Lyn Guenther, MD, FRCPC, FAAD
Division of Dermatology, Department of Medicine, Western University, London, ON, Canada
Guenther Research Inc., London, ON, Canada
Conflict of interest: Dr. Guenther has been a speaker for AbbVie, Actelion, Amgen, Altana, Aralez, Bausch, Cipher, Eli Lilly, Galderma, GSK, Janssen, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer, Sanofi Aventis and UCB. She has been a consultant for AbbVie, Actelion, Amgen, Aslan, Altana, Aralez, Bausch, BMS, Celgene, Eli Lilly, Galderma, Incyte, Johnson and Johnson, La Roche Posay, Leo Pharma, Merck, Pfizer, Regeneron, and UCB. She has been a principal investigator for AbbVie, Actelion, Amgen, Bausch, BMS, Boehringer Ingelheim, Celgene, Cipher, Eli Lilly, Galderma, Isotechnika, Innovaderm, Janssen, La Roche Posay, Leo Pharma, Merck, Novartis, Pfizer and UCB. She has been a member of the PSOLAR Janssen registry since its inception.
The lifetime risk for herpes zoster (HZ) of approximately 1 in 3 is increased with advancing age, a family history of HZ, diseases with altered immune function, immunosuppression, physical trauma and psychological stress. In dermatology, monotherapy with current biologics does not increase risk, however systemic steroids, Janus kinase inhibitors and combination biologic/conventional disease-modifying antirheumatics do. The recombinant zoster vaccine (RZV, Shingrix®), an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of varicella zoster virus, is approved for prevention of HZ in adults ≥50 years of age, and adults ≥18 years of age who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment. It is administered as two 0.5 ml intramuscular injections 2-6 months apart. In immunocompromised individuals, the spacing between injections may be reduced to 1-2 months. Where possible, the first dose should be administered at least 14 days before onset of immunosuppressive treatment. Studies in immunocompetent individuals have shown high efficacy including prevention of HZ, postherpetic neuralgia and other complications, with persistence of effect 10 years after vaccination. The acceptable safety profile and efficacy in five different immunocompromised populations support its use in at-risk adult dermatologic patients.
Keywords: Shingrix, recombinant zoster vaccine, vaccination, herpes zoster, immunocompromised, atopic dermatitis, psoriasis, systemic, biologic, JAK inhibitors
New oral and biologic treatments are being developed to treat common conditions such as atopic dermatitis and psoriasis. Some of these treatments may increase HZ, the recurrent infection caused by reactivation of the varicella-zoster virus (VZV). The lifetime risk is approximately 1 in 31 and increases with advancing age,2 immunosuppression,2 a family history of HZ,3 systemic lupus erythematosus4,5 rheumatoid arthritis,4,5 inflammatory bowel disease,4,5 chronic renal disease,5 cancer,5 multiple sclerosis,4 psoriasis,4 asthma,5 chronic obstructive pulmonary disorder (COPD),5 diabetes mellitus,5 depression,5 physical trauma5 and psychological stress (Table 1).5,6
Table 1. Factors which increase the risk of developing HZ.
Typical clinical features include a prodrome with pruritus, tingling and/or pain followed by painful erythematous macules, papules and vesicles on an erythematous base over a single dermatome.2 The eruption crusts over and usually heals within 4 weeks,2 however, complications such as postherpetic neuralgia (PHN) may persist for >1 year particularly in those over age 70 years.7 Recurrent HZ occurs in up to 6.41% of individuals.8 In immunocompromised patients, the eruption can be multi-dermatomal,9 bilateral,10 disseminated11 or necrotic,12 and there is a higher rate of HZ related complications.13
In 2006 in the US and 2011 in Canada, the first HZ vaccine, a single dose, subcutaneous, live attenuated vaccine, Zostavax™ was approved. This vaccine was discontinued in 2020 in the US and 2022 in Canada. Shingrix®, an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of VZV (recombinant zoster vaccine, RZV), received approval in 2017 for immunocompetent individuals 50 years of age and older, and in 2021 for individuals 18 years of age or older who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment.14 It has to be first reconstituted before administration and used within 6 hours after reconstitution. It is administered as two 0.5 ml intramuscular injections 2-6 months apart.14 In immunocompromised individuals the spacing between injections may be reduced to 1-2 months.14 Health Canada recommends that the first dose be administered at least 14 days before onset of immunosuppressive treatment.15 If this is not possible, it should be administered during periods with less immunosuppression when the immune response is expected to be stronger.13 For patients treated with rituximab, it is recommended that RZV be administered at least 5 months after the last dose and at least 4 weeks before the next dose of rituximab.16,17
