Recombinant herpes zoster vaccine in patients with autoimmune rheumatic diseases in Brazil: a double-blind, randomised, placebo-controlled, phase 4, non-inferiority study.

Abstract

Patients with autoimmune rheumatic diseases are at high risk of developing herpes zoster due to immunosuppressive treatment. We evaluated the effect of a recombinant zoster vaccine in patients with autoimmune rheumatic diseases compared with placebo and in healthy controls. This single-centre, double-blind, randomised, placebo-controlled, phase 4, non-inferiority, study was done at a tertiary centre in Brazil. Eligible patients were aged 18 years or older with an autoimmune rheumatic disease diagnosis. All patients had to have been managed with glucocorticoids, immunosuppressives, or disease-modifying antirheumatic drugs, provided the doses were stable for at least 4-12 weeks before the initial study visit. Patients were randomly assigned (1:1) to receive two doses of recombinant zoster vaccine or placebo, 6 weeks apart, according to computer-generated sequences, without blocks or stratification. Investigators and participants were masked to treatment allocation. Healthy controls were also included from the same centre and received two doses of the recombinant zoster vaccine. Following the double-blind phase, patients with autoimmune rheumatic diseases who initially received placebo entered an open-label phase and received two doses of the vaccine. The primary outcome was the number of patients with autoimmune rheumatic diseases with worsening of disease activity (flare) up to day 84 after the first dose of the recombinant zoster vaccine compared with placebo in the double-blind phase of the study. Non-inferiority of recombinant zoster vaccine would be declared if the upper boundary of the one-sided 95% CI for the rate of worsening in disease activity in the group receiving recombinant zoster vaccine versus the placebo group was less than 5%. The primary analysis (flare rates) and the safety analysis were done in all participants who received at least one vaccine dose. There was no involvement of people with lived experience of autoimmune rheumatic diseases in the study design. The study is registered with ClinicalTrials.gov (NCT05879419) and is complete. Between May 25, 2023, and Nov 27, 2024, 1192 patients were enrolled in the study and were randomly assigned to receive either the recombinant zoster vaccine (n=590) or placebo (n=602). 559 (95%) of 590 patients in the recombinant vaccine group and 577 (96%) of 602 in the placebo group received at least one dose of the recombinant zoster vaccine or placebo and were included in the primary outcome and safety analyses; 891 (78%) of 1136 were female, 245 (22%) were male, 555 (49%) were of African descent, and 552 (49%) were White. An additional 393 healthy controls were enrolled in the study: 380 received both doses of the recombinant zoster vaccine and were included in the safety analyses. For the primary outcome of worsening of disease activity (flare) up to day 84 for patients with autoimmune rheumatic diseases, non-inferiority was shown for the recombinant zoster vaccine group compared with placebo. 80 (14%) of 559 patients in the recombinant zoster vaccine group had a flare compared with 84 (15%) of 557 in the placebo group, equating to a between-group difference in flare rate of -1·2% (95% CI -4·7 to 2·2; p_{non-inferiority}=0·0018). Adverse events were less frequently reported after both vaccine doses in patients with autoimmune rheumatic diseases compared with the healthy control group (after first dose: 430 [77%] of 559 in the recombinant zoster vaccine group vs 179 [31%] of 577 in the placebo group vs 341 [90%] of 380 in the healthy control group; after the second dose: 402 [72%] vs 148 [26%] vs 307 [81%]). Serious adverse events were similar across the groups after the first dose (five [1%] vs six [1%] vs none) and second dose (nine [2%] vs five [1%] vs two [1%]) of the recombinant zoster vaccine. Recombinant zoster vaccine had an acceptable safety profile in patients with autoimmune rheumatic diseases who are immunosuppressed, and had no significant effect on short-term disease activity. GSK and the Fundação de Amparo à Pesquisa do Estado de São Paulo.