Reactivation of Varicella-Zoster Virus Keratitis after Recombinant Herpes Zoster Vaccination: A Case Report and Literature Review

Abstract

Introduction

Varicella-zoster virus (VZV) keratitis following recombinant herpes zoster (HZ) vaccination is rare, and its underlying mechanisms remain poorly understood. Sporadic cases of ocular inflammatory reactivation have been reported after vaccination, particularly in patients with a history of HZ infection.

Case Presentation

A 68-year-old woman with a history of trigeminal HZ without prior corneal involvement developed VZV keratitis 2 months after receiving the recombinant HZ vaccine (Shingrix^®). The condition progressed to neurotrophic keratitis, requiring advanced ocular surface therapy, including autologous serum and topical insulin, with favorable visual and symptomatic outcomes.

Conclusion

Reactivation of VZV keratitis after HZ vaccination is an uncommon but clinically relevant event. Ocular reactivation may occur even in patients without previous corneal involvement and may lead to chronic complications, supporting the need for close ophthalmologic follow-up in patients with a history of HZ infection.

Introduction

Herpes zoster (HZ) results from reactivation of the varicella-zoster virus (VZV), a neurotropic herpesvirus that remains latent in sensory ganglia following primary varicella infection [1]. The incidence of HZ is relatively high, with an estimated lifetime risk of 1 in 3 individuals, predominantly affecting adults older than 50 years [2]. In approximately 10–20% of cases, HZ involves the ophthalmic branch (V1) of the trigeminal nerve, leading to herpes zoster ophthalmicus (HZO), which may affect ocular structures [3].

The recombinant zoster vaccine Shingrix^® (GlaxoSmithKline Biologicals S.A.), introduced in 2017, has demonstrated high efficacy and is currently the preferred vaccine for HZ prevention in adults aged 50 years and older. It contains the VZV glycoprotein E combined with the AS01B adjuvant system, which induces a robust CD4+ T-cell-mediated immune response and strong humoral immunity [4, 5].

Although its safety profile, isolated cases of ocular inflammatory reactivation following vaccination have been reported, including VZV keratitis and uveitis in patients with prior HZO. The underlying mechanism remains unclear, though exaggerated immune responses triggered by the vaccine adjuvant have been proposed [6, 7]. We report a case of VZV keratitis developing after recombinant HZ vaccination in a patient with a prior history of trigeminal HZ without previous corneal involvement, which subsequently progressed to neurotrophic keratitis.

Case Presentation

A 68-year-old woman with a history of left trigeminal HZ without corneal involvement in 2020 received the Shingrix^® vaccine in July 2024. In September 2024, she was referred to the cornea service due to corneal edema and a previous diagnosis of dry eye disease.

At initial ophthalmologic evaluation, best-corrected visual acuity (BCVA) in the left eye was 20/200. Slit-lamp examination revealed corneal hypoesthesia, a pseudodendritic lesion with positive lissamine green staining, subepithelial edema, mucous plaques, and retrokeratic precipitates without anterior chamber reaction, as shown in Figure 1. A diagnosis of VZV keratitis was established, and treatment was initiated with oral valacyclovir 1 g twice daily for 14 days, topical ganciclovir 1.5 mg/g four times daily, topical sodium hyaluronate 0.4% every 2 h, and topical prednisolone acetate 1% every 2 h.

Fig. 1.

Slit-lamp photograph of the left eye showing a pseudodendritic corneal lesion with positive lissamine green staining, subepithelial edema, mucous plaques, and retrokeratic precipitates without anterior chamber inflammation.

In October 2024, 1 month after treatment initiation, the pseudodendritic lesion resolved and BCVA improved to 20/30 in the left eye. In November 2024, the patient developed anterior uveitis in the right eye, contralateral to the eye previously affected by VZV keratitis. Systemic workup revealed positive antinuclear antibodies with a homogeneous pattern, prompting referral to internal medicine; the remaining tests were unremarkable. This was considered a separate inflammatory event rather than a direct continuation of the left-eye VZV keratitis. However, given the patient’s positive antinuclear antibodies, an underlying autoimmune predisposition was also considered.

In March 2025, the patient presented with left-eye pain, photophobia, and blurred vision (BCVA 20/150). Diffuse punctate epithelial erosions and corneal anesthesia were documented, leading to a diagnosis of grade I neurotrophic keratopathy associated with severe dry eye disease. Treatment included 20% autologous serum eye drops, topical loteprednol, 0.2% polyacrylic acid, topical cyclosporine 0.05%, sodium hyaluronate 0.4%, oral medroxyprogesterone, and oral pilocarpine. Lacrimal punctal plugs were attempted but could not be placed due to canalicular fibrosis.

