MAJOR ARTICLE Real-World Effectiveness of Shingrix • CID 2021:73 (15 September) • 941 Clinical Infectious Diseases Received 19 November 2020; editorial decision 5 February 2021; published online 13 February 2021. Correspondence: Hector S. Izurieta, OVRR/CBER/FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993 (Hector.izurieta@fda.hhs.gov). Clinical Infectious Diseases ® 2021;73(6):941–8 Published by Oxford University Press for the Infectious Diseases Society of America 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciab125 Recombinant Zoster Vaccine (Shingrix): Real-World Efectiveness in the First 2 Years Post-Licensure Hector S. Izurieta, 1 Xiyuan Wu, 2 Richard Forshee, 1 Yun Lu, 1 Heng-Ming Sung, 2 Paula Ehrlich Agger, 1 Yoganand Chillarige, 2 Ruth Link-Gelles, 3, Bradley Lufkin, 2 Michael Wernecke, 2 Thomas E. MaCurdy, 2,4 Jeffrey Kelman, 5 and Kathleen Dooling 3 1 Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA; 2 Acumen LLC, Burlingame, California, USA; 3 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA; 4 Department of Economics, Stanford University, Stanford, California, USA; and 5 Centers for Medicare & Medicaid Services, Washington, DC, USA (See the Major Article by Sun et al on pages 949–56 and the Editorial Commentary by Harpaz on pages 957–60.) Background. Shingrix (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as 2 doses given 2–6 months apart among adults aged ≥50 years. Clinical trials yielded efcacy of >90% for confrmed herpes zoster, but post-market performance has not been evaluated. Efcacy of a single dose and a delayed second dose and efcacy among persons with autoimmune or immunosuppres- sive conditions have not been studied. We aimed to assess post-market vaccine efectiveness of Shingrix. Methods. We conducted a cohort study among Medicare Part D community-dwelling benefciaries aged >65 years. Herpes zoster was identifed using a medical ofce visit diagnosis with treatment, and postherpetic neuralgia was identifed using a valid- ated algorithm. We used inverse probability of treatment weighting to improve cohort balance and marginal structural models to estimate hazard ratios. Results. We found a vaccine efectiveness of 70.1% (95% confdence interval [CI], 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for 2 and 1 doses, respectively. Te 2-dose vaccine efectiveness was not signifcantly lower for benefciaries aged >80 years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. Te vaccine was also efective among individuals with immunosuppressive conditions. Two-dose vaccine efectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4–81.8). Conclusions. Tis large real-world observational study of the efectiveness of Shingrix demonstrates the beneft of completing the 2-dose regimen. Second doses administered beyond the recommended 6 months did not impair efectiveness. Our efectiveness estimates were lower than the clinical trials estimates, likely due to diferences in outcome specifcity. Keywords. herpes zoster vaccine; vaccine efectiveness; Shingrix vaccine; Medicare; real-world evidence. Shingrix, an adjuvanted recombinant zoster vaccine (RZV), was licensed in the United States in October 2017 for the prevention of herpes zoster (HZ) in adults aged ≥50 years [1–4]; it is adminis- tered intramuscularly as a series of two 0.5-mL doses 2–6 months apart [3]. Age and immunosuppression are major risk factors for HZ; the increased incidence in older individuals appears to be related to declines in varicella zoster virus immunity. Safety, immunogenicity, and efcacy of RZV were evaluated in 2 large randomized, placebo-controlled studies [5, 6]. Tese clinical trials included only generally healthy, immunocompetent persons. Efcacy estimates were derived from a cohort who received 2 doses on a 0- and 2-month schedule. HZ case confrmation was prima- rily determined by polymerase chain reaction (PCR). In study 1, among 14 759 participants aged ≥50 years, with median follow-up of 3.1 years, vaccine efcacy against confrmed HZ was 97.2% (95% confdence interval [CI], 93.7–99.0) [3]. In study 2 (13 163 partici- pants aged ≥70 years, median follow-up of 3.9 years), vaccine ef- cacy was 89.8% (95% CI, 84.2–93.7) [3]. Efcacy against HZ and postherpetic neuralgia (PHN) were evaluated in a pooled analysis using data from participants aged ≥70 years from both studies: ef- fcacy against HZ and PHN was 91.3% (95% CI, 86.9–94.5) and 88.8% (95% CI, 68.7–97.1), respectively. In an RZV schedule-fnding study, antibody concentrations afer a dose interval of 6 months were noninferior to those afer a 2-month interval; responses afer a 12-month interval were too varied to meet the noninferiority criteria [7]. Although the Centers for Disease Control and Prevention (CDC) clinical guidance [2] advised recipients not to restart the series if more than 6 months had elapsed since the frst dose, RZV efcacy administered at inter- vals greater than 2 months had not been studied [7, 8]. Because post-market vaccine performance has not been inves- tigated and to address important unanswered questions that could inform programmatic and regulatory actions relating to Shingrix vaccination, we conducted an observational study to assess: vac- cine efectiveness (VE) afer only 1 dose; VE when the second dose is administered >6 months afer the frst; VE among persons who