Previous Infection and Effectiveness of COVID-19 Vaccination in Middle- and High-School Students

During the 2021 to 2022 school year, Utah K-12 schools exceeding the case threshold defined above provided one-time SARS-CoV-2 school-based testing for students and staff. Data from students opting into TTS during the weeks of January 2 and 9, 2022, from 2 middle schools and 16 high schools across 5 counties in Utah were analyzed. The protocol for this evaluation was reviewed by the Centers for Disease Control and Prevention (CDC), determined to be non-research, and conducted consistent with applicable federal law and CDC policy as defined in 45 CRF 46.102(I)(2).¹⁴ 

Deidentified individual-level SARS-CoV-2 test results, test type, and week of test available from routine reporting during March 2020 through January 2022 to the UDHHS statewide public health surveillance system were used. Data included SARS-CoV-2 test results from middle- and high-school TTS events during the weeks of January 2 and January 9, 2022, and demographic and vaccination information including age (in years) at event onset, sex, race, ethnicity, and school type.

Given vaccination schedule recommendations, age was categorized as students aged 12 to 15 years and 16 to 19 years. Race and ethnicity were combined into 5 categories (Asian, non-Hispanic or Latino; Black or African American, non-Hispanic or Latino; other race, non-Hispanic or Latino; white, non-Hispanic or Latino, and Hispanic or Latino).

COVID-19 vaccination status, vaccine manufacturer for each dose received, and days since vaccine dose were identified from the Utah state immunization information system. Student vaccination status was categorized as (1) unvaccinated (no documented COVID-19 vaccine), (2) vaccinated with 2 doses of an mRNA vaccine, with ≥14 days from the second dose or <7 days from the third dose, or (3) vaccinated with 3 doses of an mRNA vaccine with ≥7 days from the third dose. We analyzed students with 2 or 3 vaccine doses separately, stratified by previous infection status and age group. Because of the limited sample size, 3-dose analyses were conducted for the 16 to 19 age group only. The time from the second vaccine dose to the TTS event for students with 2 vaccine doses was categorized as either <180 or ≥180 days for students with previous infection and as <120 or ≥120 days for students without previous infection. SARS-CoV-2 infection was defined as laboratory-confirmed positive by antigen or reverse transcriptase polymerase chain reaction (RT-PCR) test administered during a TTS event in January 2022 and previous SARS-CoV-2 infection as a positive SARS-CoV-2 antigen or RT-PCR test result reported to the UDHHS statewide surveillance system. Hybrid immunity was defined as students with previous SARS-CoV-2 infection paired with vaccination.

Students were excluded if they (1) were aged <12 years, (2) had a positive SARS-CoV-2 test within 90 days before the TTS test, (3) received a non-mRNA vaccine dose, only 1 mRNA dose, or second dose received <14 days before the TTS test, (4) received vaccine doses before the ACIP age-based recommendation, (5) were missing school type information, or (6) had a false-positive test (defined by UDHHS as a negative SARS-CoV-2 PCR result collected within 48 hours after a positive antigen test without other positive laboratory results).

We used log binomial regression to estimate effectiveness against infection and VE by age groups as defined above.^15,16  Generalized estimating equations were used to account for clustering by school by using an exchangeable working correlation, binomial distribution, and log link to estimate the relative risk.¹⁷  VE was calculated as (1 − relative risk) × 100. Possible confounders were systematically added to develop adjusted models, and final models were adjusted for race/ethnicity and sex covariates. We conducted stratified analyses to estimate VE against infection by time since the last dose and by previous infection. We also estimated the effectiveness of previous infection and hybrid immunity on reinfection.

A 2-sided P < .05 was considered statistically significant. All analyses were conducted by using SAS software, version 9.4 (SAS Institute Inc, Cary, NC).

A total of 19 932 students participated in TTS during January 2022 (Fig 1). Of these, 17 910 students were included in the final analysis (Fig 1). We excluded 2022 students; >85% were excluded because of having a laboratory-confirmed SARS-CoV-2 infection in the 90 days before the TTS event (n = 1030) or for only having 1 dose of mRNA vaccine or a second dose received <14 days before the TTS test (n = 697; Fig 1).

The median age was 16 years (range: 12–19 years); 64.0% were aged 16 to 19 years (Table 1). Almost one-half (49.1%) were female, three-quarters (74.9%) identified as white race, non-Hispanic or Latino ethnicity, and 14.8% identified as Hispanic or Latino (Table 1). Sixteen percent of students had documented previous SARS-CoV-2 infection (excluding infections 90 days before the TTS test). Students aged 16 to 19 years had higher previous positivity (18.5%) compared with 12- to 15-year-old students (13.6%; Table 1). Overall, 88.0% of previous SARS-CoV-2 infections occurred during the prealpha/alpha variant predominant period (March 2020–June 2021; Supplemental Fig 3). Overall SARS-CoV-2 positivity was 14.4% during a school TTS event in January 2022 (Table 1). Antigen tests were the primary testing method during school TTS events, accounting for 99.8% of tests performed (Table 1). Additionally, the overall attack rate across all schools was 8.7% (Supplemental Table 3).

