Risk of herpes zoster reactivation after messenger RNA COVID-19 vaccination: A cohort study
Authors: Morgan Birabaharan, David C. Kaelber, Maile Y. Karris
Journal: Journal of the American Academy of Dermatology (2021)

To the Editor: Recent case series and media coverage suggest an association between receiving the messenger RNA (mRNA) COVID-19 vaccine and reactivation of the varicella zoster virus (VZV).1McMahon D.E. Amerson E. Rosenbach M. et al.Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.J Am Acad Dermatol. 2021; 85: 46-55Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar, 2Furer V. Zisman D. Kibari A. Rimar D. Paran Y. Elkayam O. Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series.Rheumatology (Oxford). 2021; 60: SI90-SI95Crossref PubMed Scopus (121) Google Scholar, 3Rodríguez-Jiménez P. Chicharro P. Cabrera L.M. et al.Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: report of 5 cases.JAAD Case Rep. 2021; 12: 58-59Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Fear of a potential adverse effect will drive vaccine refusal and subsequent preventable disease and death. The purpose of the present investigation is to evaluate the relationship between mRNA COVID-19 vaccination and VZV reactivation. We performed a retrospective cohort study using the TriNetX Analytics Network (TriNetX, LLC), a federated health research network that aggregates health records from 63 health care organizations comprising 70 million patients. We included patients aged ≥18 years who received the mRNA COVID-19 vaccine either as the first or the second dose between December 15, 2020 and July 15, 2021 (Supplemental Material, available via Mendeley at https://data.mendeley.com//datasets/trkg3zfr5f/1). Herpes zoster reactivation (code B02; International Classification of Diseases, Tenth Edition) related to mRNA COVID-19 vaccine administration was defined as occurring within 28 days.4Klompas M. Kulldorff M. Vilk Y. Bialek S.R. Harpaz R. Herpes zoster and postherpetic neuralgia surveillance using structured electronic data.Mayo Clin Proc. 2011; 86: 1146-1153Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar A control population was established, comprising persons in the database diagnosed with acne, viral wart, melanocytic nevi, dry skin, lipoma, skin cysts, or seborrheic keratosis and who had no history of COVID-19 vaccination (Supplemental Material). Because persons may have received a COVID-19 vaccination at a location outside of the health care organizations participating in the database, we split our control population into 2 cohorts. The first (historical) control cohort comprised individuals who received the aforementioned diagnoses between January 1, 2020 and December 1, 2020 to establish a cohort wherein COVID-19 vaccination was not readily available. A second (contemporary) control cohort comprised individuals diagnosed between December 15, 2020 and July 15, 2021, to parallel study cohort, and to account for possible seasonal variation in VZV incidence.5Gallerani M. Manfredini R. Seasonal variation in herpes zoster infection.Br J Dermatol. 2000; 142: 588-589Crossref PubMed Scopus (27) Google Scholar We balanced cohorts using 1:1 greedy nearest neighbor propensity score matching by age, sex, race, ethnicity, HIV status, malignancy, use of antineoplastics, use of immunosuppressants, and receipt of shingles vaccine. Using the matched cohorts, we calculated the relative risk of herpes zoster in the 28 days after index events in the respective cohorts. All statistical analyses were performed within TriNetX. We identified 1,306,434 persons who received a dose of the mRNA COVID-19 vaccine. The mean age of patients in the mRNA COVID-19 vaccine cohort was 55.1 years (SD, 18.5), 57% were female, 14% were Black, 65% were White, 11% were Hispanic or Latino, and 6% were Asian. Prior to matching, the crude incidence of VZV reactivation within 28 days of mRNA vaccination was 0.1% (1228 of 1,306,434 patients). After 1:1 propensity-matching, demographic and clinical characteristics were balanced (SD <0.1). No difference in VZV reactivation was observed among persons receiving the mRNA COVID-19 vaccine within 28 days compared to both the historical cohort (relative risk, 0.91; 95% CI, 0.82-1.01) and the contemporary cohort (relative risk, 0.98; 95% CI, 0.87-1.11) (Table I).Table IRisk of varicella zoster virus reactivation after messenger RNA COVID-19 vaccinationCohortPersons in cohortPersons with VZV reactivationRisk (per 1000 person-years)∗Risk per 1000 person-years were calculated as followed: (persons with VZV reactivation)/[(Persons in cohort) × (28/365)] × 1000).Risk ratio, 95% CImRNA COVID-19 vaccination vs historical cohort†The first (historical) control cohort comprised individuals who received a diagnosis of acne, viral wart, melanocytic nevi, dry skin, lipoma, skin cysts, or seborrheic keratosis between January 1, 2020 and December 1, 2020 and who had no history of COVID-19 vaccination to establish a cohort wherein COVID-19 vaccination was not readily available.555,256673160.91 (0.82-1.01)555,25674017mRNA COVID-19 vaccination vs contemporary cohort‡A second (contemporary) control cohort comprised of individuals diagnosed between December 15, 2020 and July 15, 2021 to account for possible seasonal variation in VZV incidence.359,789492180.98 (0.87-1.11)359,78950118The relative risk compares the risk of VZV reactivation within 28 days after mRNA COVID-19 vaccination against persons in control cohorts after matching for age, sex, race, ethnicity, HIV, malignancy, use of antineoplastics, use of immunosuppressants, and receipt of shingles vaccine. The diagnoses in the control cohorts were determined upon by authors to be conditions that do not have a known relationship to VZV reactivation. Multiple diagnoses were included to help increase cohort size for robust propensity-matching.HIV, Human immune deficiency virus; mRNA, messenger RNA; VZV, varicella zoster virus.∗ Risk per 1000 person-years were calculated as followed: (persons with VZV reactivation)/[(Persons in cohort) × (28/365)] × 1000).† The first (historical) control cohort comprised individuals who received a diagnosis of acne, viral wart, melanocytic nevi, dry skin, lipoma, skin cysts, or seborrheic keratosis between January 1, 2020 and December 1, 2020 and who had no history of COVID-19 vaccination to establish a cohort wherein COVID-19 vaccination was not readily available.‡ A second (contemporary) control cohort comprised of individuals diagnosed between December 15, 2020 and July 15, 2021 to account for possible seasonal variation in VZV incidence. Open table in a new tab The relative risk compares the risk of VZV reactivation within 28 days after mRNA COVID-19 vaccination against persons in control cohorts after matching for age, sex, race, ethnicity, HIV, malignancy, use of antineoplastics, use of immunosuppressants, and receipt of shingles vaccine. The diagnoses in the control cohorts were determined upon by authors to be conditions that do not have a known relationship to VZV reactivation. Multiple diagnoses were included to help increase cohort size for robust propensity-matching. HIV, Human immune deficiency virus; mRNA, messenger RNA; VZV, varicella zoster virus. Herein our data suggest mRNA COVID-19 vaccination is not associated with increased rates of VZV reactivation. We hope this reassures patients and the providers caring for them. Our analysis is limited by potential misclassification bias, which is inherent in the use of diagnostic codes. In addition, persons may have developed herpes zoster, but did not seek care. Lastly, we cannot ascertain the completeness of records, particularly the rates of shingles vaccination. None declared.