ATLANTA -- According to new research findings presented this week at the 2019 ACR/ARP Annual Meeting, the live zoster virus vaccine is safe for people who are currently receiving tumor necrosis factor inhibitor (TNFi) biologic therapies for various indications (Abstract # 824).
In healthy individuals, excess TNF in the blood is modulated naturally, but in those who have rheumatic conditions, higher levels of TNF in the blood and joints lead to more inflammation and persistent symptoms. Medications that block TNF can alter a disease's effect on the body by controlling inflammation in the joints, gastrointestinal tract, and skin. There are five different TNF inhibitors that have been approved by the U.S. Food and Drug Administration for the treatment of rheumatic diseases.
Researchers conducted the Varicella Zoster Vaccine (VERVE) trial, a randomized, placebo-controlled, blinded trial of live, attenuated zoster vaccine (ZV) in more than 600 individuals in the U.S. receiving TNFi therapies. The study sought to evaluate safety and efficacy of the vaccine among patients who may be immunocompromised due to their TNFi treatment and other co-medications, such as low-dose glucocorticoids.
"Because patients with rheumatic diseases are at higher risk for reactivation of herpes zoster, also known as shingles, prevention of this painful condition is exceedingly important. Shingles manifests in most patients as a painful blistering rash that lasts a few weeks, but serious complications such as disseminated disease, eye involvement and even strokes can occur," said Jeffrey R. Curtis, MD, MS, MPH, a professor of medicine at the University of Alabama at Birmingham's Division of Clinical Immunology and Rheumatology, and the study's lead author. "While the need for prevention in patients with rheumatic diseases is compelling, use of any weakened (attenuated) live virus vaccine is potentially a safety risk. There is a theoretical risk that a live virus vaccine could give a patient the weakened form of infection. A major goal of the trial was to understand the safety of this live virus vaccine and to see if it caused infection in any of the participants."
Eligible participants in the trial were at least 50 years old, were current users of TNFi therapies for any disease indication and had no prior zoster vaccination. There were 617 randomized patients who were recruited at 33 centers. Demographics included an average age of 62 where 66 percent were women, 87 percent were white, about nine percent were African American, and four percent were Hispanic. Participants' TNFi indications included 59 percent with rheumatoid arthritis (RA) and 24.5 percent with psoriatic arthritis (PsA). At baseline, patients were on a variety of TNF inhibitors including, adalimumab, infliximab, etanercept, golimumab and certolizumab.
After vaccination, follow-up for safety occurred over six weeks, the specified risk window for vaccine-related infections that might occur, according to the FDA. The researchers clinically assessed any suspected cases of varicella infection or shingles, in addition to collecting polymerase chain reaction (PCR) data with subtyping to differentiate wild-type versus vaccine-related infection, and digital photographs of the patients. The researchers also collected serum and peripheral blood mononuclear cell (PBMC) samples at baseline and week six to assess participants' zoster-related immunity, and then conducted safety follow-up through six months after vaccination, when the participants were unmasked to the treatment arm.
Through the sixth week, the researchers observed zero cases of confirmed disseminated or local varicella infection of either wild-type or vaccine strain. This result yielded an upper bound of the 95 percent confidence interval for a vaccine-related varicella infection rate of approximately one percent. Eight patients that did develop a rash were tested for varicella by PCR, but none were positive for infection.
The researchers closed the VERVE trial in Summer 2019 to a blinded follow-up and will report the immunologic effectiveness of ZV in the full cohort at the ACR/ARP Annual Meeting.
"The clinical significance of the trial is to provide high quality direct evidence of the safety of this live virus vaccine in patients who previously were warned not to use it because of the theoretical risk for it to cause infection," said Dr. Curtis. "It also opens the door for the idea that for TNFi users, perhaps other live virus vaccines also may be safe and might be considered in certain circumstances. Future directions for this research group are to rigorously study the new adjuvanted shingles vaccine to better understand its safety, tolerability and effectiveness in patients with RA and inflammatory bowel disease, using similar methods. A trial of this new shingles vaccine is being planned for these patients and likely will begin in 2020."
###
The research was supported by the NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases.
About the ACR/ARP Annual Meeting
The ACR/ARP Annual Meeting is the premier meeting in rheumatology. With more than 450 sessions and thousands of abstracts, it offers a superior combination of basic science, clinical science, tech-med courses, career enhancement education and interactive discussions on improving patient care. For more information about the meeting, visit https://www.rheumatology.org/Annual-Meeting, or join the conversation on Twitter by following the official #ACR19 hashtag.
About the American College of Rheumatology
The American College of Rheumatology (ACR) is an international medical society representing over 8,500 rheumatologists and rheumatology health professionals with a mission to empower rheumatology professionals to excel in their specialty. In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases.
Abstract
Results from a Randomized Controlled Trial of the Safety of the Live Varicella Vaccine in TNF-Treated Patients
Background/Purpose: There has been minimal evaluation of the safety of live virus vaccines in patients receiving biologic therapies who may be immunocompromised. The Varicella Zoster Vaccine (VERVE) study is a blinded, 1:1 randomized placebo-controlled trial of the live attenuated zoster vaccine (ZV) in patients receiving TNF inhibitors (TNFi) to evaluate safety and immunogenicity.
Methods: Eligible participants: at least 50 years of age, current users of TNFi for any indication, and no prior ZV. Safety follow-up occurred over 6 weeks (the FDA-specified risk window for vaccine-related infection, were it to occur). Suspected cases of varicella infection or shingles had clinical assessment, PCR collection (with subtyping to differentiate wild-type vs. vaccine [Oka]-related infection), and digital photographs. Review was conducted under oversight of an NIH-appointed Data Safety Monitoring Board. Serum and PBMCs were collected at baseline and week 6 to assess ZV-related immunity, with safety follow-up through 6 months, at which time participants were unmasked to treatment arm.
Results: Recruitment closed in December 2018, with 617 randomized participants recruited at 33 centers: mean (SD) age 62.4 (7.5) years, 66.9% female, 87.2% white, 8.8% AA, 4.4% Hispanic. Most common TNFi indications: rheumatoid arthritis (59.6%), psoriatic arthritis (24.5%); TNFi medication at baseline: adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), certolizumab (5.7%). Concomitant therapies included background methotrexate (48.0%), and oral glucocorticoids (10.5%). Through week 6, there were zero cases of confirmed disseminated or local varicella infection, either wild type or vaccine strain, yielding an upper bound of the 95% confidence interval for vaccine-related varicella infection of < 1%. A total of 8 rashes were swabbed for varicella PCR; none were positive, and no clinically adjudicated varicella or shingles reactivation cases were observed through week 6. VERVE will close to blinded follow up in Summer 2019 and immunologic effectiveness of ZV will be reported in the full cohort in November 2019.
Conclusions: The randomized VERVE trial comprised of more than 600 patients receiving TNFi for multiple indications observed no cases of vaccine-related varicella infection or reactivation in the 6-week risk period following live zoster vaccination. This trial informs safety concerns of use of live virus vaccines in this population.