Off-label use of recombinant adjuvanted Herpes Zoster vaccine in a 10-year-old high-risk patient affected by epidermolysis bullosa: A case report

ABSTRACT

Epidermolysis bullosa is a rare genetic disorder characterized by skin fragility and blistering, resulting from mutations in dermal-epidermal junction structural proteins. Disease severity varies, with some cases involving extensive skin damage and complications secondary to chronic inflammation. Patients with immune-mediated dermatological conditions face a heightened risk of Herpes Zoster and Post-Herpetic Neuralgia, particularly during immunosuppressive treatments. A 10-year-old female with Recessive Dystrophic Epidermolysis Bullosa received off-label Recombinant adjuvanted Zoster Vaccine (RZV) – approved in individuals 18 years of age and older – before initiating Janus kinase inhibitor therapy, required to manage the underlying condition. Two standard RZV doses were administered on February 22 and April 29, 2024. No immediate vital sign alterations nor Adverse Events Following Immunization were documented in the first 7 days after immunization. A 6-month follow-up revealed no relevant emergent clinical events nor Herpes Zoster episodes. In conclusion, the case offers preliminary insights into RZV safety for high-risk pediatric patients. However, robust safety and efficacy studies are warranted to support the implementation of RZV for vulnerable individuals under 18 years of age.

Introduction

Epidermolysis bullosa (EB) encompasses a group of disorders characterized by congenital skin fragility, resulting in a tendency for the skin to blister or tear following minimal trauma.¹ Over 30 distinct subtypes of EB are currently recognized, grouped into four major categories primarily based on the level of tissue separation within the dermo-epidermal junction. These categories – EB simplex, junctional EB, dystrophic EB, and Kindler EB – reflect the underlying molecular abnormalities that characterize each subtype. Of note, severe generalized Recessive Dystrophic Epidermolysis Bullosa (RDEB) is the most severe form of the disease and is caused by a deficiency in collagen VII function due to alterations in the COL7A1 gene.² To date, pathogenetic mutations in at least 16 different genes have been implicated in EB, each encoding proteins that play a crucial role in maintaining cellular integrity and adhesion.^3,4 Together with genetic defects, autoimmune and inflammatory responses seem to contribute to both disease pathogenesis and worsening.^4,5

Individuals with EB present with a wide spectrum of disabilities, depending on the severity of the condition. The most severely affected patients often experience chronic skin complications such as scarring, fibrosis, and contractures, which can impact various parts of the body, including hands, feet, and joints. Pain is a pervasive issue, manifesting both acutely, as a result of blistering and wounds, and chronically, due to long-term tissue damage and inflammation. These physical limitations can significantly hinder independence in activities of daily living (ADL), requiring assistance for basic tasks such as dressing, eating, and mobility. Furthermore, the cumulative physical, emotional, and social challenges of living with EB can severely affect quality of life (QoL), leading to psychosocial distress and reduced overall well-being.⁶

No curative treatment for epidermolysis bullosa exists, and supportive care is provided for symptomatic management of EB patients.³ Gene therapy is currently the most promising approach for EB treatment,⁷ albeit symptoms related to severe forms (e.g., RDEB) may benefit from immunosuppressive treatment with Janus Kinase inhibitors (JAKi).^8,9

Patients with immune-mediated dermatological conditions, including bullous diseases, are at higher risk of Herpes Zoster (HZ) and Post-Herpetic Neuralgia (PHN) and related hospitalization,¹⁰ not only during periods of high disease activity but also during remission phases.¹¹ The risk further increases in case of administration of immunosuppressive therapy.¹¹ Additionally, HZ presentation may mimic a flare-up of an underlying immunobullous disease, thereby hindering identification and proper management,^12,13 potentially leading to a fatal outcome.¹⁴ Hence, HZ and PHN prevention should be recommended to all patients with chronic dermatological conditions characterized by altered immunity due to intrinsic disease features or therapy.¹¹

