Herpes zoster vaccination in inflammatory bowel disease: Evidence, guidelines, and reality

Abstract

Patients with inflammatory bowel disease (IBD) have a 1.3-2.0 times higher risk of developing herpes zoster (HZ) compared to the general population, mainly due to immunosuppressive treatments. The risk is greatest with Janus kinase inhibitors, combination therapies, and high-dose corticosteroids, especially in younger patients with Crohn’s disease. The recombinant zoster vaccine (RZV, Shingrix) provides high efficacy, with 65%-90% protection against HZ and a significant decrease in postherpetic neuralgia, along with a safety profile that does not increase IBD flares, even during immunosuppression. Guidelines from the American College of Gastroenterology, the European Crohn’s and Colitis Organisation, and the Advisory Committee on Immunisation Practices strongly advise RZV for all IBD patients aged 50 and above, as well as those aged 19 and over undergoing immunomodulatory therapy. Real-world evidence supports consistent benefits across different age groups, treatments, and ethnic backgrounds. Nonetheless, there are notable implementation gaps, particularly in resource-poor Asian regions such as India, due to cost, awareness, and access constraints. Adopting a risk-gradient approach that targets high-risk individuals helps optimise resource allocation. RZV is a safe, effective, and cost-efficient method to decrease HZ-associated morbidity in IBD patients. Integrating vaccination proactively into routine IBD management is crucial to close the gap between current evidence and clinical practice.

Key Words: Herpes zoster; Shingles; Recombinant zoster vaccine; Inflammatory bowel disease; Immunosuppression; Janus kinase inhibitors; Vaccination; Postherpetic neuralgia; Crohn’s disease; Ulcerative colitis

Core Tip: Patients with inflammatory bowel disease (IBD) have an elevated risk of herpes zoster due to disease-related immune dysregulation and the widespread use of immunosuppressive therapies, including corticosteroids, thiopurines, biologics, and Janus kinase inhibitors. Major international guidelines now recommend the recombinant zoster vaccine for adults aged ≥ 50 years and for younger adults who are or will be immunosuppressed. The recombinant zoster vaccine, a non-live adjuvanted vaccine, is highly effective and safe in immunocompromised populations, including those with IBD. The vaccination uptake among IBD patients remains low, largely due to gaps in awareness, uncertainty regarding timing around therapy, and cost barriers. In the setting of constrained healthcare resources, a risk-stratified approach is more feasible than blanket vaccination.

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract characterised by dysregulated immune responses to gut microbiota in genetically susceptible hosts. It includes Crohn’s disease (CD) and ulcerative colitis (UC)[1]. The disease is driven by defective mucosal innate immunity, reduced defensin expression, impaired neutrophil chemotaxis, and compromised intestinal barrier function[2].

Herpes zoster (HZ), popularly known as shingles, is a neurocutaneous condition caused by reactivation of the latent varicella-zoster virus (VZV) from the dorsal root or cranial nerve ganglia, where it remains sequestered following primary varicella infection[3]. While the lifetime risk of HZ is 25%-30%, incidence correlates with age[4], with a sharp increase in the sixth decade. In the general population, risk reaches 50% by 80 years, with an incidence rate of 11 per 1000 patient-years (PY), compared with 3.4 per 1000 PY to 4.82 per 1000 PY below 50 years[5]. Reactivation is precipitated by a diminution in VZV-specific cell-mediated immunity (CMI), due to immune senescence (age-related), immune dysregulation, or immune suppression (iatrogenic and disease-induced)[6,7].

While IBD patients are not immune-compromised themselves, malnutrition or medical intervention with immunosuppressive and immunomodulatory therapies compromises CMI and elevates the risk of opportunistic infections like HZ (Table 1). The risk is cumulative, and the combination of multiple agents increases susceptibility to reactivation and to severe complications[8].

Table 1 Epidemiology of herpes zoster in inflammatory bowel disease and general population - herpes zoster in inflammatory bowel disease vs healthy population[3,5,6,10,11,12,14].

Parameter	General	IBD
Incidence/1000 PY	3.4 to 4.82	7.0 to 18.3
Relative risk		1.3-fold to 2.0-fold higher
Lifetime risk	25% to 30%	High-risk thresholds reached much earlier
Age-specific risk	Risk rises with age	Higher relative risk than age-matched healthy controls
Gender distribution	1.3 times higher incidence in females	Higher incidence in females

PY: Patient-years; IBD: Inflammatory bowel disease.

A practical and unifying conceptual framework for HZ prevention in IBD is the immunosuppression gradient, which stratifies patients by the degree of VZV-specific CMI impairment induced by their therapeutic regimen. This gradient spans from minimal risk with aminosalicylates or budesonide to moderate risk with thiopurines (TP) or anti-tumour necrosis factor (TNF) monotherapy to the highest risk with Janus kinase (JAK) inhibitors (dose-dependent), high-dose systemic corticosteroids (≥ 20 mg prednisone equivalent/day for ≥ 2 weeks), and combination regimens[9].

This framework allows for risk-based decision-making: Patients at higher risk, especially those on JAK inhibitors or multiple drugs, should receive earlier and prioritised vaccination with the recombinant zoster vaccine (RZV), even if they are under 50, as their risk of HZ often surpasses that of older, immunocompetent individuals. In settings with limited resources, such as India and Asia, where vaccine availability is constrained by cost and infrastructure, this risk-gradient approach helps in pragmatically prioritising the highest-risk groups to achieve the greatest clinical benefit and cost-efficiency.

