Abstract
Studies have suggested the effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 reinfection among those previously infected. However, it is not yet clear if one dose of the vaccine is enough to prevent breakthrough infections compared to two doses. Using data from Optum de-identified COVID-19 Electronic Health Record (EHR) dataset, we assessed breakthrough infection risks in individuals previously infected, comparing those with one vaccine dose to those with two doses. Propensity scores were applied to mitigate confounding factors. Follow-up spanned six months, beginning two weeks post-vaccination. Among 213,845 individuals, those receiving one vaccine dose had a significantly higher breakthrough infection risk than the two-dose group (HR 1.69, 95% CI 1.54–1.85). This pattern was observed across genders, racial/ethnic groups, age categories, and vaccine types. This study reveals a substantial disparity in the risk of breakthrough infections between individuals receiving one versus two doses of the COVID-19 vaccine, suggesting that a single dose may not provide adequate protection against reinfection.
Background
The emergence of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1–5, triggered an urgent global effort to develop effective vaccines. COVID-19 vaccines (especially mRNA vaccines) have been shown to be effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization, and mortality. Previous observational studies suggest that COVID-19 vaccines are effective in preventing SARS-Cov-2 reinfection in previously infected patients6–9. These studies have pointed to a significant reduction in the risk of reinfection, indicating that the immune response elicited by prior infection is further bolstered by vaccination. This combination of natural immunity and vaccine-induced immunity offers a robust defense against SARS-CoV-2. Prior studies suggest that one dose of COVID-19 vaccines can elicit powerful immune responses among people previously infected with SARS-Cov-2, while the second dose provides little added immune responses.10–13 The first vaccine dose acts as a strong booster to the pre-existing immunity gained through the natural course of infection, effectively enhancing the immune defense. In contrast, the second dose of the COVID-19 vaccine appears to provide incremental benefits in terms of immune responses. The reason behind this phenomenon lies in the fact that the initial vaccine dose already primes the immune system, and the second dose does not seem to significantly heighten the immune response for those with prior exposure to the virus.10–12 While one vaccine dose can provide a robust immune boost for previously infected individuals, the question of whether a single dose is as effective as 2 doses in preventing breakthrough infections among previously infected individuals remains a subject of ongoing research and debate. The answer to this question is not yet definitively established, and more extensive studies are needed. In this study, we assessed the risk of breakthrough infections in individuals with prior infection who had received either a single vaccine dose or two doses.
Methods
We used data from Optum® de-identified COVID-19 Electronic Health Record (EHR) dataset which contains de-identified EHR on a cohort representative of the US population. Details of the dataset have been previously described.14 The data integrates health systems across all 50 states. The information is gathered from Optum’s extensive longitudinal database, which is compiled from dozens of healthcare provider organizations across the United States, including over 700 hospitals and 7,000 clinics. The COVID-19 data set includes a broad range of raw clinical data, featuring new, unmapped COVID-specific data points from various sources such as inpatient and outpatient EHRs, practice management systems, and several other internal systems. Data is processed from all stages of care, including acute inpatient stays and outpatient visits. The COVID-19 data includes point of care diagnostics specific to individuals previously tested positive for SARS-CoV-2 infection, with over 500 mapped labs and bedside observations, including COVID-19 specific testing. The extensive, longitudinal data includes anonymized patient-level information on demographics, hospitalizations, outpatient visits, etc. The data is organized into multiple tables that can be linked by a common patient identifier (an anonymous, randomized string of characters). We identified a COVID-19 cohort from all those who previously tested positive for (SARS-CoV-2) infection and received at least one dose of a COVID-19 vaccine after their SARS-CoV-2 infection. We excluded patients who died before they were reinfected and patients with a positive test for COVID-19 within two weeks after receiving the COVID-19 vaccine if they had a breakthrough infection. We divided individuals into three groups: the unvaccinated group, the two-dose group (two doses of Pfizer-BioNTech, Moderna or Oxford-AstraZeneca COVID-19 vaccines) and the one-dose group.
Propensity scores based on predefined covariates (age, sex, race/ethnicity, and date of first positive COVID-19 test) were estimated. Propensity scores were used to compute the overlap weight which is the probability of membership in the non-observed exposure group (one minus the propensity of the observed group). Follow-up started two weeks after receiving the COVID-19 vaccine and ended 6 months later or until January 31, 2022, whichever occurred first. The rate of breakthrough infection was defined as the number of new breakthrough infections during the follow up period divided by the person-time at risk throughout that period (infection rate = no. of new breakthrough infections/total person-time at risk). Kaplan-Meier curves were plotted to show differences in cumulative probability of reinfection between these three groups. Hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox survival models. We presented both unadjusted results and propensity-score adjusted results. Statistical analyses were conducted using SAS software version 9.4 (SAS Institute; Carey, NC) and a 2-sided p value of <0.05 was considered statistically significant for the purposes of our analysis.