Oral medroxyprogesterone was used as part of the systemic management of severe dry eye disease, given its potential modulatory effects on ocular surface inflammation and lacrimal gland function. Oral pilocarpine, a cholinergic agonist, was prescribed to stimulate tear secretion in the setting of significant ocular surface dryness and reduced lacrimal function, as supported by its use in aqueous-deficient dry eye conditions [8, 9].

In May 2025, due to persistent diffuse epithelial erosions, topical insulin (5 IU/mL, four times daily) was initiated, resulting in symptomatic improvement and visual acuity recovery (BCVA 20/50 in the left eye), with an adequate response to medical management, as shown in Figure 2. Given the complexity of the clinical course, a detailed timeline of events is provided in Table 1.

Fig. 2.

Fluorescein staining of the left eye demonstrating mild inferior punctate staining. The cornea appears clear with intact epithelium, no abrasions or active keratitis, and a stable tear film with preserved tear meniscus.

Table 1.

Clinical timeline of the present case

Timeframe	Event	Key findings	Management
2020	Trigeminal HZ (left)	No documented corneal involvement	Not applicable
July 2024	Shingrix® vaccination	Not applicable	Not applicable
September 2024	VZV keratitis (left eye)	Pseudodendritic lesion, corneal hypoesthesia, edema. BCVA in the left eye was 20/200	Oral and topical antivirals, preservative-free artificial tears, topical steroids
October 2024	Follow-up	Resolution of epithelial lesion, BCVA in the left eye 20/30	Continued treatment
November 2024	Contralateral anterior uveitis (right eye)	Anterior chamber inflammation, ANA positive	Topical steroids
March 2025	Neurotrophic keratopathy (left eye)	Epithelial erosions, corneal anesthesia	Intensive ocular surface therapy including autologous serum, topical anti-inflammatory and lubricating agents, and systemic therapy (oral medroxyprogesterone and pilocarpine)
May 2025	Persistent epithelial disease	Severe ocular surface involvement	Topical insulin
Latest follow-up	Clinical improvement	BCVA 20/50	Maintenance therapy

The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552965).

Discussion

Reactivation of VZV keratitis following recombinant HZ vaccination is an uncommon event, with limited cases reported in the ophthalmic literature. In the present case, the patient developed VZV keratitis shortly after vaccination, with clinical features suggestive of an immune-mediated reactivation associated with an adjuvanted recombinant vaccine. The temporal relationship between vaccination and symptom onset supports a possible association, although causality cannot be definitively established.

A structured review of the literature identified a limited number of reported cases of ocular VZV reactivation following the recombinant zoster vaccine since its approval in 2017. Most reported cases have occurred in older patients with a prior history of HZO, typically presenting as recurrent stromal keratitis within 1–3 weeks after vaccination. In these cases, diagnosis was primarily clinical, with virological confirmation rarely performed, and outcomes were generally favorable following antiviral and anti-inflammatory therapy [6, 10, 11]. More recent reports have described broader clinical presentations, including dermatomal HZO with polymerase chain reaction (PCR) confirmation and mild corneal involvement [12]. Additionally, observational data suggest that patients with a history of HZO may have an increased risk of recurrence in the early post-vaccination period, with keratitis being the most reported manifestation, as summarized in Table 2 [13].

Table 2.

Reported cases of ocular VZV reactivation following recombinant zoster vaccination (Shingrix)

Author (Year)	Age/sex	Prior HZO	Interval after vaccination	Ocular manifestation	Virological confirmation	Treatment	Outcome
Lehman & Matoba (2018) [10]	89/M	Yes (stromal keratitis)	3 weeks	Stromal keratitis	Not reported	Topical steroids	Resolution
Jabbour et al. (2021) [11]	78/F	Yes (HZO)	1 week (after 2nd dose)	Necrotizing stromal keratitis	Not reported	Oral antivirals, preservative-free artificial tears, amniotic membrane	Resolution
Lu & Ta (2022) [6]	75/F	Yes (HZO keratitis)	2.5 weeks (after 1st dose)	Stromal keratitis	Not reported	Topical steroids, oral antivirals	Resolution
Garcia & Haddadin (2024) [12]	59/M	No clear HZO history	2–9 days	HZO (V1 rash mild ocular involvement)	PCR positive (VZV)	Oral antivirals	Resolution
Walia et al. (2024)* [13]	Cohort study	Prior HZO	Within 56 days (risk window)	HZO recurrence/exacerbation (based on clinical diagnosis and treatment changes)	Not applicable	Not applicable	Increased recurrence risk
Present Case	68/F	Prior trigeminal HZ (no documented corneal involvement)	2 months	VZV pseudodendritic keratitis + anterior uveitis + neurotrophic keratopathy	No PCR	Oral and topical antivirals, anti-inflammatory therapy, topical insulin	Favorable

*Observational cohort study, not a single case report.