EPIDEMIOLOGY

HZ in IBD is characterized by distinctive demographic patterns and higher incidence and rates. Typically, IBD patients have a higher (1.3 times to 2.0 times) risk of HZ compared to the general population[10,11]. The incidence varies geographically, with regions such as South Korea showing high rates (18.3 cases per 1000 PY) and Europe showing lower rates (7.0 cases per 1000 PY to 10.8 cases per 1000 PY)[6,10]. The absolute risk of HZ increases with age for everyone (including IBD), and the IBD-related risk is most pronounced in younger patients[12]. Studies have shown that females, in general, have a higher incidence of HZ (12.6 cases per 1000 PY vs 8.3 cases per 1000 PY)[13,14]. Consistent with trends in the general population, females with IBD also exhibit a higher incidence of HZ than males (21.8 cases per 1000 PY vs 16.1 cases per 1000 PY)[10]. Ethnicity impacts the incidence of HZ, with higher rates from East Asians as compared to Caucasians (10.4 cases per 1000 PY vs 3.6 cases per 1000 PY)[13-15].

HZ PATTERNS: CD VS UC

While both clinical phenotypes of IBD carry a significantly elevated risk for HZ, CD is associated with a higher incidence of HZ than UC (Table 2)[10,11,14]. Data from United States insurance claims showed that the incidence of HZ in IBD was 7.3 cases per 1000 PY and was significantly higher in CD than in UC (8.1 cases per 1000 PY vs 6.3 cases per 1000 PY)[11]. Singer et al[16], in a study of more than 60000 patients, also demonstrated a higher incidence of CD (15.94 cases per 1000 PY vs 13.64 cases per 1000 PY).

Table 2 Epidemiology of herpes zoster in inflammatory bowel disease and general population - herpes zoster in inflammatory bowel disease[10,11,14,16,17,20].

Feature	CD	UC
Overall incidence rate	Higher overall burden (15.9 cases per 1000 PY)	Slightly lower burden (13.6 cases per 1000 PY)
Relative risk (vs non-IBD)	1.66 times to 1.99 times	1.34 to 1.50
Risk in young adults	Dramatic risk increases with an IRR of 3.35 compared to healthy peers	Displays a lower relative risk increase than CD in this age group, with an aIRR of 1.85
Complication risk	High risk for disseminated or visceral disease when heavily immunosuppressed	High risk for complications, though crude incidence rates are generally lower than in CD

IBD: Inflammatory bowel disease; CD: Crohn’s disease; PY: Patient-years; IRR: Incidence rate ratio; UC: Ulcerative colitis; aIRR: Adjusted incidence rate ratio.

South Korean studies also showed a stronger association of HZ with CD (as compared to healthy controls), with a 1.9-times higher incidence than in UC[10]. Ning et al[17] also demonstrated a higher risk (1.7 in CD vs 1.4 in UC) as compared to non-IBD patients. Long et al[11] assessed IBD incidence rates among more than 100000 patients compared with the general population. Even after adjusting for comorbidities, the adjusted incidence rate ratio (aIRR) was higher for CD than for UC (1.69 vs 1.34).

The excess risk of HZ in patients with IBD compared with the non-IBD population is greatest in younger individuals, particularly those with CD. IBD patients in the third decade have a 4.3-fold higher incidence than healthy controls of the same age[12]. The difference increases as patients get older (3.0 times in 30-year-olds and drops to 0.4 times in those > 60 years)[18]. In the general population, the risk reaches 50% by 80 years, but IBD patients reach high-risk thresholds much earlier[10,18,19]. Among patients aged 18-29 years, UC was associated with an age-aIRR of 1.85, whereas CD conferred a markedly higher risk, with an aIRR of 3.35. This age-related disparity progressively narrows with advancing age. In the 40-49 years age group, aIRR were 1.58 for UC and 2.00 for CD; in those aged 50-59 years, 1.40 and 1.47, respectively; and in patients older than 65 years, 1.23 for UC and 1.44 for CD[16]. Soh et al[20], in their study of young, metabolically healthy patients with IBD compared with controls, also demonstrated a similar profile in younger patients. Over a period of 5 years, the study reported incidence rates of 13.6 and 14.9 cases per 1000 PY, compared with 9.1 cases per 1000 PY among controls. Tables 1 and 2 list the differences in epidemiology of HZ in IBD vs the healthy population[3,5,6,10,11,12,14,16,17,20].

IMMUNOSUPPRESSION-RELATED RISK OF HZ

Immunosuppressive and immunomodulatory medications compromise the body’s CMI and primarily drive the medication-related risk of HZ[18]. While IBD itself is a manifestation of immune system dysregulation that increases the risk of HZ, the strongest predictor of viral replication remains the specific pharmacological regimen used[21]. The medication used in IBD can be broadly classified into “no risk”, “low risk”, “high risk”, and “highest risk”, and the odds ratios (ORs) have been found to vary as per the disease and the therapy offered (Table 3).

Table 3 Risk profile of drugs used in inflammatory bowel disease[18,21].

No risk	Low risk	High risk	Highest risk
Aminosalicylates	Vedolizumab	Corticosteroids	Tofacitinib (10 mg)
Budesonide	Ustekinumab	Azathioprine	Upadacitinib
		6-mercaptopurine	Anti-TNF + TP
		Infliximab	3 drug regimens
		Adalimumab
		Tofacitinib (5 mg)

TNF: Tumor necrosis factor; TP: Thiopurines.

5-aminosalicylic acid

5-aminosalicylic acid is not associated with an increased risk of developing HZ. Traditionally, these agents are classified as conservative therapies because they provide little or no immunosuppression compared to advanced treatments. In adjusted multivariate analyses, 5-aminosalicylic acid use has shown a non-significant association with HZ, with an adjusted OR of 1.08, indicating no meaningful increase in risk above baseline in IBD patients[11,14,16,21].

