key: cord-0874663-ejvl1930
authors: Butt, Adeel A; Talisa, Victor B; Yan, Peng; Shaikh, Obaid S; Omer, Saad B; Mayr, Florian B
title: Vaccine Effectiveness of Three vs. Two Doses of SARS-CoV-2 mRNA Vaccines in a High Risk National Population
date: 2022-03-04
journal: Clin Infect Dis
DOI: 10.1093/cid/ciac178
sha: 09de416560589c75279e398ec3851ac87fb569b7
doc_id: 874663
cord_uid: ejvl1930

BACKGROUND: Knowledge of the vaccine effectiveness (VE) of a third or booster vaccine dose in preventing SARS-CoV-2 infection or its consequences is critical in developing recommendations for their use. We determined the relative VE of a three vs. two doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease. METHODS: Among Veterans who had received two doses of an mRNA vaccine by April 30, 2021 we identified those who received a third dose of the same vaccine between September 22 and November 24, 2021 and 1:1 matched controls who had not received their third dose by then. Using Cox proportional hazards model, we calculated adjusted hazards ratios for symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2 positive test. RESULTS: Among 2,321,366 Veterans who received two doses of BNT162b2 or mRNA1273 vaccine by April 30, 2021, we matched 395,686 persons who received a third dose of the same vaccine between September 22 and November 24, 2021, to controls who did not receive a third dose. Adjusted hazards ratios (95% CI) were 0.15 (0.11-0.21) for symptomatic infection and 0.18 (0.13-0.26) for hospitalizations for 3 vs. 2 doses, corresponding to relative VE of 85% and 82%. Five ICU admissions or deaths were observed (4 among recipients of two doses). There was no difference in VE between BNT162b2 vs. mRNA1273 recipients. CONCLUSION: Third dose of a SARS-CoV-2 mRNA vaccine is associated with high VE against symptomatic infection, hospitalization, and critical disease in the pre-Omicron era.

M a n u s c r i p t 5 Several vaccines against the SARS-CoV-2 infection are now available and are highly effective in preventing asymptomatic and symptomatic infection, moderate, severe, or critical disease, and death. [1] [2] [3] [4] [5] [6] However, vaccine effectiveness wanes over time, particularly against asymptomatic infection. [7, 8] Persons who receive a third dose of the vaccine 5 or more months after the second dose have a lower risk of infection and infection-related outcomes compared with those who receive only two doses. [9] [10] [11] Vaccine effectiveness of a booster dose has been studied primarily in Israel, where the third dose was authorized before other countries. These studies often lack data on key comorbidities and represent a population which is demographically different from the population in the United States. In a just published report from the US, the adjusted odds ratio for 3 vaccine doses of an mRNA vaccine vs 2 doses was 0.16 for the Delta variant for symptomatic infection, corresponding to an 84% vaccine effectiveness in preventing symptomatic infection. [12] Veterans enrolled in the Department of Veterans Affairs Healthcare System (the VA) in the United States represent a high-risk national population due to older age and a high burden of comorbidities than the national population. [13, 14] Despite these differences, vaccine effectiveness among Veterans who received two doses of an mRNA vaccine remains high. [5, 15] We sought to determine the effectiveness of a third dose of the same mRNA vaccine five or more months after the second dose in preventing documented infection, moderate disease, or severe/critical disease in the national VA population.

The data sources used for this study have been previously described. [5, 14] Briefly, we used the VA COVID-19 Shared Data Resource for the current study, which was created by the VA in response to A c c e p t e d M a n u s c r i p t 6 the SARS- CoV-2/COVID-19 pandemic and contains information on all Veterans with a confirmed   laboratory diagnosis of SARS-CoV-2 infection within the VA and those who tested outside the VA   with a VA clinical note confirming the diagnosis. Updated regularly, the VA COVID-19 Shared Data Resource contains extensive demographic, clinical, pharmacologic, laboratory, vital signs and clinical outcomes information which is derived from multiple validated sources including the Corporate Data Warehouse and the VA electronic medical records.

For the current study, we identified Veterans in the VA COVID-19 Shared Data Resource who had received two doses of an mRNA vaccine (either BNT162b2 or mRNA1273) by April 30, 2021 and had at least 2 primary-care appointments in the preceding 18 months of vaccine rollout because these individuals are more likely to receive care through the VA. We excluded those who had died, had a positive nasopharyngeal swab PCR for SARS-CoV-2, or received a third dose of the vaccine before and widely used score that identifies persons at the highest risk for mortality over a period of time based on the presence and severity of comorbidities. [16, 17] For vaccination site, we used the VA facility where the second dose of the vaccine was administered to account for geographic variation in vaccination, testing patterns, and regional differences in community transmission. Data retrieved included demographic characteristics, clinical diagnoses, presence of symptoms at presentation, anthropometric measurements, and select laboratory results. Comorbidities were defined according to the definitions used in the VA Corporate Data Warehouse, which uses the International Classification of Diseases (Ninth or 10th Revision, as appropriate) for classifying comorbidities. [18] [19] [20] These definitions have been used in numerous previous publications related to SARS-CoV-2 infection. [5, [18] [19] [20] [21] [22] [23] [24] Baseline diagnoses included all diagnoses recorded in the 2 years before the index date. 