Results
This study included 82,382 males and 131,463 females. Compared to those who received two doses of COVID-19 vaccine, the risk for breakthrough infections was much higher among those who received only one dose (HR 1.69, 95% CI 1.54–1.85; Figure 1 and Table 1) or those unvaccinated (HR 3.05, 95% CI 2.84–3.27). This was true for both females and males and all racial/ethnic groups, age groups, and vaccine types. We also presented the unadjusted results in Table 2.
Figure 1.
Cumulative probability of breakthrough infections among previously infected patients who received one dose or two doses of COVID vaccine.
Table 1.
Breakthrough infections among previously infected patients who received one dose or two doses of COVID vaccine (propensity score adjusted).
| N | Unvaccinated (n=94072) | One dose (n=52773) | Two doses (n=67000) | Adjusted hazard ratio 95%CI (vs. two doses) | |||||
|---|---|---|---|---|---|---|---|---|---|
| Infected | Infection rate | Infected | Infection rate | Infected | Infection rate | Unvaccinated | One dose | ||
| All | 213845 | 13201 | 134.9 | 1790 | 87.8 | 2303 | 53.7 | 3.05(2.84–3.27) | 1.69(1.54–1.85) |
| Age | |||||||||
| 18–44 | 79074 | 4204 | 103.9 | 621 | 98.3 | 812 | 58.1 | 2.20(1.94–2.49) | 1.81(1.56–2.11) |
| 45–64 | 85546 | 5110 | 134.9 | 743 | 88 | 927 | 51.3 | 3.18(2.85–3.56) | 1.84(1.60–2.12) |
| 65+ | 49225 | 3887 | 186.3 | 426 | 72.3 | 564 | 53.2 | 4.22(3.69–4.82) | 1.24(1.03–1.50) |
| Sex | |||||||||
| Female | 131463 | 7934 | 132.4 | 1101 | 92.7 | 1513 | 57.1 | 2.81(2.57–3.07) | 1.65(1.47–1.85) |
| Male | 82382 | 5267 | 139 | 689 | 80.2 | 790 | 48.4 | 3.49(3.10–3.92) | 1.75(1.50–2.03) |
| Race/Ethnicity | |||||||||
| Hispanic | 20594 | 1123 | 119.1 | 173 | 94.1 | 275 | 65.7 | 2.22(1.78–2.76) | 1.49(1.14–1.96) |
| Non-Hispanic White | 141856 | 8735 | 129.6 | 1062 | 78.1 | 1365 | 49 | 3.21(2.93–3.51) | 1.68(1.49–1.89) |
| Non-Hispanic Black | 26499 | 1999 | 155.2 | 212 | 90.4 | 362 | 69.3 | 2.82(2.34–3.40) | 1.37(1.07–1.74) |
| Other | 24896 | 1344 | 160.1 | 343 | 129.5 | 301 | 55.6 | 3.38(2.81–4.06) | 2.18(1.74–2.74) |
| Vaccine type | |||||||||
| Pfizer-BioNTech | 66612 | 1076 | 93.4 | 1241 | 58.5 | 1.58(1.40–1.79) | |||
| Other | 53161 | 714 | 81.6 | 1062 | 48.9 | 1.80(1.56–2.06) | |||
Infected: number of patients who had breakthrough infections.
Infection rate: per 1000 person in 6 months. The infection rate was defined as the number of new breakthrough infections during study follow up divided by the person-time at risk throughout that period (infection rate = no. of new breakthrough infections/total person-time at risk). The infection rate was propensity-score adjusted.
Table 2.
Breakthrough infections among individuals with prior SARS-CoV-2 infections who received one dose or two doses of COVID vaccine (unadjusted).
