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

Key findings and considerations for this brief are as follows:

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.

Initial Immune Response to Infection

Multiple correlate-of-protection studies have demonstrated that higher antibody titers are associated with decreased risk of subsequent symptomatic SARS-CoV-2 infection. Data from both the phase 3 AZD1222 and mRNA-1273 vaccine efficacy trials demonstrated that quantitative titers of anti-S IgG, anti-RBD IgG, and pseudovirus and SARS-CoV-2 neutralizing antibody tests all correlate with protection against symptomatic infection (though not asymptomatic infection), with neutralizing antibodies having the strongest correlation in both of these studies ^{[43, 44]}.

Analysis of data across studies has been difficult due to a lack of standardization of serologic assays ^[45]. Two different studies used data from seven vaccine efficacy studies (standardized against mean convalescent plasma titers) and one convalescent plasma/reinfection study to model effectiveness as a function of antibody titer ^{[46, 47]}. These found a high degree of correlation between mean peak neutralizing antibody titers and anti-S IgG binding antibodies within a population, and overall decrease in risk of infection. One study estimated that neutralizing antibody titers amounting to only 20% of the mean convalescent plasma neutralizing antibody titer (54 international units/ml using the WHO standard) correlated with a 50% reduction in infection risk; this appeared robust in predicting the effectiveness of vaccines not included in the model ^{[46, 48]}. Of note, the level of antibody associated with protection against severe disease was much lower than the level required to provide protection against infection, with only 3% of the mean convalescent antibody titer level correlating with 50% protection against severe disease ^[46].

Other immune mechanisms are also important in preventing SARS-CoV-2 infection and limiting COVID-19 illness severity, although their direct correlation with protection is less defined at this time. A study of rhesus macaques found that adaptive transfer of plasma with high titers of neutralizing antibodies was sufficient to protect from infection following a SARS-CoV-2 challenge. However, depleting CD8+ T cells compromised their ability to prevent infection once neutralizing antibodies had waned ^[49]. Analysis of antibody, B-cell and T-cell responses in acutely infected and convalescent humans has shown that protection depends on coordination of all three components of the immune response ^[50]. In the mRNA-1273 phase 3 clinical trial described above, investigators estimated that 68.5% (95% CI 58.5–78.4) of the protective effect of vaccination could be attributed to initial neutralization titers with some degree of protection occurring following vaccination, even when neutralization titers were not detected ^[43]. These, along with studies noted above, suggest that, while the magnitude of antibody response following infection or vaccination is correlated with protection and the absence of antibody with risk, antibody test results (particularly when not standardized nor quantitative) provide only a partial picture of an individual’s immune response. At this time there is no specific antibody test or antibody threshold that can determine an individual’s risk of subsequent infection.

Immune Response Kinetics Following Infection

Antibody titers peak within 3-5 weeks following infection and then begin to wane in a manner that varies by individual, target antigen, antibody isotype, and assay used ^{[6, 51]}. Anti-N antibodies appear to wane fastest, followed by anti-RBD, then anti-S antibodies. Although at least 30% of persons may lose detectable anti-N antibodies within 10 months after infection, anti-S and overall SARS-CoV-2-specific IgG remain detectable in approximately 90% of persons who seroconvert up to 10 months to one year post-infection ^{[16, 52]}. Neutralizing antibodies appear to have a biphasic decline with an initial half-life of 2–3 months followed by a slower decline ^{[11, 14, 15]}. (Table 1)

For at least 2–3 months following infection, people with moderate-to-severe COVID-19 illness have higher titers of binding and neutralizing antibodies than people with mild illness ^{[9, 14]}; these differences may persist for 5–8 months following infection ^{[11, 15]}.

B cells targeting SARS-CoV-2 increase in the first month and then remain at higher concentrations for at least 8 months post infection ^{[11, 14, 53]}. SARS-CoV-2-specific CD4⁺ T cells increase then decline with a half-life of approximately 3-7 months; CD8⁺ T cell measurements varied with at least one study reporting virtually no decline over the initial 4 months post-infection ^{[11, 14]}. (Table 1).

