for all eligible persons, including those who have been previously infected with SARS-CoV-2 [1]. As of October 28, 2021, more than 45 million COVID-19 cases and over 740,000 deaths have been reported in the United States (US) [2]. Data from a seroprevalence survey that assessed for presence of antibodies and history of vaccination among US blood donors from January to August 2021 suggest that approximately half of previously infected adults in the US have not been vaccinated [3].

Both SARS-CoV-2 infection and COVID-19 vaccination induce an immune response that initially confers high levels of protection against symptomatic COVID-19 illness. This brief contains a review of evidence regarding vaccine-induced immunity and infection-induced immunity, including the initial immune response, antibody decay kinetics, protection from subsequent infection, impact of new variants, and effect of vaccinating previously infected individuals.

Separate overviews have been written on the types of assays used to assess the serologic response to SARS-CoV-2 (Interim Guidelines for COVID-19 Antibody Testing | CDC) and detailed evidence of the immunity provided specifically by vaccines (Science Brief: COVID-19 Vaccines and Vaccination).

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Protection from Reinfection in Cohort Studies

Multiple studies have compared the incidence of reinfection and primary infection during a specific time period to evaluate the level and duration of protection provided by initial infection with SARS-CoV-2. Table 2 summarizes data from seven observational cohort studies from six countries, each with >10,000 participants, assessing the risk of reinfection over time. Five studies used RT-PCR positivity to define initial infection. In these studies, primary RT-PCR-confirmed SARS-CoV-2 infection decreased risk of subsequent infection by 80–93% for at least 6–9 months [54-58]. Studies specifically assessing persons seropositive with anti-N and anti-S antibodies following infection [16, 45] found slightly higher protective effects (89–93%). Most studies had a mean or median follow-up period of approximately 7 months; the longest reported follow-up was 12 months post-infection [58]. Three studies included sub-analysis to assess if the protection waned over time; none of these found a decline in protection within the follow-up period [54, 55, 57].

It is important to note that all of these studies were observational and all but two were retrospective. Low availability of testing early in the pandemic may have biased these studies toward populations that were more likely to have had symptomatic or medically attended primary infection. Most were unable to control for any potential differences in test- or healthcare-seeking behaviors between previously infected and naïve persons, though a large proportion of the reinfections reported across the studies were asymptomatic infections (Table 2).  In one of the prospective cohort studies, over 25,000 healthcare workers were tested using RT-PCR testing every 2 weeks, allowing a more comprehensive ascertainment of reinfections. This study found that a history of previous RT-PCR-confirmed infection provided 93% protection against a subsequent symptomatic infection, 52% protection against asymptomatic infection, and 84% protection against overall infection with SARS-CoV-2 [54].

Many of these studies were completed just as vaccination was being rolled out in their respective countries, which makes it challenging to follow up and determine when immunity after infection wanes and what markers best predict this waning. Based on the trajectory of antibody decline, researchers have predicted that the immune response following infection would continue to provide at least 50% protection against reinfection for 1–2 years following initial infection with SARS-CoV-2 or vaccination [13, 46].  This would be similar to what is observed with seasonal coronaviruses [59]. Further epidemiologic analyses are needed to confirm these hypotheses.

Of note, these studies occurred when the ancestral strain and Alpha variant were the predominantly circulating variants. There is evidence that protection may decrease in the setting of more transmissible variants of concern (VoC) and variants being monitored (VBM), as discussed below.

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Duration of Immune Protection from Vaccination

Evidence is still accruing regarding the duration of protection following vaccination. Using antibody kinetics, one model predicted that an initial vaccine effectiveness of 90% would likely decline to approximately 70% around 250 days post-vaccination [46], not accounting for other factors such as non-serologic components of the immune response or the impact of new circulating variants.

Both Pfizer-BioNTech and Moderna released data from their phase 3 trials reporting overall high efficacy of mRNA vaccines against laboratory confirmed SARS-CoV-2 infection 5-6 months following vaccination. Pfizer-BioNTech reported an overall vaccine efficacy of 91% against infection and 97% against severe disease 6 months after vaccination with BNT162b2, though also reported a gradual decline in efficacy against infection from 96% at 7 days–2 months to 84% at 4–6months [62]. Moderna reported 93% efficacy at a median of 5 months after vaccination with mRNA-1273, without further details on the rate of decline in efficacy over time [63].

As described in greater detail in CDC’s COVID-19 Vaccine and Vaccination Science Brief and in a October 2021 Advisory Committee on Immunization Practices presentationpdf icon, recent studies have demonstrated waning of both antibody titers and vaccine effectiveness against infection over time, especially among older populations [42, 64]. Decreased vaccine effectiveness may reflect a combination of waning antibody titers and decreased neutralizing capacity in the setting of widespread circulation of variants with partial immune escape. Notably, multiple studies have found that vaccine effectiveness against hospitalization and/or severe disease continues to be high, ranging from 84–96%, up to 6 months following vaccination [65-68].

