Prevention of Shingles: Better Protection and Better Value With Recombinant Vaccine

Abstract

More than 95% of persons aged 50 years or older are latently infected with varicella-zoster virus and are at risk for symptomatic reactivation manifesting as herpes zoster (HZ); lifetime risk for this outcome is about 30%. Risk increases with age and is increased further by immunosuppression and a growing list of comorbid conditions, including diabetes mellitus, chronic kidney disease, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and chronic obstructive pulmonary disease. Herpes zoster causes significant illness and health care costs, especially among those who develop postherpetic neuralgia. In 2006, the U.S. Food and Drug Administration (FDA) approved a live attenuated HZ vaccine (Zostavax, Merck), also known as zoster vaccine live (ZVL), on the basis of the Shingles Prevention Study (1). This large, randomized, double-blind, placebo-controlled trial showed reductions of 51.3% in the incidence of HZ and 66.5% in the incidence of postherpetic neuralgia in adults aged 60 years or older. Age had a significant effect on ZVL efficacy: HZ incidence was reduced by 63.9% in patients aged 60 to 69 years but by only 37.6% in patients aged 70 years or older. Zoster vaccine live is given as a single subcutaneous injection. In 2008, the Advisory Committee on Immunization Practices (ACIP) recommended ZVL for immunocompetent adults aged 60 years or older. In 2011, the FDA approved it for adults aged 50 to 59 years on the basis of another large, randomized, double-blind, placebo-controlled study (2), which showed a 69.8% reduction in HZ incidence in this age group. However, the ACIP has not recommended ZVL for persons aged 50 to 59 years because of lack of cost-effectiveness in this age range (3) and waning of protection, which seems to be lost after 5 to 11 years (46), likely resulting in persons who received ZVL in their 50s being at high risk for HZ in their 60s and beyond, when HZ risk is higher. On 20 October 2017, the FDA approved a new recombinant HZ vaccine (Shingrix, GSK) consisting of varicella-zoster virus glycoprotein E as the immunogen coupled with the AS01B adjuvant system (a liposome-based adjuvant system containing 50 g of 3-O-desacyl-4 -monophosphoryl lipid A and 50 g of Quillaja saponaria Molina, fraction 21). Shingrix, also known as recombinant zoster vaccine (RZV), is administered by 2 intramuscular injections 2 to 6 months apart. Its FDA approval was based on 2 large, randomized, double-blind trials, ZOE-50 and ZOE-70 (7, 8). In ZOE-50, which enrolled patients aged 50 years or older, RZV reduced the incidence of HZ by 97.2% (7); in ZOE-70, which enrolled patients aged 70 years or older, it reduced incidence by 89.8% (8). Efficacy was similar in persons aged 70 to 79 years (90.0%) and 80 years or older (89.1%). Injection site reactions with RZV seem to be more severe than with ZVL (possibly due to the AS01B adjuvant) but are generally mild, and 95% of participants in the ZOE trials completed the second dose. Because it is not a live vaccine, RZV can be administered to immunocompromised patients. On 25 October 2017, the ACIP recommended preferential use of RZV over ZVL. It also recommended RZV for patients aged 50 years or older and for those who previously received ZVL. The article by Prosser and colleagues (9) is a nonindustry-funded study evaluating the cost-effectiveness of RZV versus ZVL and versus no HZ immunization, the cost-effectiveness of RZV in persons who previously received ZVL, and whether RZV should be preferred to ZVL in patients aged 50 years or older. The primary outcome measure was the incremental cost-effectiveness ratio. The analysis included multiple sensitivity analyses varying several variables, including vaccine efficacy over time and the proportion of patients who complete 2 doses of RZV. Base-case analysis using the unrealistic assumption of 100% completion of 2 doses yielded incremental cost-effectiveness ratios from $10000 to $47000 per quality-adjusted life-year. For all age groups older than 60 years, RZV dominated ZVL. Sensitivity analysis found that RZV dominated ZVL in more than 95% of scenarios, including those with 50% completion of the second dose. These analyses support the September 2017 ACIP recommendations to favor RZV over ZVL, to actively recommend HZ immunization starting at age 50 years, and to give RZV to persons older than 60 years who previously received ZVL. A challenge with RZV is the need to administer a second dose. In the ZOE studies, 95% of participants completed the second dose. Clinical trial patients tend to be highly motivated, and trial staff typically try much harder than staff in routine clinical care to ensure that participants complete all study procedures. Lower completion rates of the second dose will surely occur in the real world. In 1 of the few studies that examined completion rates of multiple-dose vaccines in adults, completion rates for the 2-dose hepatitis A vaccine within 1 year of the first dose were only 43.6% for adults aged 50 years or older (10), the same age range recommended for RZV. Another limitation of the current study is that the efficacy values it used for a single dose of RZV90% for persons aged 50 to 69 years and 69% for those aged 70 years or olderwere derived from a post hoc analysis of the ZOE trials. In these trials, the mean duration of follow-up was less than 90 days because 95% of participants received the second dose and most of the rest withdrew consent or were lost to follow-up. Thus, the true efficacy beyond 90 days after a single dose of RZV is unknown. As with all newly approved vaccines, the duration of protection with RZV will require ongoing surveillance in large cohort studies, and subsequent booster dosing may still be needed; this occurred with measles vaccine and, perhaps more relevant, with live attenuated varicella vaccine, which is directed against the same virus as RZV. Nevertheless, the best available data, including the analysis by Prosser and colleagues (9), support the ACIP recommendations for preferential use of RZV over ZVL starting at age 50 years and for administering RZV to those who previously received ZVL.