Varicella Zoster vaccination in hemodialysis patients: The state of the art

ABSTRACT

Varicella Zoster Virus (VZV) infection is a common childhood exanthematous disease, which in adults and immunocompromised people may result in severe neurologic complications. Up to one-third of infected subjects may have VZV clinical reactivation particularly if immunocompromised. Patients affected by end-stage renal disease on hemodialysis present immunodepression that contributes to their higher incidence of VZV infections and reactivation. While antiviral treatment in these patients shows low efficacy, the prevention of VZV through vaccination avoids the primary infection and the risk of reactivation. Two VZV vaccines are currently available: the live attenuate Zoster Vaccine (LZV) and a Recombinant Zoster Vaccine (RZV), with the latter appearing to provide greater efficacy. Given the higher incidence of VZV infection and reactivation, the lesser response to antivirals and the lower impact of VZ vaccine in hemodialysis patients in terms of side effects, a higher diffusion of VZV vaccination should be promoted by nephrologists in these patients in particular in those with future transplant opportunities.

KEYWORDS:

• Varicella Zoster virus infection
• Varicella Zoster virus reactivation
• Zoster vaccines
• hemodialysis
• end stage renal disease

Chickenpox (also known as varicella) is the primary infectious disease caused by Varicella Zoster Virus (VZV), an alpha herpes virus belonging to the Herpesviridae family.

VZV infection is a worldwide common childhood exanthematous disease, highly contagious, associated with a benign and self-limiting course. Primary VZV infection in adults and immunocompromised people may result in severe neurologic complications such as meningoencephalitis, myelitis, vasculopathy, temporal arteritis and acute retinal necrosis.¹ Specifically, VZV primary infection strongly impacts stroke risk within the first 30 days² and although its impact on the death risk seems modest, it increases only among immunocompromised subjects.³

After primary infection, VZV becomes latent in the ganglia of the peripheral somatic, autonomic, and enteric nervous systems. Up to one-third of infected subjects may have VZV clinical reactivation or zoster in their lifetimes. Usually, the reactivation risk factors are age over 60 years or treatment with immunosuppressive drugs. Clinical manifestations of VZ reactivation are vesicular eruption on an erythematous base in one to three dermatomes, and severe radicular pain.⁴ Postherpetic neuralgia is the most common long-term complication: it consists of severe and burning pain in a unilateral dermatomal pattern that persists for three or more months after the onset of VZ outbreak. It is often resistant to painkillers and antiviral treatments and comports a significantly worsening quality of life.⁵ Recent findings show that VZV reactivation can lead also to severe cardiovascular and neurological complications by generating VZV-related focal vasculopathies.^6,7

Patients affected by end-stage renal disease (ESRD) present an immune dysfunction⁸ characterized by immunodepression that contributes to the high incidence of infections and reactivation among these patients. Persistent, low-grade inflammation has been recognized as an important component of ERSD, contributing to the immune dysfunction. Specifically, ESRD patients have about double the risk of VZV of reactivation than the general population with an adjusted HR of 1.98.⁹ Hemodialysis does not improve immune impairment due to ESRD.¹⁰

Antiviral agents, including acyclovir, valacyclovir, and famciclovir are used in the treatment of acute herpes zoster infection. In the general population, acyclovir is a widely used and generally well-tolerated antiviral agent in VZV reactivation. In patients with ESRD, its half-life is significantly increased from 3 to more than 20 hours, predisposing to neurological side effects and requiring a mandatory dose modification. Furthermore, in hemodialysis patients, the antiviral treatment shows lower efficacy, and the need for longer treatment therefore increasing the rate of side effects and viral resistance. Valacyclovir is preferred in clinical practice because it entails less frequent dosing compared with acyclovir and lower costs compared with famciclovir. Because valacyclovir is excreted through the kidneys, patients with impaired renal function might be the most susceptible to valacyclovir-associated neurotoxicity.¹¹

Prevention of VZV through vaccination avoids the primary infection and the risk of reactivation in susceptible subjects. Live attenuated vaccine (Live Zoster Vaccine – LZV) and a recombinant subunit vaccine (Recombinant Zoster Vaccine – RZV) are currently authorized in Europe.