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Comparison of Infection- and Vaccine-induced Immune Responses

A systematic review and meta-analysis including data from three vaccine efficacy trials and four observational studies from the US, Israel, and the United Kingdom, found no significant difference in the overall level of protection provided by infection as compared with protection provided by vaccination; this included studies from both prior to and during the period in which Delta was the predominant variant [79].  In this review, the randomized controlled trials appeared to show higher protection from mRNA vaccines whereas the observational studies appeared to show protection to be higher following infection.

A more recent analysis of data from a network of 187 hospitals in the United States found that, among more than 7,000 COVID-19–like illness hospitalizations whose prior infection or vaccination occurred 90–179 days beforehand, there was a 5.5 times higher odds of laboratory-confirmed COVID-19 among previously infected patients than among fully vaccinated patients [80]. This study included data on persons more recently infected and/or vaccinated than the studies in the systematic review, though the authors noted one limitation of the design was the potential of missing testing that may have occurred outside of the healthcare network.

The Office of National Statistics in the United Kingdom used data from a large-scale longitudinal community survey of COVID-19 to compare the risk of infection among fully vaccinated, partially vaccinated, unvaccinated/previously infected, and unvaccinated/uninfected persons during two different periods 1) when Alpha was the predominant variant (December 2020–May 2021) and 2) when Delta was the predominant variant (May–August 2021) [81]. Based on results that included over 26,000 RT-PCR positive tests, they found full vaccination to provide the greatest protection during the Alpha predominant period (79% vs. 65% reduction in risk), but equivalent protection from full vaccination and infection during the Delta predominant period (67% vs. 71% reduction in risk).

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Risk of Reinfection in Unvaccinated vs. Vaccinated Individuals with a History of Infection

In studies directly comparing risk of reinfection among previously infected individuals who were never vaccinated versus individuals who were vaccinated after infection, most, but not all, studies show a benefit of vaccination. One retrospective cohort study described risk of reinfection from December 2020–May 2021 among 2,579 US-based healthcare users previously infected with SARS-CoV-2, about 47% of whom were vaccinated over the course of the study. Investigators did not detect any cases of reinfection, regardless of vaccination status during 5 months of observation and so could not detect a benefit of vaccination [91]. In contrast, a case-control study conducted among 738 residents of Kentucky with reported infection during March–December 2020 found that previously infected persons who were unvaccinated had 2.3 times greater odds of reinfection during May–June 2021 than previously infected but vaccinated individuals [92]. Both studies occurred before Delta became the dominant variant in the United States.

More recent observational cohort studies including over 700,000 health system users in Israel and over 11,000 healthcare workers in India reported that history of prior infection provided greater protection from subsequent infection than vaccination alone, but overall risk of infection was lowest among those that were vaccinated following infection during periods of Delta predominance [93, 94]. In the systematic review described above, a pooled analysis across seven studies showed a modest but significant increase in protection from infection when previously infected individuals were vaccinated [79].

Limitations

This review summarizes characteristics of infection- and vaccine-induced immune responses, evidence regarding duration of immunity, and the potential impact of circulating variants. The approach was limited in scope focusing primarily on articles that were published in high-impact journals or novel in their findings; therefore, this does not represent a systematic review of all the scientific literature on SARS-CoV-2 infection-induced immunity. Particular biases related to observational study designs have been discussed above. The majority of studies included in this review came from a small number of countries, often with limited diversity in participants. Many of the immunologic studies did not include detailed demographic data. More consistent inclusion of descriptive data about demographics of participating populations (e.g., race/ethnicity, socioeconomic status, educational attainment) and conscious efforts to improve the racial, ethnic, and social diversity of participants in studies would be of great benefit in ensuring that related policies address the needs of all populations.Top of Page

Conclusions

Multiple studies in different settings have consistently shown that infection with SARS-CoV-2 and vaccination each result in a low risk of subsequent infection with antigenically similar variants for at least 6 months. Numerous immunologic studies and a growing number of epidemiologic studies have shown that vaccinating previously infected individuals significantly enhances their immune response and effectively reduces the risk of subsequent infection, including in the setting of increased circulation of more infectious variants.

Although the Delta variant and some other variants have shown increased resistance to neutralization by both post-infection and post-vaccination sera in laboratory studies, observed reduction in effectiveness has been modest, with continued strong protection against hospitalization, severe disease, and death.

Multiple studies have shown that antibody titers correlate with protection at a population level; however, data are presently insufficient to determine an antibody titer threshold that indicates if an individual is protected from infection. At this time, there is no FDA-authorized or approved test that providers or the public can use to reliably determine whether a person is protected from infection.

CDC will continue to follow and evaluate evolving scientific evidence in these areas and update recommendations accordingly.

https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/vaccine-induced-immunity.html

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