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.

Immune Response Kinetics Following Vaccination

Anti-S, anti-RBD and neutralizing antibodies remain detectable at least 6–8 months following vaccination ^{[21, 22, 60]}. Neutralizing titers following vaccination with the mRNA-1273 vaccine are estimated to decay with a half-life of 68–202 days, whereas binding anti-RBD antibodies decline with a half-life of 52–109 days ^[60]. These rates of antibody decay overlap with those reported for convalescent individuals (as shown in Table 1), though at least one preprint study reported less rapid decay among people recovered from infection compared with those vaccinated with BNT162b2 ^[28]. As with infection, the protective effect of vaccine-induced immunity is also supported by longer-term components of the humoral response, including memory B cells ^{[21, 23, 61]}; vaccine-induced CD4+ and CD8+ T cells continue to be relatively stable up to 6–8 months following vaccination ^{[21, 61]}.

Although some studies have reported a faster decay of antibodies in persons 65 years or older, as compared to persons less than 65 years, lower anti-S and neutralizing antibodies at 2–6 months post vaccination appear to be at least partially attributable to lower peak antibody titers in this population ^{[39, 40}]. Nursing home residents are a unique population given age, co-morbidity, and congregate-setting associated risks. One study reported that detectable pseudovirus neutralization fell from 84% to 30% among nursing home residents (median age: 76 years, age range: 48–100 years) between 2 weeks and 6 months following vaccination; this was significantly faster than the rate of decline reported among staff-member controls (median age: 48 years, age range: 26–76 years), 81% of whom continued to have detectable neutralization at 6 months post-vaccination ^[42].

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].

Variants of SARS-CoV-2 have emerged with multiple mutations in the spike protein that can result in decreased neutralization by antibodies, including those induced by either prior infection or vaccination ^{[19, 69]}.

There is laboratory evidence that persons previously infected with the original lineage of SARS-CoV-2 have reduced neutralizing antibody titers against certain variants (i.e., Beta, Gamma, and Delta variants) ^[70-73]. One study found that among 367 unvaccinated persons assessed 12 months after infection, 98% had detectable anti-S IgG and 91% had neutralizing antibodies against wild-type virus. By comparison, among a subset of 78 persons assessed for neutralizing antibodies against particular variants, these were detectable in 84%, 68%, and 55% for Alpha, Delta, and Beta variants respectively ^[72]. Of note, absence of neutralization activity was higher among people reporting mild infection versus those with severe disease ^[72].

In studies examining neutralization from convalescent sera and vaccinated individuals together, the relative reduction in neutralization appears to be similar across both groups. A number of studies reported a 2- to 4-fold reduction in neutralization against Delta and a 6-fold (or higher) reduction in neutralization against Beta but minimal decreased neutralization against Alpha, as compared to the original SARS-CoV-2 lineage, for both convalescent and vaccinated individuals ^{[70, 74, 75]}.

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).

Although there appears to be varying evidence regarding the relative protection that occurs after surviving COVID-19 as compared with completing vaccination, there is substantial immunologic and increasing epidemiologic evidence that vaccination following infection further increases protection against subsequent illness among those who have been previously infected.

Immunologic Data on Vaccination Following Infection

There is clear evidence that neutralizing antibody and memory B cell response elicited by a single dose of mRNA vaccine following previous infection with SARS-CoV-2 results in an increased antibody titer that is approximately equivalent to a two-dose vaccine regimen in individuals who were not previously infected (Table 3) ^{[22, 23, 82-89]}. In one study of healthcare workers vaccinated 7–11 months after infection with SARS-CoV-2, antibody titers measured 6 days following their first vaccination dose were twice as high as the antibody titers measured the month after their initial infection, and were able to neutralize wild-type, Alpha, and Beta variants, irrespective of vaccine type, number of doses, or pre-vaccination antibody titers ^[90].

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].

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.

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.