Corticosteroids

Systemic corticosteroids increase HZ risk in IBD patients, but the risk varies by steroid type. Budesonide, a gut-specific steroid, is safe with no added HZ risk and has a similar risk to IBD itself. HZ incidence on budesonide is about 12.2 per 1000 PY, doubling to 24.1 per 1000 PY with other corticosteroids[16]. Systemic corticosteroids independently increase the risk of viral reactivation by 1.3-fold to 3.3-fold[11,21,22]. Scientifically, the risk is highest with daily doses of ≥ 20 mg prednisolone for two weeks or more[23]. Patients on long-term corticosteroids face higher risks of complicated HZ, such as hemorrhagic lesions and prolonged post-herpetic neuralgia (PHN)[24].

JAK inhibitors

This class of small molecules carries the highest HZ risk among advanced therapies. Tofacitinib, a non-selective JAK inhibitor, shows a dose-dependent risk of HZ. Curtis et al[25] found that 10 mg doses increased HZ risk compared with 5 mg, with placebo having the lowest risk (5.5 per 100 PY vs 3.1 per 100 PY). Sandborn et al[26], over four years, showed similar results. The HZ incidence rate (per 100 PY) was dose-dependent, with the highest at 10 mg (6.6), compared with 5 mg (2.2) and placebo (1.0). However, the proposed dose-dependent effect is questioned, as one study found a similar risk profile with tofacitinib without a clear dose-response relationship. Studies also show that risk factors for HZ include older age [hazard ratio (HR) = 1.6], prior anti-TNF failure (HR = 1.9), and Asian ethnicity (HR = 1.8)[27].

Upadacitinib

It is a selective JAK1 inhibitor approved for UC and CD. Clinical trials showed HZ rates of 1.5% to 2.9%, with higher doses increasing the risk of reactivation[28,29]. Filgotinib, a selective JAK1 inhibitor for UC, has shown a good safety profile in limited trials. HZ occurred in 0.6% during induction and 0.5% during maintenance, but the risks and benefits remain unclear[14,30].

TP

TP, especially azathioprine and 6-mercaptopurine, are known risk factors for HZ in IBD patients[9,11]. These medications, classified as “conventional” therapies, impair viral latency and increase HZ risk by 1.8 times to 4.2 times compared with those who are not immunosuppressed[21,22,31]. In multivariate analyses, TP use is associated with an adjusted OR of 1.85 for shingles.[11] with incidence rates of 18.50 per 1000 PY for UC and 28.20 per 1000 PY for CD[16]. Risk expression may vary by ethnicity or phenotype. Although most global studies show a strong link, a Korean study found no increased HZ risk with thiopurine use in their population, suggesting that risk factors differ by ethnicity or cohort[10].

Anti-TNF agents

Infliximab, adalimumab, and golimumab are known risk factors for HZ in patients with IBD. Soh et al[20] found that the HZ risk increased by 1.55-fold in CD patients and by 2.09-fold in UC patients. While absolute incidence increases with age due to immune ageing, the relative risk from anti-TNF is often higher in younger groups, as shown here. A United States cohort study found that anti-TNF therapy was associated with an adjusted OR of 1.81 for IBD (2.36 for UC and 1.72 for CD)[11]. In South Korean cohorts, anti-TNF use was linked to a 2.1-fold higher risk in young UC patients[10]. Interestingly, a study by Khan et al[31] among veterans showed that, compared with amino-salicylates, anti-TNF (adjusted HR = -1.15) was associated with a similar risk. Adalimumab, which has been less extensively evaluated, showed an HZ incidence of 1.5% in trials involving CD[32]. A comparison of adalimumab and vedolizumab in UC patients showed a higher incidence of HZ with adalimumab (42 per 1000 PY) than with vedolizumab (5 per 1000 PY)[33].

Combination therapy

Combination therapy in IBD greatly increases HZ risk due to cumulative immunosuppression[8,11]. The combination of an anti-TNF agent and TP carries the highest clinical risk, with epidemiological studies reporting an adjusted OR of 3.29[11]. Studies show that anti-TNF agents alone might not increase risk, but when combined with TP, risk rises 1.4-fold to 1.7-fold in UC and CD[17,31]. Patients on systemic corticosteroids (≥ 20 mg/day for ≥ 2 weeks) with other therapies have a higher incidence rate, often doubling the baseline risk of IBD patients on conservative treatments. Singer et al[16] found that combination therapy with a biologic and a thiopurine had lower incidence rates than regimens that included systemic corticosteroids. Specifically, the incidence was 15.75 per 1000 PY and 22.80 per 1000 PY for UC and CD, respectively, in the biologic-immunomodulator group, whereas corticosteroid combinations had higher rates of 24.07 per 1000 PY and 28.64 per 1000 PY[16]. Tables 3 and 4 list the immunosuppression-related risks in IBD and the risk of HZ in IBD[10,11,14,16-18,21,22,25-27,31].

Table 4 Adjusted odds ratio for herpes zoster in inflammatory bowel disease by therapy and disease type.