| N | Infection rate | Hazard Ratio 95%CI (vs. two doses) | ||||
|---|---|---|---|---|---|---|
| Unvaccinated (n=94072) | One dose (n=52773) | Two doses (n=67000) | Unvaccinated | One dose | ||
| All | 213845 | 146.5 | 92.1 | 51.2 | 3.49(3.34–3.64) | 1.48(1.39–1.58) |
| Age | ||||||
| 18–44 | 79074 | 114.3 | 101.7 | 54.9 | 2.56(2.38–2.76) | 1.65(1.48–1.83) |
| 45–64 | 85546 | 148.2 | 92.8 | 48.7 | 3.71(3.45–3.97) | 1.63(1.48–1.80) |
| 65+ | 49225 | 206.5 | 79.6 | 51.3 | 4.91(4.49–5.36) | 1.11(0.98–1.26) |
| Sex | ||||||
| Female | 131463 | 143.6 | 96.5 | 54.6 | 3.21(3.04–3.39) | 1.44(1.33–1.56) |
| Male | 82382 | 150.9 | 85.6 | 45.8 | 4.01(3.72–4.32) | 1.57(1.42–1.74) |
| Race/Ethnicity | ||||||
| Hispanic | 20594 | 125.7 | 96.7 | 60.8 | 2.52(2.21–2.88) | 1.42(1.17–1.71) |
| Non-Hispanic White | 141856 | 141.2 | 82.5 | 47.0 | 3.67(3.47–3.89) | 1.47(1.36–1.59) |
| Non-Hispanic Black | 26499 | 168.3 | 95.3 | 64.0 | 3.32(2.96–3.71) | 1.32(1.11–1.56) |
| Other | 24896 | 179.4 | 131.5 | 52.9 | 4.00(3.53–4.54) | 1.80(1.54–2.10) |
| Vaccine type | ||||||
| Pfizer-BioNTech | 66612 | 97.8 | 55.5 | 1.78(1.63–1.93) | ||
| Other | 53161 | 86.2 | 47.1 | 1.98(1.80–2.18) | ||
Infection rate: per 1000 person in 6 months. The infection rate was defined as the number of new breakthrough infections during study follow up divided by the person-time at risk throughout that period (infection rate = no. of new breakthrough infections/total person-time at risk). The infection rate was unadjusted.
Discussion
In this study, we evaluated whether one dose of the COVID-19 vaccine would provide enough protection against reinfection compared with two doses using data from a large national cohort. We found that the reinfection risk was much higher in previously infected patients who received one dose of the COVID-19 vaccine compared to those who received two doses. Although both one dose and two doses of COVID-19 vaccines can elicit similarly strong immune responses among previously infected individuals,10 our findings suggest that the effectiveness of one dose in preventing reinfection may be lower. The underlying reason requires further study. In contrast to our findings, some other studies15–18 showed a higher risk of COVID-19 infection during the Omicron wave among those previously infected who received more prior vaccine doses. The breakthrough infections we observed in our study mostly occurred before the Omicron wave, which may partly explain the difference between our findings and others. The findings of our research could offer valuable insights for informing vaccination strategies during future occurrences of comparable viral outbreaks.
The strength of this study is that we used data from a large national cohort covering both young and elderly individuals. This study has some limitations. Reinfection in this study was defined as a positive test for COVID-19 and thus we may have missed individuals with reinfections who did not receive a COVID-19 antigen test or who received the test at home and did not report the positive results to their doctors. It is expected that undiscovered reinfections would affect both one-dose and two-dose vaccine recipients equally and not significantly impact the overall results of our study, as we tracked a cohort of previously infected individuals (with a documented positive COVID-19 test). Additionally, we did not have data on comorbid conditions for the study cohort. We were also not able to determine their levels of exposure to SARS-Cov-2. COVID-19 vaccine doses may only partly explain differences in the reinfection risk between these two groups. Furthermore, SARS-Cov-2 breakthrough infections investigated in this study predominantly occurred prior to the emergence of the Omicron wave. Consequently, our findings might not be directly transferable to Omicron variants and subsequent viral strains. Further investigation is warranted to assess the efficacy of both one and two doses of the COVID vaccine in preventing breakthrough infections associated with these newer variants among individuals with prior SARS-CoV-2 infections.
In conclusion, the risk of breakthrough infections was higher among previously infected individuals who received only one dose of the COVID-19 vaccine, providing evidence that one dose may not provide sufficient protection against reinfection compared to two doses.
Funding statement
Dr. Guo is currently supported by the National Cancer Institute of NIH under Award Number K07CA222343. Dr. Adekanmbi is supported by a research career development award K12HD052023: Building Interdisciplinary Research Careers in Women’s Health Program-BIRCWH; from the National Institutes of Health/Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD). Dr. Hsu is supported by a research career development award (K12AR084228–20S1: Building Interdisciplinary Research Careers in Women’s Health Program-BIRCWH; Berenson, PI) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
No financial disclosures were reported by the authors of this paper.
Footnotes
Ethics approval statement
This study was approved by the Institutional Review Board at University of Texas Medical Branch.
Patient consent statement
Not applicable.
Permission to reproduce material from other sources
Not applicable.
Clinical trial registration
Not applicable.
Conflict of interest disclosure
The authors have no conflict of interest to report.
Data availability statement
Data from Optum® de-identified COVID-19 Electronic Health Record dataset are available through Optum.com. The authors are not allowed to share data with any third party due to legal restrictions. For analytical data of individual beneficiaries, investigators need to sign a data reuse agreement following the procedure specified by Optum. The authors did not have any special access privileges that others would not have.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from Optum® de-identified COVID-19 Electronic Health Record dataset are available through Optum.com. The authors are not allowed to share data with any third party due to legal restrictions. For analytical data of individual beneficiaries, investigators need to sign a data reuse agreement following the procedure specified by Optum. The authors did not have any special access privileges that others would not have.