Association of COVID-19 Vaccination With SARS-CoV-2 Infection in Patients With Cancer: A US Nationwide Veterans Affairs Study

Key Points

Question  What is the effectiveness of SARS-CoV-2 vaccination in patients with cancer?

Findings  In this cohort study of US Veterans Affairs patients who received systemic therapy for cancer between August 15, 2010, and May 4, 2021, a proxy measure for effectiveness of the vaccine starting 14 days after the second dose was 58%. The measure of effectiveness starting 14 days after the second dose was 85% in patients who had not received systemic therapy within the 6 months prior to vaccination and 76% among those receiving hormonal treatment.

Meaning  Results suggest that SARS-CoV-2 vaccination associated with lower infection rates in patients with cancer, especially in those not receiving current systemic therapy and those receiving hormonal treatment.

Importance  Patients with cancer are at increased risk for severe COVID-19, but it is unknown whether SARS-CoV-2 vaccination is effective for them.

Objective  To determine the association between SARS-CoV-2 vaccination and SARS-CoV-2 infections among a population of Veterans Affairs (VA) patients with cancer.

Design, Setting, and Participants  Retrospective, multicenter, nationwide cohort study of SARS-CoV-2 vaccination and infection among patients in the VA health care system from December 15, 2020, to May 4, 2021. All adults with solid tumors or hematologic cancer who received systemic cancer-directed therapy from August 15, 2010, to May 4, 2021, and were alive and without a documented SARS-CoV-2 positive result as of December 15, 2020, were eligible for inclusion. Each day between December 15, 2020, and May 4, 2021, newly vaccinated patients were matched 1:1 with unvaccinated or not yet vaccinated controls based on age, race and ethnicity, VA facility, rurality of home address, cancer type, and treatment type/timing.

Exposures  Receipt of a SARS-CoV-2 vaccine.

Main Outcomes and Measures  The primary outcome was documented SARS-CoV-2 infection. A proxy for vaccine effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared with unvaccinated controls.

Results  A total of 184 485 patients met eligibility criteria, and 113 796 were vaccinated. Of these, 29 152 vaccinated patients (median [IQR] age, 74.1 [70.2-79.3] years; 95% were men; 71% were non-Hispanic White individuals) were matched 1:1 to unvaccinated or not yet vaccinated controls. As of a median 47 days of follow-up, 436 SARS-CoV-2 infections were detected in the matched cohort (161 infections in vaccinated patients vs 275 in unvaccinated patients). There were 17 COVID-19–related deaths in the vaccinated group vs 27 COVID-19–related deaths in the unvaccinated group. Overall vaccine effectiveness in the matched cohort was 58% (95% CI, 39% to 72%) starting 14 days after the second dose. Patients who received chemotherapy within 3 months prior to the first vaccination dose were estimated to have a vaccine effectiveness of 57% (95% CI, –23% to 90%) starting 14 days after the second dose vs 76% (95% CI, 50% to 91%) for those receiving endocrine therapy and 85% (95% CI, 29% to 100%) for those who had not received systemic therapy for at least 6 months prior.

Conclusions and Relevance  In this cohort study, COVID-19 vaccination was associated with lower SARS-CoV-2 infection rates in patients with cancer. Some immunosuppressed subgroups may remain at early risk for COVID-19 despite vaccination, and consideration should be given to additional risk reduction strategies, such as serologic testing for vaccine response and a third vaccine dose to optimize outcomes.

Although patients with cancer have poor COVID-19–related outcomes,^1-4 the effectiveness of SARS-CoV-2 vaccination in this population is unclear because they were excluded from vaccination trials.^5,6 Recent studies suggest that patients with cancer mount less robust antibody responses to vaccination than immunocompetent controls.^7-10 The objective of this retrospective cohort study in the national Veterans Affairs (VA) health care system was to estimate the SARS-CoV-2 vaccination effectiveness in patients with cancer in a real-world setting during the 140-day period following initial vaccine availability.

Patients were included if they were administered cancer-directed therapy within 7 days before or after a solid tumor or hematologic cancer International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code during August 15, 2010, to May 4, 2021, and were alive without documented SARS-CoV-2 infection prior to vaccine availability on December 15, 2020 (eFigure 1 in the Supplement). Patients were excluded if they were vaccinated with Janssen/Johnson & Johnson Ad26.COV2.S or were not regular VA users (eMethods in the Supplement). This study was approved by the VA Boston Healthcare System Research and Development Committee and received a waiver of informed consent because the study presented minimal risk and could not practicably be conducted without a waiver.

Vaccinated patients were matched 1:1 to unvaccinated controls using a previously described approach designed to emulate a randomized clinical trial.¹¹ The purpose of this procedure is to reduce bias by matching vaccinated patients to unvaccinated patients who had a similar probability of vaccination and SARS-CoV-2 exposure but had not yet been vaccinated.