The LZV was authorized for the first time in 2006. In the phase III study LZV, the administration reduced the burden of illness due to VZV among immunocompetent people 60 years of age or older by 61.1%, reduced the incidence of postherpetic neuralgia by 66.5%, and reduced the incidence of reactivation by 51.3%.¹² According to the European Medicines Agency (EMA) the LZV, given as a single dose injected under the skin or into the muscle, is indicated for immunocompetent individuals over 50 years old, to prevent VZV primary infection and/or reactivation. Currently, there is no recommendation for LZV booster doses. Post-marketing studies have shown that protection with LZV quickly declines: LZV can provide at least a decade of protection against reactivation after initial vaccination. LZV is contraindicated in immunocompromised individuals by HIV/AIDS or another disease that affects the immune system, in patients on active treatment with drugs that affect the immune system, and in patients undergoing cancer treatment due to the risk of severe disseminated infection.¹³ The RZV was approved in Europe in 2020. This vaccine is based on VZV glycoprotein E, as an antigen, associated with AS01B, as an adjuvant system. The glycoprotein E plays an essential role in VZV replication and transmission between ganglia cells and the AS01B induces innate immunity activation, improving the immune response’s quality and strength to the vaccine.^14,15 In the phase III studies (ZOE-50 study evaluated efficacy and safety of RZV in adults 50 years of age and older, and ZOE-70 evaluated efficacy and safety of RZV in adults 70 years of age and older) RZV showed protective rates of 96.6%, 97.4% and 91.3% for people aged 50–59, 60–69 and over 70 years, respectively. RZV also showed a rate of 88.8% in the reduction of postherpetic neuralgia in those over 70 years old.¹⁶ According to the EMA, RZV is indicated in adults aged 50 and older and in adults aged 18 years and older who are or will be at increased risk of VZV due to immunodeficiency or immunosuppression caused by known diseases or therapies.

The vaccination course consists of 2 intramuscular injections given two months apart, or in some cases within six months after the first dose. Current data shows that RZV has optimal efficacy and is long-lasting in the elderly and frail population.¹⁷ A re-immunization with two doses of RZV may be considered at least one year after LZV or at least one year after the VZV primary infection or reactivation.^18,19

Unfortunately, few data are available regarding the efficacy and safety of VZV vaccination in the ESRD population treated with hemodialysis. Regarding LZV, Tseng et al. performed a large cohort study including ESRD patients aged 60 years old and older, showing better LVZ protection if the VZV vaccine was given before the initiation of hemodialysis; receiving LZV in the first months after dialysis could potentially induce better protection than receiving LZV after long-term dialysis vintage. LZV was also associated with a lower incidence of reactivation, 11.7 per 1000 persons/year among vaccinated people versus 22.3 per 1000 persons/year among those unvaccinated.²⁰ In 2018, the meta-analysis by Ong et al.²¹ investigated the efficacy and safety of two doses of LVZ in the ESRD population. Three studies out of 29 examined the seroconversion rate after the administration of two doses of vaccine. Crespo et al. reported a highly encouraging response rate of 94%,²² while the studies of Geel et al. and Kho et al. found a sub-optimal response rate around 64–77%.^23,24

Regarding the possible side effects, Crespo et al. and Geel et al. did not report severe side effects after vaccination,^22,23 while Kho et al. reported rare but present cases of VZ primary infection and reactivation after vaccination.²⁴ A more recent meta-analysis by Hamad et al. showed similar effectiveness and adverse events rate in the ESRD population, suggesting better effectiveness in the non-dialysis CKD group.²⁵

In 2023, we have provided the first retrospective report which evaluated RZV in 196 adult patients treated with hemodialysis, showing a satisfactory adherence to the vaccination campaign (70%) and a good safety profile with only mild side effects and no serious adverse events after vaccination.²⁶

Currently, very few data concerning RVZ are available for patients affected by chronic kidney disease and in particular dialysis patients. The lack of data is probably due to the relatively recent commercialization and distribution of RZV. Given the higher incidence of VZ infection and reactivation, the lower answer to antiviral treatment, and the lower impact of the vaccine in terms of side effects in hemodialysis patients, a higher distribution of VZV vaccination should be promoted by nephrologists, especially in older patients. According with current knowledge, it is difficult to suggest which vaccine is more suitable for hemodialysis patients. If LZV shows significant effectiveness in hemodialysis patients although with a side effect profile showing rare but present reactivation or primary infection of VZV, RZV showed an encouraging side effect profile and a greater efficacy, although no data are yet available in the hemodialysis patients regarding its efficacy in the medium-long term.

Considering the balance between the risks and benefits of VZV vaccination, a VZV vaccine campaign with LVZ or, preferably, with RVZ should be suggested in hemodialysis patients in particular in those patients with future transplant opportunities especially if over 60 years old, frail and with other comorbidities.

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Funding

The authors have no financial or non-financial competing interest to declare.