Some immunomodulatory medications can increase the risk of HZ and zoster-related complications. A systematic review of 35 rheumatoid arthritis studies,16 and study of psoriasis patients in the Israeli Clalit Health Services database18 showed that methotrexate was not associated with an increase in HZ. Tumor necrosis factor (TNF) antagonists do not appear to increase HZ in patients with psoriasis.18-20 A network meta-analysis showed no effect of monotherapy with anti-TNFs, ustekinumab or rituximab.21 Another systematic review in psoriasis and psoriatic arthritis (PsA) also showed no effect with biologic monotherapy, but an increased risk was associated with systemic steroids, tofacitinib and combination biologic/conventional disease-modifying antirheumatics.17 Interleukin (IL)-17 and IL-23 inhibitors do not appear to increase the risk of HZ.22,23
Janus kinase (JAK) inhibitors may increase HZ risk. In the tofacitinib psoriasis trials, HZ events per 100 patient years (PY) were 2.55 vs. 0 for placebo.24 Asian descent (HR 2.92), 10 mg vs. 5 mg twice daily dosing (HR 1.72), prior use of biologics (HR 1.72) and older age (HR 1.30) were risk factors.24 Tofacitinib has approval for PsA, rheumatoid arthritis (RA), and ulcerative colitis (UC), but not psoriasis, or alopecia areata (AA) for which there are case reports of successful hair regrowth.25 Baricitinib is a JAK inhibitor which has approval for AA as well RA, and in some countries, atopic dermatitis (AD). In AA and AD trials, the HZ events per 100 PY (1.4 and 2.3 respectively) were lower than the RA rate (3.0/100 PY).26 Psoriasis studies with 6 mg deucravacitinib, a once daily Tyk2 inhibitor, showed a rate of 0.9/100 PY during the first year and 0.7/100 PY during year 2.27 However, in a phase II PsA trial involving 203 patients randomized 1:1:1 to placebo, deucravacitinib 6 mg or 12 mg once a day, there were no cases of HZ after 16 weeks of treatment.28
During the first 16 weeks of treatment in upadacitinib AD studies, HZ rates were 0.6% for placebo, 1.6% for 15 mg and 1.5% for 30 mg.29 In adolescents, the 30 mg rate was comparable to the adult rate.29 Upadacitinib was initially approved for RA. In a pooled safety analysis of 5306 RA patients, HZ rates were also higher with the 30 mg dose than the 15 mg dose (5.3 vs. 3.0/100 PY)30 and higher than the comparators methotrexate (0.8/100 PY) and adalimumab + methotrexate (1.1/100 PY). Asian patients were at higher risk.30 In abrocitinib AD studies, the rates of HZ in patients aged 18-65 years was 3.44/100 PY and for those ≥age 65 years, 7.40/100 PY. Nine patients on 200 mg and one on 100 mg developed mild/moderate multidermatomal zoster.31
Supporting RZV Efficacy Evidence from Clinical Trials
Two randomized, placebo-controlled studies in >30,000 immunocompetent individuals (ZOE-50 for those 50 years of age and older32 and ZOE-70 for those 70 years and older33) had initial 3.1 and 3.9 year respective follow-ups.14 Assessment of efficacy was restricted to individuals who received the two vaccine doses and did not have a confirmed episode of HZ before 1 month after the second dose. In ZOE-50, vaccine efficacy in individuals ≥50 years was 97.2% (p<0.001). In individuals 70 years and older, vaccine efficacy was 91.3% and prevention of PHN 88.8%.14 There was only 1 case of other zoster complications in the ZOE-50/70 RZV group vs. 16 in the placebo group. At 5 years, participants were offered participation in a long-term follow-up study; 7277 subjects were included in efficacy assessments.34 An interim analysis of vaccine efficacy over the period from 1 month post-initial vaccination to a mean of 9.6 +/-0.3 years follow-up, showed 89% (95% CI 85.6%- 91.3%) efficacy in preventing HZ.35 Immune responses remained >5 fold higher than pre-vaccination levels.35