Drug	IBD	UC	CD
Aminosalicylates[11,14,21] (baseline reference)	1.0	1.0	1.0
Budesonide[16]	1.0	1.0	1.0
Systemic steroids[11,21,21] (dose dependent)	1.7–2.0	1.6-1.9	1.8-2.1
Thiopurines[10,11,21,22,31]	1.8-2.2	1.6-2.0	2.0-2.4
Anti-TNF monotherapy[17,31]	1.5-1.8	1.4-1.7	1.6-1.9
Anti-TNF and thiopurine[17,31] (synergistic effect)	3.0-3.5	2.6-3.2	3.3-4.0
Vedolizumab[26,27]	0.9-1.1	0.9-1.0	1.0-1.1
Tofacitinib (5 mg)[25,26]	2.5-3.0	2.5-3.5	2.0-3.0
Tofacitinib (10 mg)[26,27] (highest risk in UC)	3.5-4.5	4.5-6.5	3.0-4.0
Other JAK inhibitors[26,27] (data from RA trials)	3.0-5.0	3.5-6.0	2.5-4.5

TNF: Tumor necrosis factor; UC: Ulcerative colitis; JAK: Janus kinase; RA: Rheumatoid arthritis; IBD: Inflammatory bowel disease; CD: Crohn’s disease.

VACCINES FOR HZ: TYPES AND AVAILABILITY

Two primary HZ vaccines are discussed in the literature for preventing VZV reactivation in patients with IBD: The live attenuated zoster vaccine (LZV, such as Zostavax) and the RZV (such as Shingrix). Table 5 lists the key differences in composition, administration, safety, efficacy, indications 8, and contraindications between the LZV and the RZV[14,15,34-41].

Table 5 Differences between live attenuated zoster vaccine and recombinant zoster vaccine.

Aspect	LZV (e.g., Zostavax)	RZV (e.g., Shingrix)	Ref.
Composition	Weakened live varicella-zoster virus (Oka/Merck strain) at high titer	Recombinant glycoprotein E antigen + AS01B adjuvant (MPL and QS-21)	[14,15,34,35]
Mechanism	Stimulates immunity via replication of attenuated virus	Boosts humoral and cell-mediated immunity without viral replication	[14,15,34]
Administration	Single subcutaneous injection	Two intramuscular injections, 2-6 months apart	[14,34,37]
Efficacy in general population	Approximately 51% against HZ in ≥ 60 years; approximately 67% against PHN; wanes to 20%-30% after 8-10 years	97% against HZ in ≥ 50 years; 91% in ≥ 70 years; > 90% against PHN; sustained for 7-10+ years	[15,34,35]
Efficacy in IBD/immunocompromised	Limited data; not recommended due to risks; approximately 50%-60% in non-IS but inferior long-term	65%-90% against HZ; 68%-90% in broader IS groups; reduces complications like PHN by 75%-89%	[35,37-39]
Safety	Generally safe in immunocompetent; mild local reactions common	Mild-moderate reactogenicity (pain, fatigue); no increased IBD flares (RR = 0.80)	[34,37,40]
Safety in immunosuppressed	Contraindicated; risk of dissemination and vaccine-strain infection	Safe; robust immunogenicity even on anti-TNF or vedolizumab; no flare risk	[14,15,34,35,40]
Contraindications	Immunosuppression (e.g., high-dose steroids, biologics, JAKi); pregnancy; history of anaphylaxis to gelatin/neomycin	History of anaphylaxis to components; acute febrile illness (delay until resolved)	[14,15,34,41]
Availability/preference	Phasing out; still used in some low-resource settings for immunocompetent	Preferred globally; widely available in United States/Europe; private/costly in India/Asia	[14,15,34,36]

IBD: Inflammatory bowel disease; HZ: Herpes zoster; PHN: Post-herpetic neuralgia; IS: Immunosuppressed; LZV: Live attenuated zoster vaccine; JAKi: Janus kinase inhabits; RZV: Recombinant zoster vaccine; AS01B: Adjuvant system 01B; MPL: 3-O-desacyl-4’-monophosphoryl lipid A; QS-21: Quillaja saponaria Molina fraction 21; RR: Relative risk; TNF: Tumor necrosis factor.

EFFICACY AND SAFETY DATA

Efficacy data

The RZV (Shingrix) demonstrates consistent, high-level effectiveness in preventing HZ and its complications in adults with IBD, primarily supported by real-world observational studies and prospective immunogenicity trials in non-Indian populations.

Real-world effectiveness against HZ incidence

A United States cohort of adults aged 50+ with IBD found that RZV vaccination reduced HZ risk by 56% over approximately 900 days (adjusted OR = 0.44). Protection was consistent across UC, CD, and age groups 50-65 and over 65. Incidence rate dropped from 24.2 per 1000 person-years to 10.9 per 1000 person-years[40]. A Kaiser Permanente cohort reported an adjusted vaccine effectiveness (VE) of 65% (95% confidence interval: 24-83) against HZ among IBD adults aged 50+[37].

Efficacy against HZ complications

A study using the TriNetX database found that vaccination significantly reduced complications of HZ (shingles), including PHN and central nervous system involvement. Fewer vaccinated people experienced these issues compared to unvaccinated ones, especially among those with UC, women, and non-immunosuppressed individuals[38].

Immunogenicity in IBD patients on immunosuppressive therapy and efficacy across immunosuppressive regimens

A study of IBD patients receiving vedolizumab or anti-TNF agents showed strong, sustained immune responses for at least 1 year, with no major differences between groups[40,42]. Biologics showed no significant differences in immunogenicity; responses remained robust[40,42]. JAK inhibitors like tofacitinib (highest HZ risk; dose-dependent relative risk > 2) reduced RZV risk, with VE of 65%-75% across immunosuppressive groups[37,43,44]. High-dose corticosteroids (> 20 mg prednisone daily for 14+ days) reduced HZ incidence after vaccination without affecting immunogenicity[39,45]. VE in IBD and immunocompromised individuals ranges from 65%-90%, reducing complications such as PHN (75%-89%) and requiring fewer vaccinations in high-risk groups[37,38,42]. The non-live vaccine is suitable for use during immunosuppression, aiding targeted vaccination[35,37,40]. The LZV has limited data in IBD, is contraindicated in immunosuppressed individuals, and has 50%-60% efficacy that wanes over time in general populations[33].