Two vaccines exist for HZ prophylaxis, i.e., a live attenuated vaccine (ZVL),¹⁵ authorized after 50 years of age and contraindicated in immunosuppressed individuals, and a Recombinant adjuvanted Zoster vaccine (RZV).¹⁶ RZV is currently approved by the European and the Italian Medicines Agency for the prevention of HZ and PHN in individuals aged 18 and older at increased risk of HZ.¹⁶ RZV demonstrated >90% efficacy in preventing HZ at 3 years post-vaccination in the pivotal phase III trials ZOE-50¹⁷ and ZOE-70.¹⁸ Protection remained robust for 7 years (>84% annual vaccine efficacy) and showed only modest decline 10 years post-vaccination (73.2%).¹⁹ A post-hoc analysis revealed comparable RZV safety and efficacy profiles in patients with preexisting potentially immune-mediated diseases.²⁰ Subsequent clinical investigations in immunocompromised populations supported the expansion of authorization to include individuals ≥18 years with compromised immunity.^21,22 Overall, evidence indicates that RZV is generally safe in immunocompromised populations, both regarding Adverse Events Following Immunization (AEFIs) and exacerbations of underlying conditions.^23,24 While immunocompromised individuals demonstrate reduced immunological responses and vaccine efficacy compared to immunocompetent populations, these remain acceptable, supporting the importance of RZV use in immunocompromised individuals ≥18 years.^24–27 On the other hand, at present, no comprehensive data are available about RZV safety and efficacy in the pediatric and adolescent population.²⁸ Hence, any administration in patients under 18 years of age would be considered off-label.

Patient presentation

We present the case of a 10-year-old female with a confirmed genetic diagnosis of recessive dystrophic epidermolysis bullosa (two COL7A1 gene mutations, i.e., c.3355C>T (p.Gln119]) in exon 25 and c.815 G>C (P.Gly2719A1a) in exon 10). Referring physicians documented a chronic inflammatory state, characterized by persistently elevated serum inflammatory markers, i.e., C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Interleukin 16 (IL-16) over several years. The patient’s medical history also included poorly controlled iron deficiency anemia. Nutritional support had been provided via a percutaneous endoscopic gastrostomy (PEG) tube since April 2023.

Due to the severity of the baseline disease, the patient was a candidate for Janus Kinase inhibitor (JAKi) therapy with Baricitinib (2 mg/b.i.d based on patient’s weight). However, according to both the Summary of Product Characteristics (SmPC) of Baricitinib²⁹ and more recent literature findings, Jaki administration, and in particular Baricitinib, is associated with a high risk of Herpes Zoster (HZ) reactivation.³⁰

Vaccination history of the patient was compliant with the national immunization schedule; in particular, she completed the varicella immunization schedule (2 doses) in infancy. No significant Adverse Events Following Immunization (AEFIs) were referred for the received vaccines. No history of measles, mumps, rubella, or varicella was documented. In addition, the patient had never suffered from HZ.

Given the severe skin condition of the patient and the potential risks associated with a possible HZ episode, referring physicians requested age-related off-label Recombinant Zoster Vaccine (RZV) prophylaxis before the beginning of JAKi therapy.

Prior formal request and approval of off-label administration by the Institutional Ethics Committee of “Burlo Garofalo Scientific Institute for Research, Hospitalization and Healthcare” and by Board of Medical Directors of the healthcare facility providing care to the patient, the child was admitted to hospital as a day patient. This setting was chosen to combine scheduled routine examinations and infusions with vaccine administration, thereby providing the opportunity for extended observation. No serological evidence of varicella zoster virus (VZV) IgG antibody titer was available prior vaccine administration. At the time of vaccination, the child was not receiving any long-term treatment for the underlying condition.

The patient was admitted to hospital on February 22, 2024, to receive the first RZV dose. In the vaccination anamnesis, the recent medical history included an episode of acute otitis media treated with amoxicillin-clavulanic acid (February 9th–13th) and ciprofloxacin (since February 13th and still ongoing on February 22nd) due to an extensive, excavated wound on the anterior surface of the tibia, with Pseudomonas aeruginosa isolated in wound specimens. Moreover, the lesion was treated with laser therapy sessions. At the time of vaccination, the patient was in a stable clinical condition with no immediate concerns. Weight was 20.2 kg and height was 117.6 cm. The physical examination revealed no abnormal thoracic, abdominal, or cardiovascular findings. As regards the underlying medical disease, bullous lesions, and areas of de-epithelialization were present in the abdominal and thoracic regions. Blood tests performed on the same day indicated below-normal hemoglobin levels (9.3 g/dL, reference range 12–14) – albeit showing an increasing tendency compared to previous tests – and elevated inflammatory markers (CRP 146.4 mg/L, normal <5; ESR 93 mm/h, reference range 2–20), as well as low albumin levels (2.17 g/dL, reference range 3.90–4.90).

Thus, the first standard adult RZV dose (Shingrix 0.5 mL batch ZR3TC exp. 02/2026) was administered intramuscularly in the deltoid area on February 22, 2024. On the same day, the patient also received 300 mg ferric carboxymaltose infusion and 10 g albumin infusion. In addition, a laser therapy session was performed, and wounds were treated with appropriate dressings.