Using an unadjusted Poisson regression accounting for follow-up time, we estimated the incidence rate/10,000 person-weeks by various baseline characteristics among those with and without the third vaccine dose. Adjusted hazard ratios (HR adj ) comparing 3 doses to 2 doses for each outcome (and 95% confidence intervals) were estimated using Cox proportional hazards models adjusted for A c c e p t e d M a n u s c r i p t 8 all variables used for matching except the time of matching. Vaccine effectiveness (VE) was calculated as . Where p-values were used to compare variables, a two-side p-value of <0.05 was considered statistically significant.

We used Kaplan-Meier curves to demonstrate the probability of remaining event-free for each group. Test of equality among strata was determined by using log-rank p-values, with a p value < 0.05 considered statistically significant.

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

We Kaplan-Meier curves demonstrated that the probability of remaining free of symptomatic infection and hospitalization was significantly higher among those who received three doses compared with A c c e p t e d M a n u s c r i p t 10 those who received only two doses of the vaccine (log-rank p-value <0.001 for both). There was no difference among recipients of BNT-162b2 vs. the mRNA1273 vaccine for documented infection (logrank p-value 0.40) or hospitalization (log-rank p-value 0.08). (Figure 3 )

In this large national retrospective study, we demonstrate that a third dose of an mRNA vaccines is highly effective preventing PCR-confirmed symptomatic infection, acute care hospitalization, and severe/critical disease over a short term follow up.

There is strong evidence that immunity wanes over time after two doses of an mRNA vaccine. [7, 8] In key studies, vaccine effectiveness dropped to less than 25% against confirmed infection, and to less than 60% against severe/critical disease, after 6 months of receiving the second dose. [7] A third dose of the vaccine five or more months after the second dose is associated with a sharp increase in the antibody levels and reduced risk of symptomatic and severe infection and mortality. [10, 11, 25] Previous vaccine effectiveness studies of a third dose of the vaccine are often limited by a lack of information on comorbidities, or are in a demographically different population than the US. We found that the overall vaccine effectiveness was 85% against documented infection, and 82% against moderate disease (hospitalization). There were no severe/critical disease events among those who received three doses. Our study provides robust estimates of incidence and effectiveness in a large national population at a particularly high risk of infection and adverse outcomes after infection. Our study groups are also well matched demographically and clinically to provide assurance regarding the results.

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

Among population subgroups, we found the vaccine effectiveness against symptomatic infection to be consistently above 80% among those younger or older than 70 years, among Whites and Blacks, among those with a body mass index of less or more than 30 kg/m 2 , and among those with a Charlson Comorbidity Index score of less or more than 2. Infection among older persons, those with higher body mass index and those with a higher burden of comorbidities has been associated with poor clinical outcomes. [22, 26] Our study provides assurance regarding the effectiveness of a third dose in preventing infection among these high risk strata.

Several previous studies have suggested higher vaccine effectiveness with the mRNA1273 vaccine compared with the BNT162b2 vaccine. [15, 27] Various reasons have been suggested for these differences, including difference in dose and interval between first and second dose of the vaccine.

Whether inherent differences among the two types of vaccines play any part is not known. In our study, we did not find any difference in vaccine effectiveness against symptomatic infection or hospitalization among the two vaccines.

The strengths of our study include a large national population with validated data extracted over the duration of the pandemic. We used established methods to construct the cohort and the comparison groups, and to determine the risk of outcome events. Several limitations also need to be noted when interpreting our data. We retrospectively analyzed existing data, with the associated limitations inherent in such analyses. The most notable limitation is the lack of information on vaccine effectiveness against the Omicron variant, which was not in circulation during the study period. The overwhelming variant during the study period was the Delta variant.

[28] We accounted for the geographic and temporal variations in testing and immunization pattern by matching the A c c e p t e d M a n u s c r i p t 12 groups for testing facility and time of vaccination. Finally, the follow-up time after the third dose was short, and longer term effectiveness of a third dose needs to be determined in longer-term studies.

In conclusion, a third dose of an mRNA vaccine is highly effective in preventing symptomatic infection as well as acute care hospitalizations in the short term compared with a two-dose regimen.

Whether the effectiveness of a three dose regimen will be long-lasting, and the effect of the introduction of the Omicron variant in this high-risk population need further study. This study used data created and maintained by the Veterans Health Administration, Department of Veterans Affairs. These data are freely available to approved individuals upon fulfilling the specified requirements.

 Design and conduct of the study: None A c c e p t e d M a n u s c r i p t

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Age in years; median (IQR) 73 (66,77) 789 (72%)

BNT-162b2

A c c e p t e d M a n u s c r i p t Note: There were no COVID-related ICU or death events among recipients of three doses.