key: cord-0709355-fb6e8khp
authors: Butt, Adeel A; Yan, Peng; Shaikh, Obaid S; Mayr, Florian B; Omer, Saad B
title: Rate and Risk Factors for Severe/Critical Disease Among Fully Vaccinated Persons with Breakthrough SARS-CoV-2 Infection in a High-risk National Population
date: 2021-12-10
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab1023
sha: 6002ac5b9910cb9a7e2a9db8b53fb0373cd33471
doc_id: 709355
cord_uid: fb6e8khp

BACKGROUND: Breakthrough SARS-CoV-2 infections after vaccination have been reported. Outcomes among persons with breakthrough infection are poorly understood. METHODS: We identified all Veterans with a confirmed SARS-CoV-2 infection >14 days after the second dose of an mRNA vaccine between December 15, 2020 and June 30, 2021, and propensity-score matched unvaccinated controls with SARS-CoV-2 infection. Primary outcome was severe/critical disease, defined as admission to an intensive care unit, mechanical ventilation, or death within 28 days of diagnosis or during index hospitalization. RESULTS: Among 502,780 vaccinated and 599,974 unvaccinated persons, there were 2,332 (0.5%) breakthrough infections in the vaccinated group and 40,540 (6.8%) infections in the unvaccinated group over a follow up period of 69,083 person-days in each group. Among these groups, we identified 1,728 vaccinated persons with breakthrough infection (cases) and 1,728 propensity-score matched unvaccinated controls with infection. Among the former, 95 (5.5%) persons met the criteria for severe/critical disease, while 200 (11.6%) persons met the criteria among the latter group. Incidence rate for severe/critical disease per 1,000 person-days (95% CI) was 0.55 (0.45-0.68) among the former and 1.22 (1.07-1.41) among the latter group (P<0.0001). Risk was higher (HR, 95% CI) with increasing age (per 10-year increase 1.25; 1.11-1.41), and those with >4 comorbidities (2.85; 1.49-5.43), while being vaccinated was associated with strong protection against severe/critical disease (HR 0.41; 0.32-0.52). CONCLUSION: Rate of severe/critical disease is higher among older persons and those with >4 comorbidities, but lower among fully vaccinated persons with breakthrough infection compared with unvaccinated controls who develop infection.

A c c e p t e d M a n u s c r i p t 3 Effective vaccines against the SARS-CoV-2 infection are now available. The efficacy of the first two authorized vaccines, the Pfizer-BNT-162b2 and the Moderna-mRNA-1273 vaccines, in randomized phase 3 clinical trials was 94-95% in preventing symptomatic disease. [1, 2] In the real-world setting, effectiveness of these vaccines is similarly very high, consistently exceeding 90%. [3, 4] The Pfizer-BNT-162b2 vaccine retains high level of effectiveness even in the Alpha (previously known as the B1.1.7 variant) and Beta (previously known as the B1.351 variant) variants, with 89% effectiveness against the former and 75% effectiveness against the latter variant. [5] Current vaccines have also been found to be highly effective against the Delta (previously known as the B1.617 variant) variant, particularly in preventing severe and critical disease, though their effectiveness is somewhat lower compared with their effectiveness against the previous variants. [6] [7] [8] [9] [10] Despite such remarkable efficacy and effectiveness, breakthrough infections have been reported among fully vaccinated persons.

In a previous study, we found the rate of breakthrough infection among fully vaccinated persons to be 0.66 per 1,000 person-days after full vaccination. [11] In an earlier study of the Veterans in the United States, breakthrough infections were reported in 0.1% of the fully vaccinated Veterans. [12] However, certain subgroups are at a higher risk. These include older persons, those with multiple comorbidities, and residents of rural areas. [11] Clinical trials for vaccine efficacy have shown the vaccines to be highly protective against severe disease and death, with efficacy approaching 100% for these outcomes. [1, 2] However, the comparative severity of illness and outcomes in persons with breakthrough infection versus infection in unvaccinated persons in the real-world is not well known.

A recent report from skilled nursing facilities reported 22 breakthrough infections among 627 residents with SARS-CoV-2 infection over a 3 month period. Two-thirds of these persons were asymptomatic, A c c e p t e d M a n u s c r i p t 4 while 2 (9%) required acute hospitalization and one person died. [13] Our aim was to compare the rate of SARS-CoV-2 breakthrough infection among fully vaccinated persons, and to determine the rate of severe/critical disease among fully vaccinated persons who developed breakthrough infection compared with appropriately matched unvaccinated persons who developed infection. Identifying those at the highest risk of severe consequences of breakthrough infection is critical in optimal utilization of the approved and emerging therapeutic agents and improving outcomes.