The second standard adult RZV dose (Shingrix 0.5 mL batch ZR3TC exp. 02/2026) was administered intramuscularly on April 29, 2024. The child had just completed (April 28, 2024) an additional 2-week ciprofloxacin course for the management of the aforementioned Pseudomonas aeruginosa-complicated cutaneous lesion.

At the time of the second RZV dose, the patient was found to be in good clinical conditions by referring physicians: weight was increasing (22 kg), hemoglobin levels were improving (10.7 g/dL, reference range 12–14), as well as CRP (131.9 mg/L, normal <5). The electrocardiogram (ECG) revealed no abnormal findings. A slight increase in ESR value was detected (120 mm/h, reference range 2–20).

Vital signs were measured right before and after both RZV administrations. No immediate Adverse Events Following Immunization (AEFIs) occurred after vaccination. No AEFIs manifested during the hospital stay, nor alterations in vital signs were recorded. Therefore, the child was regularly discharged on the same day.

A first telephone follow-up was performed by referring physicians in the first 7 days after both the first and the second RZV dose, in order to record any AEFIs occurred in the post-vaccination period. Parents referred no adverse events following either vaccine dose.

The patient’s clinical conditions remained stable, with no exacerbations nor newly onset clinical manifestations of the underlying disease recorded in the 6 months following vaccination. In the same time interval, no incident HZ episodes occurred. Assessment of post-vaccination serological response is not available.

Discussion and conclusion

In this case report, we describe the outcome of off-label administration of recombinant adjuvanted zoster vaccine (RZV) in a 10-year-old female patient affected by a severe form of epidermolysis bullosa (EB), i.e., Recessive Dystrophic Epidermolysis Bullosa (RDEB). RDEB is a rare and critical form of EB, usually presenting at birth and characterized by significant clinical, financial, and human burden.³ Clinically, continuous blistering and inflammation, with wounds often complicated by relapsing infections by pathogenic bacteria, contribute to the severity of the cutaneous manifestations observed in the affected patients.⁴ Hence, any other concomitant cutaneous disease would further complicate an extremely compromised cutaneous condition.³¹

In the case under discussion, the use of Baricitinib was expected to provide clinical benefits for the underlying disease.³² However, literature has already explored the association between JAKi therapy and an increased risk of herpes zoster.^33,34 Hence, while this treatment could effectively address the patient’s baseline condition, it could concurrently increase the patient’s risk to develop Herpes Zoster (HZ), potentially leading to severe and unpredictable dermatological complications.

Given these considerations, HZ prophylaxis was deemed a priority before starting JAKi therapy in this 10-year-old patient with RDEB diagnosis. However, as of current regulatory guidelines, neither of the available HZ vaccines (i.e., ZVL and RZV) could be administered to this patient, as both would be off-label due to age restrictions.^15,16 In addition, ZVL was also contraindicated due to patient’s eligibility to immunosuppressive therapy, as the live-attenuated zoster vaccine carries a risk of disseminated VZV infection and death even in subjects who are mildly immunocompromised.^35,36 Thus, RZV was considered the most appropriate option for the present case, given its broader indications for preventing both HZ and PHN in younger (approved for use starting at 18 years of age,¹⁶ as opposed to ZVL,¹⁵ which is indicated from age 50) high-risk and immunocompromised patients, as well as individuals eligible for immunosuppressive treatment. Indeed, despite reduced immunogenicity^37,38 and efficacy²⁴ of the Recombinant Zoster Vaccine in patients receiving JAKi therapy compared to immunocompetent individuals, breakthrough HZ infections remain rare.³⁹ Thus, the use of RZV is still recommended for this vulnerable population to provide protection against HZ reactivation.⁴⁰

Additionally, even in the absence of regulatory provisions, literature documented RZV administration in a pediatric patient, further supporting its applicability in this context.⁴¹ Indeed, one case of pediatric RZV administration was described in literature at the time of the request for off-label prescription. In that case, RZV was used for primary prevention of varicella in a susceptible 10-year-old boy with primary immunodeficiency. The age and indication-based off-label administration of a two-doses RZV series in this subject demonstrated a satisfying response in terms of immunogenicity (i.e., protective anti-Varicella Zoster Virus IgG titer was detected) and safety (i.e., fever was the only AEFI reported). To our knowledge, no further literature evidence about RZV use in pediatric population is available as of December 15, 2024.