Efficacy: Younger vs older adults

RZV shows strong effectiveness in adult IBD and immunocompromised populations, with VE ranging from 60% to 90% and no decline, unlike LZV. In older adults (50-70+ years), real-world data indicate significant protection and reduced shingles cases[37,39]. In immunocompromised groups, such as ZOE-HSCT trial participants, VE was 68.2%, similar for those ≥ 50 (67.3%) and 18-49 (71.8%)[35]. Evidence for younger adults (19-49) is limited, but VE remains comparable or higher among immunocompromised adults, with guidelines now recommending RZV for those ≥ 19 years on immunosuppressants due to their increased HZ risk[34,35,41].

Summary of key findings

The RZV (Shingrix) demonstrates consistent high effectiveness in preventing HZ and its complications in adults with IBD. Real-world studies show a 56%-65% reduction in HZ incidence among IBD patients aged 50 and above, with protection consistent across UC, CD, and various age groups, while also significantly lowering complications such as PHN. RZV maintains strong immunogenicity and VE of 65%-90% even in patients on immunosuppressive therapies including anti-TNFs, vedolizumab, JAK inhibitors, and corticosteroids. As a non-live vaccine, it can be safely administered during immunosuppression, unlike the live zoster vaccine, which has lower efficacy and is contraindicated in these patients. Overall, RZV offers robust, durable protection across age groups and supports broader use in high-risk IBD patients starting from age 19.

Safety profile

RZV has a well-established safety profile characterised by transient mild-to-moderate reactogenicity and no increased risk of serious adverse events, potential immune-mediated diseases, deaths, or HZ episodes compared with placebo[35,46].

General safety profile (including in Indian patients): In large phase 3 trials, adverse events were common among recipients of the RZV vaccine, occurring in about 81% to 85% of participants, compared to around 12% to 31% in the placebo group), mainly involving local pain (77.8%-88.4%) and systemic symptoms such as fatigue, muscle aches, headache, and fever. Severe events were less frequent and typically resolved within a few days[35]. Unsolicited adverse events occurred at similar rates in both groups. Serious adverse events and potential immune-related diseases showed no significant differences between the groups[35]. In a phase 3 trial with Indian adults aged ≥ 50 (n = 143 RZV, 145 placebos; median age 57, 91% aged 50-69, 68% male; no immunocompromised or IBD participants), solicited AEs within 7 days were observed in 72% of RZV vs 59% of placebo, mostly mild to moderate[46]. Local AEs: Pain in 67% vs 49%; redness and swelling were lower, with no grade 3 events. Median pain duration was 2 days. Systemic AEs: Fatigue in 44% vs 24%; fever in 28.0% vs 9.7%; headache in 28.7% vs 7%; myalgia. Median systemic AE duration was 1-2 days. Unsolicited AEs over 30 days occurred in 13.3% of each group, mainly gastrointestinal: 2% in the RZV group vs 6% in the placebo group. Serious adverse events were reported in 0.7% of RZV (pneumonia, unrelated, resolved within 5 days) vs 4% of placebo (accidental poisoning or head injury, unrelated or resolving). No potential immune-mediated diseases, HZ episodes, deaths, or discontinuations due to AEs within 6 months after dose 2[46]. This safety profile closely aligns with global data, confirming acceptable safety in Indian adults.

Safety in IBD patients: In IBD cohorts (mainly United States/Korea; n > 1000), RZV does not increase flare risk (relative risk = 0.80, 95% confidence interval: 0.47-1.35 in 1199 recipients) or serious adverse events[37,40]. Mild AEs like injection-site pain and fatigue are common, transient, with low flare rates (1.5%) and no causal link[40]. Immunogenicity data confirm no worsening of IBD despite strong immune responses[40]. Real-world analyses show no elevated serious events or hospitalisations[38,39]. No safety or efficacy data for Indian IBD patients, as the Indian phase 3 excluded those with immunosuppressive or immunodeficient conditions[47]. Existing IBD safety data are from non-Indian populations. Extrapolation suggests similar reactogenicity, but Indian-specific studies are needed.

Safety in patients across different age groups: Safety remains consistent across adult age groups in IBD and immunocompromised groups, with no evidence of increased flares or serious adverse events related to age[35,37,40]. Reactogenicity (pain, fatigue, myalgia) is similar overall; younger adults (18-49 years) in immunocompromised settings (e.g., HSCT trials) may report slightly higher local reactions, but this does not affect series completion or serious outcomes[35]. Older adults (≥ 70 years) have AE rates similar to those of those aged 50-69, despite higher baseline HZ risk, indicating a favourable benefit-risk profile[35]. The Indian trial (median age 57, 91.3% aged 50-69) found no age-specific safety differences, though few participants were ≥ 70 years old (8.7%)[46]. IBD cohorts lack detailed age-specific data on serious adverse events, but mixed-age analyses show a low flare risk (relative risk = 0.80) across age groups[37,40].

