Dr. Bella Mehta

Globally, there are two available vaccine formulations against herpes zoster: Shingrix, a non-live vaccine, and the live attenuated zoster vaccine Zostavax.

Non-live vaccine
The Shingrix vaccine is a non-live vaccine. It is a subunit vaccine, composed of parts of the Varicella Zoster Virus. The vaccine is recommended for adults 50 years and older, including immunosuppressed patients, and administered in two intramuscular doses provided 2 to 6 months apart. According to The European Alliance of Associations for Rheumatology (EULAR), Safety and efficacy of the subunit zoster vaccine have not yet been investigated in autoimmune inflammatory rheumatic diseases (AIIRD) patients. However, Shingrix has been shown to be safe and more efficacious compared with live-attenuated vaccine in elderly adults in general public.1

As of August 2021, According to the Joint Committee on Vaccination and Immunization (JCVI), healthcare workers should offer the Shingrix vaccine to all those who are eligible for shingles vaccination but are clinically contraindicated to receive the live vaccine Zostavax due to their immunocompromised status.2

The CDC published on January 2022 recommendations for vaccination against herpes zoster with recombinant (nonlive) herpes zoster vaccine to include all immunocompromised adults ≥19 years of age.3 The CDC indicates that a person who is taking a low-dose immunosuppressive therapy or is going to begin taking an immunosuppressive medication can take Shingrix.4

Vaccination should ideally be completed ≥2 weeks prior to the start of immunosuppression to help ensure maximal immune response. When vaccination cannot be given prior to immunosuppression, the vaccine should be given as soon as feasible and ideally during a period when immunosuppression is low. Although the immune response may be diminished, vaccination is still expected to provide protective benefit for most patients.5

Importantly, Shingrix is used only for the prevention of shingles. For the prevention of varicella (chicken pox), the only available vaccine is a live-virus vaccine.6

Live vaccine (ZVL)

Based on the EULAR, live-attenuated vaccines generally should be avoided whenever possible in immunosuppressed patients (bDMARDs and tsDMARDs are defined as immunosuppressive therapy) with AIIRD. However, vaccinations such as measles, mumps, rubella (MMR) and live-attenuated herpes zoster vaccines may be an exception. In settings where non-live vaccines are not available, ZVL can be an alternative option for the vaccination of patients with AIIRD who are planning to start immunosuppression soon.

A large cohort study of Medicare beneficiaries 60 years and older with AIIRD, treated with immunosuppressive therapies, including bDMARDs, did not show any increase in the incidence of herpes zoster during the first 42 days after vaccination.7

ZVL is given as a one-time dose and should ideally be administered at least one month prior to the initiation of immunosuppressive agents to avoid risk of dissemination. ZVL is contraindicated in patients receiving immunosuppressive agents due to the risk of dissemination.8  The EULAR recommends considering ZVL before initiating RA therapies and while receiving csDMARD monotherapy or csDMARD combination therapy but not when receiving bDMARDs.910

There is no clear consensus on when the live zoster vaccine can be given following receipt of moderately to highly immunosuppressive agents. In general, it is reasonable to wait for at least one month (depending on the half-life of the immunosuppressive medication) or one dosing interval following the last receipt of the agent before giving the vaccine and then defer any additional immunosuppressive therapy for at least one month thereafter.

patients with uncertain varicella exposure, evaluation of varicella zoster serostatus may be considered before the administration of live-attenuated HZ vaccine in order to prevent primary varicella infection following the vaccine.

Vaccination in relation to drugs

The CDC states that the live vaccine can be used safely with MTX, low to intermediate dose corticosteroids, intraarticular, bursal, or tendon corticosteroid injections, and azathioprine, but suggests, as well as the ACIP, to avoid it in patients taking bDMARDs or high dose corticosteroids.11

bDMARDS – Anti TNF

Immune responses to vaccination among patients treated with tumor necrosis factor inhibitors (TNFis) tend to be well preserved, with the exception of the response to hepatitis B virus (HBV) vaccination. A Randomized Controlled Trial tested the effectiveness of Live Varicella-Zoster Vaccine in 617 Patients Receiving Tumor Necrosis Factor Inhibitor Therapy. After 6 weeks no cases of confirmed varicella infection were found.12

Another analysis of claims data from a nationwide US health plan looked at 47 patients with rheumatic conditions who were exposed to biologics (primarily anti-TNF) at the time of vaccination, and again found no cases of shingles within 30 days of vaccination.13

Rituximab

Rituximab is an anti-CD20 antibody that causes B-lymphocyte depletion and is thus an immunosuppressive drug. Rituximab is known to decrease immunoglobulin levels for multiple targets and is expected to reduce the effectiveness of vaccinations that rely on humoral immunity. According to the CDC, for patients receiving anti-B cell therapies, administer a dose of Recombinant zoster vaccine (RZV) approximately 4 weeks prior to the next scheduled therapy.14 

Immune responses directly to the Shingrix vaccine in RA patients who are treated with Rituximab are not well studied. However, a controlled clinical trial that examined immunization responses in patients with rheumatoid arthritis treated with rituximab showed a decreased response to some vaccines (such as pneumococcal polysaccharide vaccine). These data suggest that primary immunizations should be administered prior to rituximab infusions to maximize responses.15

Early observational data suggest that administering the live vaccine under bDMARD may not significantly increase the incidence of shingles, however more robust prospective data are needed to establish whether this is true. Once again, vaccination seems to be much safer 1 month prior to starting a bDMARDs or tsDMARD, or 1 month after discontinuing such therapy.16

Shingrix vaccine experience in immunocompromised patients is limited, but initial observational studies suggest use is feasible and well tolerated, and some guidelines recommend it as the preferred option, despite limited data on the magnitude and duration of benefit, and the risk of disease flare or severe reactions.17

JAK Inhibitors

The risk of herpes zoster (HZ) is increased with Janus kinase inhibitor use.18 A recent study observed similar risk for all bDMARDs, and a dose-dependent risk with corticosteroids. Medicare (2006- 2013) and Marketscan (2010-2014) American databases were analyzed to evaluate, in RA patients, the risks of HZ infection associated with tofacitinib compared with biologic agents and found the incidence rate was highest among patients that received tofacitinib.19 In a Randomized Phase II Trial, Administration of ZVL vaccine to active RA patients ≥50 years old treated with MTX, 2 to 3 weeks before starting tofacitinib, was reported to be safe and immunogenic at 14 weeks follow-up.20

The Shingrix vaccine has been shown to be safe and effective in healthy elderly but data on patients with rheumatic disease are scarce. A Swedish study (NCT03886038) examined Shingrix vaccine use in patients initiating or already treated with JAK inhibitors. Preliminary results from the study show satisfactory serological responses and acceptable tolerability of two doses of Shingrix vaccine in RA patients treated with JAKi. Data from 40 RA patients treated with JAKi and 20 controls were analyzed. Compared to pre vaccination sera, OD levels increased significantly in both patients and controls No patient experienced worsening or flare of RA and no case of HZ has been reported.21

The Live zoster vaccine may be safe in patients with RA receiving bDMARDs or tofacitinib; however, it may not provide adequate long-term protection for patients initiating JAK inhibitor therapy.22