In contrast, the present case differs from previously reported cases in several important aspects. First, the patient had no documented prior corneal involvement during her initial trigeminal HZ episode, whereas most published cases involve individuals with pre-existing corneal disease. Second, the interval between vaccination and symptom onset was approximately 2 months, which is longer than the 1–3 weeks typically reported [6, 10, 11]. Although this may reflect delayed presentation or incomplete early documentation at an external institution, it introduces uncertainty regarding the temporal relationship.

Notably, the anterior uveitis occurred in the contralateral eye, making a direct extension of the VZV keratitis unlikely. Instead, this finding suggests either a separate inflammatory event or a possible systemic immune-mediated response. The presence of positive antinuclear antibodies further supports the possibility of an underlying predisposition to immune dysregulation contributing to bilateral ocular involvement. Finally, the clinical course progressed beyond epithelial keratitis to neurotrophic keratopathy, a complication not described in prior post-vaccination reports.

The mechanisms underlying VZV reactivation following recombinant zoster vaccine still remain incompletely understood. The vaccine contains a recombinant VZV glycoprotein E combined with the AS01B adjuvant system, which induces a strong CD4+ T-cell-mediated immune response [4, 5]. It has been hypothesized that this immune activation may paradoxically trigger reactivation of latent VZV in susceptible individuals, particularly those with prior infection. In this context, the autoimmune/inflammatory syndrome induced by adjuvants has been proposed as a potential explanatory framework [7], whereby adjuvants may trigger immune dysregulation in genetically predisposed individuals. Although this hypothesis remains speculative, it may be relevant in this case given the presence of positive antinuclear antibodies, suggesting a possible underlying autoimmune predisposition.

Neurotrophic keratopathy in this patient likely reflects cumulative trigeminal nerve dysfunction associated with HZ infection and subsequent inflammatory damage [14]. Reduced corneal sensitivity impairs epithelial healing and predisposes to chronic ocular surface disease. Notably, this case required advanced therapy, including autologous serum and topical insulin, with favorable clinical response. Topical insulin has emerged as a promising and accessible therapeutic option for neurotrophic keratitis, promoting corneal epithelial healing through stimulation of cellular proliferation and migration, as well as enhancement of epithelial metabolism, particularly in settings where recombinant nerve growth factor (cenegermin) is not readily available, and its use represents an effective approach [15, 16].

This report has several important limitations. First, the diagnosis of VZV reactivation was made clinically, without PCR confirmation, which limits etiologic certainty. Second, the temporal association between vaccination and disease onset does not establish causality, particularly given the longer interval. Third, the presence of positive antinuclear antibodies raises the possibility of an underlying autoimmune contribution. Fourth, corneal sensitivity was assessed clinically but not quantified using esthesiometry. Additionally, the occurrence of contralateral anterior uveitis introduces uncertainty regarding the relationship between vaccination and ocular findings, as it may reflect an independent or immune-mediated process. Finally, the prior episode of trigeminal HZ was based on patient history, without documented slit-lamp examination to confirm the absence of corneal involvement.

Despite these limitations, this case highlights an important clinical scenario: ocular VZV reactivation following recombinant zoster vaccination in a patient without previously documented corneal involvement, progressing to keratitis and neurotrophic keratopathy. Although rare, such cases underscore the importance of clinical vigilance, particularly in patients with a history of HZ. Further studies are needed to better characterize the risk, mechanisms, and optimal management of post-vaccination ocular inflammatory events.

Conclusion

This case highlights the importance of considering viral ocular disease reactivation as a rare but clinically significant adverse event following recombinant HZ vaccination. While the benefits of Shingrix^® far outweigh its risks, close post-vaccination ophthalmologic monitoring may be warranted in patients with a history of VZV-related ocular disease. Further clinical evidence is needed to better characterize immunologic risk profiles and to develop specific management guidelines for post-vaccination ocular reactivations.

Statement of Ethics

Ethical approval was not required for this study in accordance with local or national guidelines, as this manuscript describes a single anonymized case report. Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

The authors received no financial support for the research, authorship, or publication of this article.

Author Contributions

S.M.-M. contributed to study supervision and final manuscript revision. S.M.M.-C. contributed to the conception of the case report, data collection, literature review, and manuscript drafting. All authors approved the final version of the manuscript.

Funding Statement

The authors received no financial support for the research, authorship, or publication of this article.

Data Availability Statement

The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of the patient but are available from the corresponding author upon reasonable request.