This study was conducted in the United States Veterans Health Administration (VA) healthcare system. primary outcome was severe/critical disease, defined as admission to an intensive care unit, mechanical ventilation, or death within 28 days of the index positive test date or hospitalization (whichever was longer). Moderate disease was defined as admission to the hospital and/or need for supplemental oxygen, but no intensive care unit admission, mechanical ventilation, or death.

Baseline characteristics of persons with SARS-CoV-2 infection with and without prior vaccination were compared using Chi-squared test for categorical and students t-test for continuous variables. We determined the rate/1,000 person-days of severe/critical infection by various baseline characteristics.

We used Cox proportional hazards model to calculate the hazards ratios and 95% confidence intervals for factors associated with development of severe/critical disease. Assumptions for proportional hazards were checked using Schoenfeld residuals. For variables not meeting the proportional hazards assumptions, we stratified our analyses by those variables and conducted additional analyses after removing those variables.

A two-side p-value of <0.05 was considered statistically significant.

A c c e p t e d M a n u s c r i p t 7

The study was approved by the Institutional Review Board at VA Pittsburgh Healthcare System with waiver of informed consent requirement.

We identified 502,780 persons who had received both doses of vaccines. Among these, a total of 2,332 Among the vaccinated persons with breakthrough infection, median age was 71 (IQR 63-76) years, 93.9% were male, 23.4% were Black, and the mean body mass index (SD) was 30.2 (6.8) kg/m 2 . Among the unvaccinated controls who developed infection, the median age was 68 (IQR 60-74) years, 92.3% were male, 25.0% were Black, and the median body mass index (SD) was 30.6 (6.7) kg/m 2 . Comorbidities were more common among the vaccinated persons with breakthrough infection, but they were less likely to be symptomatic at baseline ( 

We also reanalyzed factors associated with severe/critical disease using a Cox proportional hazards model with individual comorbidities as covariates instead of a comorbidity count. Coronary artery A c c e p t e d M a n u s c r i p t 10 disease diagnosis did not meet the assumptions of proportional hazards; therefore, results were stratified by presence or absence of this diagnosis. In both models, vaccinated persons had a similarly low hazards of developing severe/critical disease as in the main model. (Supplementary table 4 

Since we did not have the data on variants of concern, we plotted the number of diagnosis during each Increasing age and presence of 4 or more comorbidities was independently associated with a higher risk of severe/critical illness. In analysis including individual comorbidities, chronic kidney disease and cancer diagnosis were associated with a higher risk of severe/critical disease. Lower antibody levels have been demonstrated in persons with chronic kidney disease on renal replacement therapy and those with hematologic malignancies and could at least partially explain this finding. [27] [28] [29] It also suggest higher vigilance for consequences of infection in these subgroups. Whether this is true for other populations and plays a part in mediating outcomes needs further study.

There are several strengths of this study, including a large national and geographically diverse population. The US Veterans population is an especially vulnerable population due to older age and a higher burden of comorbidities. Effectiveness of vaccination in reducing the risk of severe/critical disease in persons with breakthrough infections is particularly reassuring and suggestive of an even larger benefit in the general population. However, certain limitations of our study should be noted. We did not study the effect of different variants of concern upon outcomes. However, we have previously shown that the Pfizer-BNT162b2 vaccine has an effectiveness of 89.5% against the Alpha variant and 74.5% against the Beta variant. The vaccine is nearly 100% effective in preventing critical illness or death against these variants. [5] More recent data have also demonstrated the effectiveness of current vaccines against the Delta variant, with two doses of the Pfizer-BNT-162b2 and the Oxford-AstraZeneca vaccines being 93.7% and 67% protective against symptomatic infection by the delta variant. [8, 30] A c c e p t e d M a n u s c r i p t 13 Since we only included persons vaccinated with the approved mRNA vaccines, our data cannot be extrapolated to persons vaccinated with other vaccines.

Our population was predominantly male and older, with a higher burden of comorbidities than the general population. This may limit the generalizability of our findings to the larger population. However, demonstration of effectiveness in this high-risk population is critically important in reassuring that the general population may have at least similar level of response.

In conclusion, we found that the rate of severe/critical disease is significantly lower among those with breakthrough infection after vaccination compared with infection in unvaccinated persons. These data further underscore the importance of vaccination in response to the SARS-CoV-2 global pandemic. M a n u s c r i p t A c c e p t e d M a n u s c r i p t 22 

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting

National Study Group for, C-V. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants

Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant -National Healthcare Safety Network

Effectiveness of inactivated SARS-CoV-2 vaccines against the Delta variant infection in Guangzhou: a test-negative casecontrol real-world study

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Table 3. Factors associated with severe/critical disease (multivariable Cox proportional hazards analysis). Hazards ratio (95% CI)

Comorbidities (comparator: None)

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t