RZV administration to our 10-year-old patient as a two-dose series, with the latter being administered approximately 9 weeks after the former, did not raise any safety concerns in terms of Adverse Events Following Immunization (AEFIs), baseline condition flares, and incident HZ episodes over the 6 months following vaccination. A careful post-vaccination safety monitoring was needed due to concerns that RZV might potentially trigger exacerbation of bullous skin diseases in patients with autoimmunity.⁴² However, an analysis of spontaneous reports in the GSK worldwide safety database, encompassing over 32 million doses, did not identify any safety signals regarding the onset of non-HZ vesicular and bullous cutaneous eruptions following RZV vaccination.⁴³ On the other hand, it must be noted that the absence of AEFIs manifested by our patient is unusual, given that injection site reactions have been consistently reported at high rates in both pre- and post-marketing studies.^26,38 While a post hoc analysis of two phase 3 trials revealed a minor statistical correlation between injection site pain intensity and immunogenicity following RZV, the authors concluded that reactogenicity could not serve as a reliable predictor of vaccine-induced immune protection, as the impact of vaccine reactogenicity on the immune response was minimal and adequate immune response was achieved even in individuals without pain.⁴⁴

In this context, however, the absence of serological testing both prior to and after vaccination did not allow for vaccine immunogenicity assessment. Despite this aspect representing a major limitation of this case report, as we could not definitely assess actual immune response to vaccination, especially considering the implications of the scheduled JAK inhibitor treatment, it is important to underline that the relationship between humoral immunity and protection against HZ reactivation remains incompletely elucidated. Rather, current literature evidence highlights the pivotal role of cell-mediated immunity (CMI) in controlling HZ onset, influencing the severity of its skin lesions, and mitigating the risk of post-herpetic neuralgia (PHN), as evidenced in a cohort of 12,522 individuals over 50 years of age. In contrast, in the same cohort, similar effects were not attributed to Varicella-Zoster Virus (VZV)-specific antibody titers.^45,46 This fundamental immunological insight had been also considered during RZV development. Indeed, as demonstrated in a phase II clinical trial exploring adjuvant use for what was at the time an investigational recombinant zoster vaccine, the adjuvant eventually selected for RZV proved to be valuable because it enhanced both humoral immunity and, crucially, cell-mediated immunity (CMI). As argued by authors, this dual effect was particularly significant, as the persistence of CMI could possibly counteract the reduction in vaccine efficacy.⁴⁷ In the present case, in absence of immunogenicity data, it will thus be important to monitor the patient’s long-term vaccination effectiveness in preventing HZ episodes, especially considering the impact of ongoing immunosuppressive therapy.

In conclusion, the present case demonstrates the safety profile of recombinant zoster vaccine (RZV) in a 10-year-old female subject at increased risk of HZ, while also providing preliminary effectiveness data for the initial 6-month post-vaccination period. This case offers a valuable insight into the potential application of RZV in the pediatric population, which remains susceptible to HZ secondary to concomitant disease or immunosuppressive treatment.⁴⁸ However, robust safety and efficacy studies are warranted to support the potential implementation of RZV vaccination protocols for high-risk individuals under 18 years of age.

Biography

Pasqale Stefanizzi qualified in Medicine at the University of Parma in 2014, and he achieved a post degree in Hygiene and Preventive Medicine at the University of Bari in 2019. He is a consultant of the Apulian Observatory for Epidemiology in the field of immunization policies (focus on safety and effectiveness of vaccination programs), surveillance and management of infectious diseases, health organization. From July 2020, he has been Assistant Professor of Public Health at the School of Medicine in Bari. He works as a medical doctor at the Bari Policlinico General Hospital – Hygiene Unit, in which he is charged of the management of vaccination activities; since March 2020, he is a member of the COVID-19 Control Room Unit.

He is a member of the National Group of monitoring safety of vaccines coordinated by the National Drug Agency.

He is author or coauthor of 120 indexes scientific papers and over 10 teaching books in the fields of epidemiology and public health.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Disclosure statement

The undersigned hereby formally declare that there are no conflicts of interest regarding the manuscript submitted for publication. We affirm that we have no financial, professional, or personal relationships that could inappropriately influence our work in the context of this manuscript. In the event of a potential conflict of interest arising during the review or publication process, we commit to promptly communicating it to the editors of the journal.

Ethical statement

The study was approved by the Ethics Committee of Burlo Garofalo Scientific Institute for Research, Hospitalization and Healthcare. The study follows the principles of the World Medical Association.