RZV has been studied in 1587 patients with 5 different immunocompromising (IC) situations – autologous hematopoietic stem cell transplant (auHSCT), hematologic malignancies (HM) vaccinated during or following cancer therapy course, solid tumors (ST) undergoing chemotherapy, renal transplant patients on chronic immunosuppressive therapy at the time of vaccination, and patients with human immunodeficiency virus.14 In all of these populations, RZV induced humoral and cell-mediated immune responses persisting for at least 1 year of follow-up.36 In auHSCT, vaccine efficacy was 68.2% overall with a median follow-up of 21 months.37 PHN (1 vs. 9 cases, p=0.02), other zoster-related complications (3 vs. 13 cases, p=0.02) and hospitalizations (2 vs. 13 cases, p=0.01) were also significantly reduced in vaccine vs. placebo groups, respectively.37 In the hematologic malignancies study, zoster incidence was reduced from 6.62 (placebo group) to 0.85 per 100 PY (p=0·0021) giving an 87.2% efficacy rate in a post hoc analysis.38
In immunocompetent studies, local (pain and swelling at the injection site) and general adverse events (fatigue, myalgia, headache, shivering, fever, nausea, vomiting diarrhea, and/or abdominal pain) were more common in the 50-69 year age group vs. the ≥70 year group, and generally mild to moderate with a median duration of 3 days.14 New onset or exacerbation of existing potential immune-mediated diseases (pIMDs) were noted in 1.2% who received RZV vs. 1.4% treated with placebo (median 4.4 year follow-up).14 In each group, psoriasis and autoimmune thyroiditis were each reported in 0.1%, and polymyalgia rheumatica in 0.2%. RA was reported in 0.1% treated with RZV vs. 0.2% with placebo.14 In a ≥ 65 year old post-marketing observational study, an estimated 3 excess cases per million doses administered of Guillain-Barre syndrome was noted during the 42 day follow-up period after vaccination.14 Safety in IC individuals was similar to that in immunocompetent older individuals.38
RZV is highly efficacious (>90%) in immunocompetent individuals with a modest decline in clinical efficacy as well as humoral and cellular immunity over 10 years. It prevents PHN and other zoster complications. The acceptable safety profile and efficacy in a broad population of IC adults including demonstration of immune responses in 5/5 different IC populations and efficacy in two different IC populations, including auHSCT at a time of greatest risk, support its use in our IC adult dermatologic patients. Dermatologists should be proactive in recommending RZV to all patients over age 50 years, particularly those with a family history of zoster and diseases with altered immune function. Adult patients who are immunocompromised because of their diseases or treatment (e.g., systemic steroids, JAK inhibitors, combination biologic/conventional disease-modifying antirheumatics), should also be encouraged.
- Harbecke R, Cohen JI, Oxman MN. Herpes zoster vaccines. J Infect Dis. 2021 Sep 30;224(12 Suppl 2):S429-42.
- Guenther LC, Lynde CW. A refresher on herpes zoster, current status on vaccination, and the role of the dermatologist. J Cutan Med Surg. 2011 Jul-Aug; 15(4):185-91.
- Tanuseputro P, Zagorski B, Chan KJ, et al. Population-based incidence of herpes zoster after introduction of a publicly funded varicella vaccination program. Vaccine. 2011 Nov 3;29(47):8580-4.
- Chen SY, Suaya JA, Li Q, et al. Incidence of herpes zoster in patients with altered immune function. Infection. 2014 Apr;42(2):325-34.
- Marra F, Parhar K, Huang B, et al. Risk factors for herpes zoster infection: a meta-analysis. Open Forum Infect Dis. 2020 Jan 9;7(1):ofaa005.
- Lasserre A, Blaizeau F, Gorwood P, et al. Herpes zoster: family history and psychological stress-case-control study. J Clin Virol. 2012 Oct;55(2):153-7.
- De Moragas JM, Kierland RR. The outcome of patients with herpes zoster. AMA Arch Derm. 1957 Feb;75(2):193-6.
- Shiraki K, Toyama N, Daikoku T, et al; Miyazaki Dermatologist Society. Herpes zoster and recurrent herpes zoster. Open Forum Infect Dis. 2017 Jan 28;4(1):ofx007.
- Beuerlein KG, Strowd LC. Multidermatomal herpes zoster: a pain in the neck? Dermatol Online J. 2019 Nov 15;25(11):13030/qt9kz407dx.
- Kantaria SM. Bilateral asymmetrical herpes zoster. Indian Dermatol Online J. 2015 May-Jun;6(3):236.
- Yoon KJ, Kim SH, Lee EH, et al. Disseminated herpes zoster in an immunocompetent elderly patient. Korean J Pain. 2013 Apr;26(2):195-8.
- Wollina U. Variations in herpes zoster manifestation. Indian J Med Res. 2017 Mar;145(3):294-8.