For each day from December 15, 2020, to May 4, 2021, every newly vaccinated patient was matched with a patient not yet vaccinated. Patients who had a positive SARS-CoV-2 test result prior to vaccination date or matching as control were excluded. Follow-up time was censored by the earliest of the following: vaccination (for unvaccinated controls), vaccination of the matched control (for vaccinated patients), end of study period, or death.

Matching was based on factors potentially associated with SARS-CoV-2 vaccination and exposure to SARS-CoV-2, specifically age, race and ethnicity, VA facility, rurality of home address, cancer type, and treatment type/timing. We used minimum distance matching for age and exact matching for the others (see eMethods, eFigure 6, and eTable 13 in the Supplement for matching algorithm and variable definition details).

The primary outcome was reverse transcriptase–polymerase chain reaction or antigen-confirmed SARS-CoV-2 infection. Secondary outcomes included COVID-19–related death, or death within 4 weeks of COVID-19 diagnosis (eMethods in the Supplement). A proxy measure of vaccine effectiveness was defined as 1 minus the risk ratio of SARS-CoV-2 infection for vaccinated individuals compared with unvaccinated controls. For example, if there were 10 cases out of 100 among the unvaccinated, a vaccine effectiveness of 90% would mean there was 1 case among the vaccinated. The Fine-Gray subdistribution hazard function was used to measure risk. Statistical analysis is detailed in eMethods in the Supplement. Subgroup analyses were determined a priori based on potential association with vaccine effectiveness: solid tumor vs hematologic cancer, time from last treatment, and type of treatment received.

Among 184 485 eligible patients, 113 796 (62%) were vaccinated during the study period (eFigure 1 in the Supplement). Of these, 29 152 vaccinated patients (median [IQR] age, 74.1 [70.2-79.3] years; 95% were men; 71% were non-Hispanic White individuals) were matched 1:1 to 29 152 unvaccinated controls. Among 109 338 patients who received the first vaccine dose and had at least 28 days of follow-up, 106 109 (97%) received a second dose. For analysis of second dose vaccine effectiveness, 18 312 pairs were included. Baseline demographics of the unmatched and matched cohorts are shown in eTables 1 and 2 in the Supplement.

As of a median 47 days of follow-up, 436 SARS-CoV-2 infections were detected in the matched cohort (161 infections in vaccinated patients vs 275 in unvaccinated patients). There were 17 COVID-19–related deaths in the vaccinated group vs 27 COVID-19–related deaths in the unvaccinated group.

Figure 1 shows cumulative incidence of SARS-CoV-2 infection in the full matched cohort. Estimated overall vaccine effectiveness following first dose was 42% (95% CI, 28% to 53%). The difference in infections between the vaccinated and unvaccinated cohorts remained near zero in the 2 weeks following the first dose, when immunity is building. Both messenger RNA vaccines had similar effectiveness (eFigure 2 in the Supplement).

The Table shows estimated vaccine effectiveness in the period starting 14 days after the second dose in the overall cohort and predetermined subgroups (additional time periods in eTable 3 in the Supplement). Overall effectiveness in this period was 58% (95% CI, 39% to 73%). Effectiveness estimates were higher among patients with solid tumors (effectiveness starting 14 days after the second dose, 66%; 95% CI, 48% to 79%) than hematologic cancers (19%; 95% CI, −68% to 65%) (eFigure 3, eTables 4 and 5 in the Supplement). Patients who last received systemic therapy more than 6 months before vaccination exhibited effectiveness of 85% starting 14 days after the second dose (95% CI, 29% to 100%), vs 63% (95% CI, 23% to 87%) among patients whose last therapy was 3 to 6 months prior and 54% (95% CI, 28% to 72%) in patients who received therapy within 3 months prior (eFigure 4, eTables 6-9 in the Supplement).

Figure 2 shows the cumulative incidence of SARS-CoV-2 infection in patients who received chemotherapy-containing regimens vs endocrine therapy within 3 months before vaccination (additional treatment types in eFigure 5 in the Supplement). Vaccination appears less effective for patients receiving chemotherapy (effectiveness starting 14 days after the second dose, 57%; 95% CI, –23% to 91%) vs endocrine therapy (76%; 95% CI, 50% to 91%) (eTables 10-12 in the Supplement).

Vaccination in VA patients with cancer is effective at reducing the incidence of SARS-CoV-2 infection. Fewer COVID-19–related deaths were observed in vaccinated than in unvaccinated patients, although estimation of vaccine effectiveness for death is limited by low event rates. Our study is the first, to our knowledge, to demonstrate vaccine effectiveness against SARS-CoV-2 infection in patients with cancer.