Unvaccinated students accounted for 35.8% overall, whereas 55.6% received 2 doses of an mRNA vaccine (Table 1). Vaccination status by age group was similar, although students aged 12 to 15 years had a slightly higher proportion of unvaccinated (38.9%) compared with students aged 16 to 19 years (34.1%). Additionally, 13.4% of students aged 16 to 19 years received 3 doses of an mRNA vaccine (Table 1). The median interval between the receipt of a second dose and the TTS test was 211 days (range: 14–387 days), overall, and was similar by age group. Most students with 2 doses received the second dose ≥180 days before their SARS-CoV-2 TTS test (67.8%), although the proportion of students aged 16 to 19 years receiving a second dose ≥180 days before was higher (70.5%) compared with students aged 12 to 15 years (63.8%). Students aged 16 to 19 years who had received their third dose had a median of 21 days (range: 7–54) before their SARS-CoV-2 TTS test (Table 1).

Compared with unvaccinated students with no previous SARS-CoV-2 infection, 2-dose VE without previous infection was not significant for students aged 12 to 15 years. However, when stratified by time, 2-dose VE without previous infection was 30.9% (95% confidence interval [CI]: 7.9%–48.1%) in the <120 days since the second vaccine dose (Fig 2). Protection against infection for those with previous infection only was 35.9% (95% CI: 12.9%–52.8%). In the same age group, the effectiveness of hybrid immunity among students with 2 vaccine doses was 55.0% (95% CI: 36.5%–68.2%) and was similar across time since vaccination with effectiveness of 58.7% (95% CI: 33.2%–74.4%) in the <180 days since second dose and 51.1% (95% CI: 21.2%–69.6%) ≥180 days since second dose (Fig 2).

When compared with unvaccinated students aged 16 to 19 years without previous SARS-CoV-2 infection, protection against infection was highest for those with hybrid immunity and 3 vaccine doses, from 24.2% (95% CI: 3.8%–40.3%) for 2-dose hybrid immunity to 70.0% (95% CI: 42.3%– 84.5%) for 3-dose hybrid immunity (Fig 2). When stratified by time, protection of 2-dose hybrid immunity was 54.7% (95% CI: 31.0%–70.3%) when <180 days since the second dose and was not significant after 180 days. Among those with no previous infection, 2 doses were not protective, regardless of stratification by the time since the last dose (Fig 2).

For students aged 16 to 19 years receiving 3 doses without previous infection, VE was 44.2% (95% CI: 33.4%–53.3%). Overall, protection was highest (70.0%, 95% CI: 42.3%–84.5%) among students with 3-dose hybrid immunity, although confidence intervals overlapped with the estimate for 3 doses without previous infection (Fig 2).

Among students aged 16 to 19 years, analysis stratified by the presence of previous infection revealed that the effectiveness for students with 3 doses was higher among those with previous infection (63.6%, 95% CI: 30.1%–81.1%) compared with those without (44.2%, 95% CI: 33.4%–53.3%), but confidence intervals overlapped (Table 2). No protection was noted among students aged 16 to 19 years with or without previous infection for 2 doses (Table 2).

In the context of a surge in SARS-CoV-2 infections due to the emergence of omicron BA.1 sub-lineage, we evaluated 2- and 3-dose VE and protection from previous infection in a population of almost 18 000 students who underwent school-based testing as part of a local TTS strategy to keep schools open. Our findings reveal that point estimates for infection paired with vaccination (ie, hybrid immunity) were higher than either previous infection or vaccination alone against presumed omicron (BA.1) infection, but confidence intervals often overlapped. Among students aged 16 to 19 years, point estimates for 2-dose hybrid immunity were significantly higher than 2 doses of vaccine alone. However, in the same age group, only the estimate for 3-dose hybrid immunity was higher than vaccine or previous infection only. Regardless of previous infection status, VE was higher for students with a recent vaccination with a third dose compared with 2-dose VE among students aged 16 to 19 years.

Our findings align with other studies revealing that hybrid immunity improves the overall protection and duration of protection against omicron (BA.1)^18–20  and our estimates for 3-dose VE are comparable with studies assessing VE against omicron (BA.1) infection in similar age groups. The authors of at least 3 studies found BNT162b2 2-dose VE against infection for persons aged 12 and older ranging from 40% to 59% for those without previous infection.^21–23  The authors of at least 1 study noted significantly higher 2-dose mRNA VE against omicron infection for previously infected compared with noninfected (68% vs 42%, respectively) in persons 12 years of age and older.¹⁸  Studies not excluding persons with previous infection revealed a 2-dose mRNA VE against omicron infection from 51% to 78% in adolescents 12 to 17 years of age, although both studies revealed declines in VE against infection as time since the second dose increased.^24–26 