Safety in patients on steroids, biologics, and JAK inhibitors: RZV remains safe during immunosuppression, without therapy-related flares, reduced immunogenicity, or contraindications[35,37,38,40]. In biologics (anti-TNF/vedolizumab), the flare rate is 1.5%, with mild, transient AEs and no exacerbations, in a cohort of 67[3,20]. JAK inhibitors (e.g., tofacitinib/upadacitinib) are associated with no post-vaccine flares or serious adverse events, and their tolerability is supported by real-world data[37,47]. High-dose corticosteroids (> 20 mg prednisone for ≥ 14 days) do not cause flares or loss of efficacy; subgroup data suggest safe co-administration with reduced HZ risk[39,45]. The non-live formulation minimises risks, causes mild reactogenicity, and doesn’t affect adherence[35,37,38,40]. These findings support prioritising RZV in older (≥ 50 years) and younger (≥ 19 years) immunosuppressed IBD patients, in whom therapy, rather than age, is the main factor influencing HZ risk[37,39].

Summary of key findings

The RZV (Shingrix) has a favourable safety profile in adults with IBD, characterised by common but transient mild-to-moderate reactogenicity, including injection-site pain, fatigue, headache, and myalgia, which typically resolve within 1-3 days. Real-world data in IBD patients show no increased risk of disease flares, serious adverse events, hospitalisations, or immune-mediated diseases compared to unvaccinated individuals. Safety remains consistent across immunosuppressive therapies, including steroids, anti-TNFs, vedolizumab, and JAK inhibitors, with no contraindications or impact on disease activity. The Indian phase 3 trial in adults ≥ 50 years confirmed a similar reactogenicity pattern to global data, with low rates of severe events and no safety concerns. Overall, RZV demonstrates an acceptable benefit-risk profile across age groups and in immunocompromised IBD patients. Table 6 summarises key studies on the efficacy and safety of RZV in IBD[37-40,42].

Table 6 Key studies on recombinant zoster vaccine in inflammatory bowel disease - efficacy against herpes zoster and complications.

Ref.	Study	Population	Sample size	Key findings on HZ/complications	Vaccine effectiveness/HR/OR (95%CI)	Complications
Desai et al[39], 2024	Propensity-matched United States cohort	Adults ≥ 50 years with IBD (UC/CD)	5489 vaccinated (2 doses) vs 5265 unvaccinated (after PSM: Approximately 4774 per group)	Lower HZ incidence post-RZV; reduced short-term HZ risk. No significant difference in severe complications or PHN among those with HZ	aOR = 0.44 (0.32-0.62) for HZ; incidence 109 vs 24.2 per 1000 PY	Prevention-focused; no major difference in PHN/severe HZ post-onset
Tseng et al[37], 2025	Kaiser Permanente matched cohort	Adults ≥ 50 years with IBD	872 (2-dose vaccinated) vs 2550 unvaccinated (VE cohort); 1199 in SCCS for flares	Adjusted VE 65.1% against HZ; no increased IBD flare risk	VE 65.1% (24.8%-83.8%) against HZ	Supports HZ prevention (implying lower complications); no flare increase [RR = 0.80 (0.47-1.35)]
Wang et al[38], 2025	TriNetX real-world matched analysis	Adults with IBD (mixed ages, primarily adults)	1260 vaccinated vs 1260 unvaccinated (after matching from n = 12086)	Significantly lower HZ complications (PHN, CNS); no CNS cases in vaccinated. Stronger in UC, females, non-immunosuppressed	HR = 0.75 (0.58-0.97) for HZ complications; HR = 0.66 for PHN; uncomplicated HZ HR = 0.31 (0.26-0.37)	Direct complication reduction: PHN 5.8% vs 12.5%; CNS 0% vs 0.8%; ocular/disseminated similar
Caldera et al[40], 2025	Prospective immunogenicity/safety	Adults with IBD on vedolizumab or anti-TNF	67 patients (33 enrolled: 16 vedolizumab, 17 anti-TNF)	Robust immunogenicity (sustained antibodies/CMI); no IBD flares; mild AEs	N/A (immunogenicity focus); strong responses through day 425	Low flare rate (1.5%); indirect benefit via HZ avoidance
Khan et al[42], 2022	ZOE-HSCT and broader immunocompromised (IBD overlap)	Immunocompromised adults ≥ 18 years (e.g., post-HSCT, hematologic; proxy for immunosuppressed IBD)	Varies (approximately 1800 in pivotal trials)	VE approximately 68% against HZ; high against PHN (approximately 89%). Lower NNV for complications in high-risk groups	VE 68.2% (55.6%-77.5%) against HZ; 89.3% against PHN	Proxy data; reduced PHN/hospitalization; comparable across ages

HSCT: Hematopoietic stem cell transplantation; IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn’s disease; PSM: Propensity score matching; VE: Vaccine effectiveness; SCCS: Self-controlled case series; TNF: Tumor necrosis factor; HZ: Herpes zoster; RZV: Recombinant zoster vaccine; PHN: Post-herpetic neuralgia; CNS: Central nervous system; CMI: Cell-mediated immunity; AE: Adverse event; NNV: Number needed to vaccinate; HR: Hazard ratio; OR: Odds ratio; CI: Confidence interval; aOR: Adjusted odds ratio; PY: Patient-years; N/A: Not applicable; RR: Relative risk.

Efficacy and safety of HZ vaccination in children with IBD

Evidence on HZ vaccination in children with IBD is limited and mainly indirect, with no large pediatric trials for the LZV (Zostavax) or the RZV (Shingrix). Neither is routinely approved for those aged 18-19. LZV, mainly licensed for adults over 50, is usually contraindicated in immunosuppressed children due to safety issues. Small observational studies in mildly immunosuppressed pediatric IBD patients show no disseminated infections, minor side effects, rare flares, and good tolerability. Still, guidelines like the Canadian Association of Gastroenterology do not recommend LZV for children with IBD, especially when immunosuppressed[35,48]. For RZV (non-live), observational reports in immunocompromised VZV-naive pediatric patients - including those at risk for autoimmune disease - show acceptable safety, strong immunogenicity (positive VZV-IgG), stable disease, and mild breakthrough infections, with no serious adverse events or dissemination. However, direct evidence of HZ prevention in pediatric IBD is lacking, and efficacy is inferred from adult data (approximately 68%-90%)[49,50]. While RZV shows promise with limited immunogenicity and safety data in high-risk pediatric immunocompromised groups, its efficacy against HZ and long-term safety in children with IBD are unproven. It requires risk-benefit assessments, specialist oversight, and more research before routine use, with inactivated vaccines preferred when possible[40,51].