- Anderson TC, Masters NB, Guo A, et al. Use of recombinant zoster vaccine in immunocompromised adults aged ≥19 years: recommendations of the Advisory Committee on Immunization Practices – United States, 2022. MMWR Morb Mortal Wkly Rep. 2022 Jan 21;71(3):80-4.
- SHINGRIX (Herpes Zoster vaccine non-live recombinant, AS01B adjuvanted) [ product monograph ]. Date of revision: November 15, 2022. GlaxoSmithKline Inc., Mississauga, ON. Available from: https://ca.gsk.com/media/6259/ shingrix-pm-en.pdf
- Government of Canada. Immunization of immunocompromised persons: Canadian immunization guide (for health professionals). Available from: https://www.canada.ca/en/public-health/services/publications/healthy-living/ canadian-immunization-guide-part-3-vaccination-specific-populations/ page-8-immunization-immunocompromised-persons.html#a26. Accessed June 5, 2023.
- Zhang N, Wilkinson S, Riaz M, et al. Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review. Clin Exp Rheumatol. 2012 Nov-Dec;30(6):962-71.
- Baumrin E, Van Voorhees A, Garg A, et al. A systematic review of herpes zoster incidence and consensus recommendations on vaccination in adult patients on systemic therapy for psoriasis or psoriatic arthritis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2019 Jul;81(1):102-10.
- Dreiher J, Kresch FS, Comaneshter D, et al. Risk of Herpes zoster in patients with psoriasis treated with biologic drugs. J Eur Acad Dermatol Venereol. 2012 Sep;26(9):1127-32.
- Failla V, Jacques J, Castronovo C, et al. Herpes zoster in patients treated with biologicals. Dermatology. 2012 Jul;224(3):251-6.
- Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMA. 2013 Mar 6;309(9):887-95.
- Tang Z, Shen M, Chen X. Risk of herpes zoster among psoriasis patients taking biologics: a network meta-analysis of cohort studies. Front Med (Lausanne). 2021 Jun 4;8:665559.
- Wu KK, Lee MP, Lee EB, et al. Risk of herpes zoster with IL-17 inhibitor therapy for psoriasis and other inflammatory conditions. J Dermatolog Treat. 2020 Jun;31(4):359-65.
- Yang K, Oak ASW, Elewski BE. Use of IL-23 inhibitors for the treatment of plaque psoriasis and psoriatic arthritis: a comprehensive review. Am J Clin Dermatol. 2021 Mar;22(2):173-92.
- Winthrop KL, Lebwohl M, Cohen AD, et al. Herpes zoster in psoriasis patients treated with tofacitinib. J Am Acad Dermatol. 2017 Aug;77(2):302-9.
- Liu LY, Craiglow BG, Dai F, et al. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017 Jan;76(1):22-8.
- Bieber T, Feist E, Irvine AD, et al. A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19. Adv Ther. 2022 Nov;39(11):4910-60.
- Warren RB, Sofen H, Imafuku S, et al. Deucravacitinib long-term efficacy and safety in plaque psoriasis: 2-year results from the phase 3 POETYK PSO program [abstract no. POS1046]. Ann Rheum Dis. 2022;81(Suppl 1).
- Mease PJ, Deodhar AA, van der Heijde D, et al. Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Jun;81(6):815-22.
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- Lal H, Cunningham AL, Godeaux O, et al; ZOE-50 Study Group. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015 May 28;372(22):2087-96.
- Cunningham AL, Lal H, Kovac M, et al.; ZOE-70 Study Group. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016 Sep 15;375(11):1019-32.
- Boutry C, Hastie A, Diez-Domingo J, et al.; Zoster-049 Study Group. The adjuvanted recombinant zoster vaccine confers long-term protection against herpes zoster: interim results of an extension study of the pivotal phase 3 clinical trials ZOE-50 and ZOE-70. Clin Infect Dis. 2022 Apr 28;74(8):1459-67.
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- Bastidas A, de la Serna J, El Idrissi M, et al.; ZOE-HSCT Study Group Collaborators. Effect of recombinant zoster vaccine on incidence of herpes zoster after autologous stem cell transplantation: a randomized clinical trial. JAMA. 2019 Jul 9;322(2):123-133. Erratum in: JAMA. 2019 Aug 27;322(8):785.
- Dagnew AF, Ilhan O, Lee WS, et al.; Zoster-039 study group. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis. Lancet Infect Dis. 2019 Sep;19(9):988-1000. Erratum in: Lancet Infect Dis. 2020 Jan;20(1):e1