Among students aged 16 to 19 years with 2-dose hybrid immunity, protection against infection <180 days since vaccination was moderate yet not significant after 180 days. In the same age group, 2 doses with no previous infection were not protective against infection. In contrast, 2 doses, <120 days since vaccination, and with no previous infection were moderately effective for students aged 12 to 15 years. The differences in protection between age groups may be due to changes in risky behavior after vaccination, given comparable median days since the second dose for both age groups. Age-group differences may be explained by risk compensation (ie, a tendency to adjust behavior given perceived risk), potentially leading to riskier behavior. Risk compensation is more likely to occur when people are both highly motivated to take on risky behavior and it is within their control to do so.²⁷  There are likely important differences in the opportunities for independent decision-making for students aged 16 to 19 years compared with those aged 12 to 15 years. This, paired with the demonstrated efficacy reported postclinical trials for COVID-19 mRNA vaccines,²⁸  may have led to further reduced adherence to other precautions, such as mask-wearing, physical distancing, and increased participation in higher-risk behaviors among those vaccinated with 2 doses.

Although 3 doses among students aged 16 to 19 years were moderately effective (44.2%), protection increased to 70% among students with 3-dose hybrid immunity, although confidence intervals overlap. The addition of a third dose increased protection regardless of previous infection status, highlighting the importance of booster doses. In assessing the effect of previous infection on VE, students aged 16 to 19 years with previous infection had better protection with 2 and 3 doses compared with those without previous infection. The rates of past infection and vaccination likely affected the overall observed school attack rates during the omicron (BA.1) surge. These observations suggest that, absent infection-induced and vaccine-induced immunity, the school-level impact of the BA.1 surge on students may have been much worse.

This analysis is subject to several limitations. First, we were unable to evaluate VE for 12- to 15-year-olds receiving 3 doses of an mRNA vaccine because of a low sample size, given the short time window between the recommendation of a third dose for this age group and the TTS events analyzed. Second, we were unable to distinguish between students vaccinated with a third dose because of a risk-based indication (ie, immunocompromising status), which may lead to an underestimated VE. Third, most schools used antigen tests during TTS events because of ease of use and rapid results turn-around. Antigen test sensitivity for SARS-CoV-2 is generally lower compared with nucleic acid amplification tests, increasing the potential for false-negatives and the misclassification of outcomes, which may impact estimated effects. Fourth, this analysis was based on data from a single state; there may be individual-level (socioeconomic, behavioral) or state-level characteristics (variations in mandates of mitigation measures) that differ across the country. In addition, race/ethnicity was included in adjusted models, although race/ethnicity is likely a proxy for other unmeasured social/behavioral drivers of risk. Fifth, for children with hybrid immunity, we stratified by time since vaccination rather than time since last exposure (vaccine or past infection). Thus, students who were vaccinated a long time before, but had a more recent infection, may not be comparable to those who were vaccinated at the same time but were infected before vaccination because the time from the last exposure to an immunity-producing event (vaccination or infection) will differ. Sixth, previous infection status may be misclassified if it was not captured by the state surveillance system (eg, positive on an at-home antigen test and not reported). Finally, individual students/parents could opt out of TTS testing, and during the time period for this analysis, the participation of students in TTS events was 71% median (range: 48%–90%) across all schools. We were unable to assess the differences between those opting in compared with those opting out of TTS testing, and students opting in may have higher risk tolerance of SARS-CoV-2 exposure. These factors limit the generalizability of the findings.

The continual circulation of SARS-CoV-2 in the United States in the context of the reduction of other prevention measures highlights the importance of vaccination to protect both individuals and communities. Although protection with primary series vaccination against infection for previously SARS-CoV-2 naïve students was not found, our results reveal that protection against infection increased for those with hybrid immunity or with the addition of a third vaccine dose in the absence of infection-induced immunity. We were unable to measure protection against other severe outcomes of SARS-CoV-2 infection, such as hospitalization, yet current evidence suggests that VE remains strong against these severe outcomes.^24–26,29  Real-world VE estimates can guide the prioritization of resources and help focus messaging needed, particularly at the state and local levels to protect against the risk of infection.

As this investigation illustrates, these real-world, programmatic data from school-based testing were useful to reveal the relative effectiveness of past infection and/or vaccination in preventing infections in child and adolescent populations. Age-stratified VE estimates for child and adolescent populations are more challenging to obtain throughout other postmarketing platforms. These estimates are especially important in the context of school or other congregate settings, in which transmission risk may be high but other prevention measures can be difficult to implement on a large scale. Further studies are needed to assess both the impact of additional boosters in children and adolescents, considering infection-induced immunity with emerging variants, as well as the impact of vaccination on the reduction of other indirect effects of symptomatic SARS-CoV-2, such as school absenteeism and family economic burden.

We would like to acknowledge Jason Barnes, Joe Jackson, Utah Department of Health and Human Services Mobile Testing Team, and the leadership and staff of Utah’s Local Education Agencies and Local Health Departments.

ACIP

Advisory Committee on Immunization Practices

CDC

Centers for Disease Control and Prevention

CI

confidence interval

COVID-19

coronavirus disease 2019

mRNA

messenger ribonucleic acid

RT-PCR

reverse transcriptase polymerase chain reaction

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

TTS

Test to Stay

UDHHS

Utah Department of Health and Human Services

VE

vaccine effectiveness