INDICATIONS AND VACCINE STRATEGY IN IBD

Many guidelines worldwide have outlined indications and vaccination strategies for HZ vaccination in IBD patients. Table 7 lists the indications for the use of different types of HZ vaccination in IBD patients across various guidelines[14,15,23,35,41,52-54]. Table 8 lists the vaccination strategy for HZ prevention in IBD patients[14,15,23,35,41,52,54].

Table 7 Indications for use of different types of herpes zoster vaccines in various guidelines.

Guideline	Indications for LZV (live attenuated)	Indications for RZV (recombinant)	Ref.
ACG 2025 (United States)	Not recommended for IBD patients; contraindicated in those on immune-modifying therapy or aged < 50 if immunosuppressed	All IBD patients ≥ 50 years; ≥ 19 years on or planning immune-modifying therapy (e.g., JAKi, TNFi, high-dose steroids); regardless of prior HZ or varicella status	[41]
ECCO 2021 and 2025 (Europe)	Contraindicated in immunosuppressed IBD; limited to immunocompetent adults ≥ 50-60 years without IBD risks	Strong recommendation for all adult IBD on immunosuppression (≥ 18-19 years); treatment-tailored, prioritize JAKi users due to dose-dependent HZ risk; all ≥ 50 years	[23,52]
Indian Consensus Guidelines 2024 (general)	Not preferred	≥ 50 years universally; recommended in patients with immune compromising conditions including HIV	[53]
Asian (e.g., Korean, AOCD 2023-2025)	Contraindicated in immunosuppressed; optional for immunocompetent ≥ 50 in low-access settings	≥ 50 years in all; ≥ 19 years on JAKi or other IS; emphasize in high-HZ-burden populations (e.g., 10-12/1000 PY in IBD)	[14,15,54]
ACIP 2022 (United States, general with IBD overlap)	Contraindicated in immunocompromised; for immunocompetent ≥ 50-60 years	≥ 19 years if immunocompromised (including IBD on IS); ≥ 50 years universally	[35]

ACG: American College of Gastroenterology; ECCO: European Crohn’s and Colitis Organization; AOCD: Asian Organization for Crohn’s and Colitis; ACIP: Advisory Committee on Immunization Practices; LZV: Live attenuated zoster vaccine; IBD: Inflammatory bowel disease; RZV: Recombinant zoster vaccine; JAKi: Janus kinase inhabits; TNFi: Tumor necrosis factor inhabits; HZ: Herpes zoster; HIV: Human immunodeficiency virus; IS: Immunosuppressed; PY: Patient-years.

Table 8 Vaccination strategy for herpes zoster prevention in inflammatory bowel disease patients.

Aspect	Recommendation	Ref.
Who	(1) All IBD patients ≥ 50 years; and (2) IBD patients ≥ 19 years on JAK inhibitors, TNF inhibitors, or high-dose corticosteroids (> 20 mg/day prednisone equivalent for ≥ 14 days)	[14,15,23,35,41,52,54]
When	(1) At diagnosis or during remission; (2) Before starting immunosuppression if possible; (3) During stable immunosuppression for RZV; and (4) Avoid LZV if immunosuppressed
How	(1) RZV: Two doses/ 0.5 mL each, 2-6 months apart, intramuscular; (2) LZV: Single dose (contraindicated in immunosuppressed); and (3) No routine boosters; revaccinate if incomplete series
Monitoring	(1) Assess for flares post-vaccination (low risk); and (2) Serologic testing not required pre-vaccination

IBD: Inflammatory bowel disease; JAK: Janus kinase; TNF: Tumor necrosis factor; RZV: Recombinant zoster vaccine; LZV: Live attenuated zoster vaccine.

COST-EFFECTIVENESS OF THE VACCINES AND VACCINE RECOMMENDATIONS

Studies show that the RZV reduces long-term costs for people with IBD because shingles affects this group more severely, leading to more hospitalisations. An analysis of adults with CD and UC found that administering adjuvanted RZV keeps costs below 100000 dollars per quality-adjusted life year gained, a common measure of value in healthcare[55]. This indicates that the upfront cost is justified for both types of IBD, especially when considering fewer doctor visits and less time off work due to complications. A broader review of older adults supports this, suggesting that the vaccine is most beneficial for those in their 60s, and that even a small price reduction would make it cost-effective for everyone over 50[56]. In countries like Korea, where shingles rates reach 10-12 cases per 1000 person-years among IBD patients, the over 90% effectiveness of the recombinant vaccine makes it a worthwhile investment for health systems managing high infection rates[15]. Cost models for JAK inhibitors project even greater savings due to the increased HZ risk, as vaccination prevents costly outbreaks in this group[49]. On the other hand, the live vaccine is less cost-effective now because it carries a higher risk for immunosuppressed individuals and offers less long-term protection. In Asia, clinicians tailor advice based on factors like higher risks associated with certain ethnicities or common medications, encouraging the integration of vaccination into routine check-ups or national programs to improve coverage[54]. In India, where no public adult vaccination program exists, experts advise prioritising high-risk groups to optimise limited resources[36]. The Grading of Recommendations Assessment, Development and Evaluation rates these recommendations as strong, based on high-quality evidence supporting prevention in immunocompromised populations[35].