Vaccine effectiveness may decrease with age,^11,12 and malignancy and anticancer treatments may be immunosuppressive.^7-10,13,14 These factors may account for the reduced effectiveness we observe among some patients with cancer vs effectiveness reported in the general population recently estimated to be 89% to 92%.^11,12 Notably, in our study, vaccine effectiveness in patients receiving endocrine therapy and those last receiving therapy more than 6 months before vaccination was similar to general population estimates. We independently identify previously demonstrated risk factors for poor vaccination response. Hematologic cancers and immunosuppressive therapies are associated with reduced antibody response to vaccination^7-10,13,14 and lower effectiveness in our study. Our findings suggest that high-risk populations may benefit from additional mitigation measures, such as extended masking. Data from other immunosuppressed populations suggest that a third vaccine dose may improve effectiveness¹⁵; additional work is needed to determine efficacy of a similar approach in patients with cancer, particularly those who were vaccinated during active treatment.

This study has limitations. Owing to limited power, we cannot robustly assess vaccination effectiveness against severe COVID-19 and COVID-19–related deaths. However, we found a reduction in SARS-CoV-2 infections, suggesting that vaccines mitigate against these important outcomes. An in-study comparison of patients with cancer with patients without cancer is not possible because the latter were not included. Because veterans may receive care outside the VA, exposure to vaccination, SARS-CoV-2, and covariates may be misclassified. However, the cohort included only patients receiving cancer care within the VA to reduce potential for missing data and matched on a wide range of factors associated with likelihood of vaccination and SARS-CoV-2 exposure. Reassuringly, the matched vaccinated and unvaccinated cohorts demonstrated similar rates of infection until day 14, when antibody-mediated immunity begins. This early period serves as a negative control that demonstrates the robustness of our matching.

In this cohort study, COVID-19 vaccination was associated with lower risk of SARS-CoV-2 infections in patients with cancer in a real-world setting. Additional studies including a different patient population with longer follow-up period will be valuable, as will studies to delineate optimal vaccination regimen and administration relative to cancer and treatment type.

Accepted for Publication: September 1, 2021.

Published Online: December 2, 2021. doi:10.1001/jamaoncol.2021.5771

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wu JTY et al. JAMA Oncology.

Corresponding Author: Nathanael R. Fillmore, PhD, VA Boston Healthcare System; Dana-Farber Cancer Institute; Harvard Medical School, 150 S Huntington Ave, Boston, MA 02141 (nathanael.fillmore@va.gov).

Author Contributions: Dr Fillmore had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wu, La, Lin, Munshi, and Fillmore contributed equally.

Concept and design: Wu, La, Branch-Elliman, Han, Brophy, Do, Lin, Munshi, Fillmore.

Acquisition, analysis, or interpretation of data: Wu, La, Branch-Elliman, Huhmann, Parmigiani, Tuck, Brophy, Lin, Munshi, Fillmore.

Drafting of the manuscript: Wu, La, Branch-Elliman, Lin, Munshi, Fillmore.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: La, Huhmann, Parmigiani, Fillmore.

Obtained funding: Brophy.

Administrative, technical, or material support: Huhmann, Do, Lin.

Supervision: Wu, Han, Brophy, Do, Lin, Munshi, Fillmore.

Conflict of Interest Disclosures: Dr Branch-Elliman reported receiving grants (site PI for multicenter study) from Gilead Sciences and funds to institution and grants from VA Health Services Research and Development Service outside the submitted work. Dr Parmigiani reported being a cofounder of Phaeno Inc, which is pursuing novel technologies for full-length sequencing of RNA molecules. Dr Brophy reported receiving nonfinancial support from the VA Cooperative Studies Program during the conduct of the study. Dr Lin reported receiving grants from the Department of Defense outside the submitted work. Dr Munshi reported receiving personal fees from Bristol Myers Squibb, Janssen, Amgen, Takeda, OncoPep, AbbVie, Karyopharm, Novartis, Legend, Raqia, Adaptive Biotechnology, and Pfizer outside the submitted work; in addition, Dr Munshi had a patent for OncoPep licensed; and held stocks in C4 Therapeutics. No other disclosures were reported.

Funding/Support: This work was supported by the Stanford Cancer Institute Innovation Award, SPO #216151 (Dr Wu), the VA Office of Research and Development, Cooperative Studies Program (Drs La, Huhmann, Brophy, Do, and Fillmore), the Department of Defense (Dr Lin), the VA Merit Review Award 1I01BX001584 (Dr Munshi), National Institutes of Health grants P01-155258-07 and P50-100707 (Dr Munshi), and the American Heart Association CAT-HD Center grant No. 857078 (Dr Fillmore).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government.

Additional Information: All data used in this study are available to any VA investigator upon relevant research approvals through the VA Corporate Data Warehouse and VA COVID-19 Shared Data Resource.