PROJECT SUMMARY/ABSTRACT Herpes zoster (HZ, or shingles) is a major cause of morbidity, affecting one in three Americans during their lifetime. HZ can be particularly devastating when it involves the eye (herpes zoster ophthalmicus, HZO) and can result in permanent vision loss. The FDA approved a highly effective HZ vaccine (Shingrix, recombinant zoster vaccine [RZV]) in late 2017 for ages 50 and above. Our group published the first post-licensure observational studies of real-world effectiveness of RZV using two years of data. Long-term monitoring of RZV uptake, effectiveness and safety, as well as its impact on HZ/HZO incidence is critical to guide vaccination efforts. During our current R01 grant period, we found that incidence rates of HZ/HZO increased significantly from 2007 to 2018 in the middle-aged groups. In this current proposal, we propose to assess the incidence in the era of RZV vaccination to determine if the incidence is increasing in age groups which are not currently eligible for vaccination (Aim 1). This could have ramifications for policies regarding age recommendations for RZV. Despite the high efficacy of RZV, there is concern that vaccine uptake may be low among specific demographic groups due to early shortages and healthcare disruptions during the COVID-19 pandemic. There are no studies on RZV vaccination coverage of the eligible US population, but an understanding of factors associated with lower likelihood of vaccination, including social determinants of health, could help better target vaccination efforts (Aim 2). Our previous studies were the first to demonstrate high short-term effectiveness of RZV in general practice, and we now propose to assess how long the protection against HZ and HZO will last (Aim 3). Additionally, we will provide estimates of vaccine effectiveness and waning in the immunocompromised subgroup, a group at high risk for HZ which was excluded from clinical trials. Understanding the long-term vaccine effectiveness is critical for informing vaccine policy recommendations for different groups, including the need for and timing of re- vaccination. Lastly, patients with a history of HZO are a subgroup for which there are concerns regarding RZV vaccination, as reflected in a survey conducted by our group showing hesitancy among cornea specialists to recommend RZV. This uncertainty may be due to a lack of evidence on the vaccine’s safety and efficacy to inform clinical recommendations for this patient population. We will determine whether there is an increased risk of post-RZV HZO exacerbations, and we will estimate the effectiveness of RZV in preventing future recurrences and exacerbations of HZO in patients with a history of HZO (Aim 4). Rigorous information on the relative risks and benefits of RZV will facilitate making evidence-based recommendations regarding vaccination.