GUIDELINES VS REALITY

Global scenario

Globally, advice from major organisations such as the American College of Gastroenterology and the European Crohn’s and Colitis Organisation recommends vaccinating IBD patients against shingles starting at age 50, or earlier if they’re on potent immunosuppressants, with the recombinant vaccine[31]. The most recent European update from 2025 includes details on newer drugs such as JAK inhibitors and IL-23 agents, emphasising vaccination to reduce infection risk and the use of treatment-specific algorithms[46]. United States experts concur, advising a two-dose series for all over 19 with compromised immunity due to illness or medication[38]. However, in routine practice, implementation often falls short - surveys reveal that only about half of doctors regularly recommend vaccines, which are frequently omitted due to time pressures or forgotten amid other treatments[45]. Uptake remains below 50% in many IBD clinics, even in countries like the United States, where vaccines are more accessible[50]. For JAK users, guidelines emphasise the importance given the higher risk, but actual application remains inconsistent[36].

India/South Asia/Asia

In India, the local gastroenterology society aligns with global guidelines but notes the absence of a government-supported adult vaccination program, leaving most decisions to private doctors[39]. A 2025 Indian study of 100 UC patients in a public hospital found that only 8% received any vaccinations after diagnosis, with awareness at 41%, and even lower among poorer families[49]. Main obstacles? Doctors not mentioning it (68% of cases), concerns about side effects (41%), and high costs (17%). Across Asia, a survey of 384 doctors from countries like Korea, Japan, and China showed that 57% believe vaccines are very important, but only half actually administer them regularly - influenza gets priority, while vaccines like hepatitis A are ignored by over half, especially in Japan (93%)[45]. Uptake remains low, with Korean reviews reporting rates well below what is necessary despite known risks associated with immunosuppressants[15]. Local regulations and inconsistent insurance coverage significantly hinder vaccination efforts, leaving reality far behind official guidance. For JAK inhibitors, Asian data indicate higher rates of HZ, yet vaccination remains insufficient[50].

PRACTICAL CONSIDERATIONS FOR INDIA/ASIAN REGION AND SUGGESTED RECOMMENDATIONS

Evidence is accumulating that the RZV reduces shingles by 65%-90% in IBD patients without triggering flares, aligning with global and local guidance[37,40]. With the rapid increase of IBD cases in India and nearby regions, providing vaccines faces real-world challenges such as high costs - the recombinant vaccine can cost 10000-15000 Indian Rupee per dose, making it inaccessible for many without subsidies[57]. Incorporate vaccination into routine IBD visits at public clinics by using simple conversations to reassure patients about potential reactions, which has been shown to deter 41% in studies. Focus on the most vulnerable groups, such as those on JAK inhibitors or steroids, especially in resource-limited settings[15]. Across wider Asia, customise plans to address the higher shingles incidence in Korean populations and ensure consistent vaccine supplies. Organisations like the Asian IBD Society can train healthcare workers to identify gaps, while monitoring for disease flares post-vaccination can be reassuring - studies show no increase[37,40]. Use apps or reminders to encourage physicians to recommend vaccines, and partner with pharmaceutical companies to obtain more affordable options in low-income areas[36]. For JAK inhibitor users, perform early screening at the start of therapy start, educate about dose-dependent risks, and monitor closely following vaccination[47]. Engage rural communities through outreach, combine vaccination messages with coronavirus disease 2019 education to build trust, and track vaccination rates via registries to refine strategies. Figure 1 depicts the suggested flowchart for RZV in adults with IBD in India/Asia[14,23,37,41,55,56].

Figure 1 Decision-tree flowchart for recombinant zoster vaccine vaccination in patients with inflammatory bowel disease. To be applied at diagnosis, annually, or at the time of therapy change. The algorithm prioritises vaccination in older adults (≥ 50 years) and in patients on or planned for immunosuppressive therapy (particularly Janus kinase inhibitors, tumour necrosis factor inhibitors, high-dose steroids, or thiopurines)[23,41]. Key features include: (1) High efficacy (65%-90% overall; > 90% in immunocompromised per Korean data)[14]; (2) Favorable safety profile (no increased risk of inflammatory bowel disease flares)[37]; (3) Special considerations for Asia/India (low vaccination uptake and rising inflammatory bowel disease burden)[55,56]; and (4) This tool shall support clinicians in identifying high-risk inflammatory bowel disease patients who would benefit most from herpes zoster prevention. IBD: Inflammatory bowel disease; RZV: Recombinant zoster vaccine; HZ: Herpes zoster; JAK: Janus kinase; TNF: Tumor necrosis factor; RR: Relative risk.

CONCLUSION

HZ remains a preventable yet serious complication in IBD patients, heightened by immunosuppression, including JAK inhibitors. RZV (Shingrix) provides superior efficacy (65%-90%), excellent safety (no increased flares), and favourable cost-effectiveness, making it the preferred vaccine according to the 2025 American College of Gastroenterology[41] and European Crohn’s and Colitis Organisation guidelines[52]. Despite strong evidence and clear recommendations, uptake remains low (< 50%) due to physician oversight, patient concerns, and access barriers, especially in resource-limited regions such as India and Asia. Bridging this gap requires gastroenterologists to routinely check vaccination status, priorities RZV vaccination for eligible patients (≥ 50 years universally and ≥ 19 years if immunosuppressed), and advocate for policy changes such as subsidies and inclusion in national programmed. Proactive implementation will reduce HZ-related morbidity, lower healthcare costs, and improve the quality of life for IBD patients.