Exploring the Link between Varicella-Zoster Virus, Autoimmune Diseases, and the Role of Recombinant Zoster Vaccine

Abstract

The varicella-zoster virus (VZV) is a human neurotropic herpes virus responsible for varicella and herpes zoster (HZ). Following primary infection in childhood, VZV manifests as varicella (chickenpox) and enters a period of latency within the dorsal root ganglion. A compromised cellular immune response due to aging or immunosuppression triggers viral reactivation and the development of HZ (shingles). Patients with autoimmune diseases have a higher risk of developing HZ owing to the immunodeficiency associated with the disease itself and/or the use of immunosuppressive agents. The introduction of new immunosuppressive agents with unique mechanisms has expanded the treatment options for autoimmune diseases but has also increased the risk of HZ. Specifically, Janus kinase (JAK) inhibitors and anifrolumab have raised concerns regarding HZ. Despite treatment advances, a substantial number of patients suffer from complications such as postherpetic neuralgia for prolonged periods. The adjuvanted recombinant zoster vaccine (RZV) is considered safe and effective even in immunocompromised patients. The widespread adoption of RZV may reduce the health and socioeconomic burdens of HZ patients. This review covers the link between VZV and autoimmune diseases, assesses the risk of HZ associated with immunosuppressant use, and discusses the benefits and risks of using RZV in patients with autoimmune diseases.

Keywords: Janus kinase inhibitors; autoimmune diseases; herpes zoster; recombinant zoster vaccine.

Figure 1

The life cycle of varicella-zoster virus. Varicella-zoster virus (VZV) infects humans when virions contact the respiratory mucosa of the host. The virus initially replicates locally and subsequently spreads to the tonsils and regional lymph nodes. It is then transported to the skin via T lymphocytes, causing a vesicular rash. During this period, the virion retrogradely travels to the nerve cell body of a sensory ganglion neuron from the site of skin replication, establishing a latent infection. Cellular immunity subsequently regulates VZV replication; however, with declining levels of cellular immunity due to aging or immunodeficiency, VZV reaches the skin through anterograde axonal transport, resulting in a vesicular rash on the skin segments innervated by the affected ganglia.

Figure 2

The potential mechanism of VZV vasculopathy. Varicella-zoster virus (VZV) reaches the vessel wall via anterograde axonal transport and infects arterial adventitial cells. VZV-infected adventitial cells show reduced expression of programmed death-ligand 1 (PD-L1) expression, which promotes persistent inflammation. Interleukin (IL)-6 and IL-8 levels are elevated in the cerebrospinal fluid of VZV-infected patients, facilitating neutrophil chemotaxis and macrophage differentiation in the vasculature. In addition, macrophages produce proteases such as matrix metalloproteinase (MMP)-2 and MMP-9, which disrupt the basement membrane and tight junctions between endothelial cells. These processes amplify vascular inflammation, leading to vascular damage and remodeling.

Figure 3

The effective compositions of the adjuvanted recombinant zoster vaccine. The adjuvanted recombinant zoster vaccine (RZV) is composed of the varicella-zoster virus (VZV) glycoprotein E (gE) antigen and liposome-based AS01B adjuvant. The VZV gE antigen is essential for virion assembly and viral replication, and it is recognized as a major target for VZV-specific CD4+ T-cell responses. The AS01B adjuvant contains two immune stimulants: monophosphoryl lipid A and QS-21. Monophosphoryl lipid A promotes nuclear factor-κB transcription and cytokine production. It works as a Toll-like receptor 4 agonist and stimulates antigen-presenting cells. QS-21 activates CD4+ T-cell-mediated immune responses and antibody production. The effective components of RZV can induce gE-specific CD4+ T-cell and humoral immune responses.

Figure 4

The risk–benefit balance of the adjuvanted recombinant zoster vaccine. The administration of the adjuvanted recombinant zoster vaccine (RZV) is associated with both benefits and risks. The sustained immune response induced by RZV provides long-term protection against herpes zoster (HZ). RZV can reduce the duration of HZ-associated pain. Furthermore, RZV has been demonstrated to be effective and safe for immunocompromised individuals and older adults. The benefits of RZV can mitigate individual complications and medical costs, potentially decreasing the public health burden. Conversely, there is a theoretical risk that AS01B adjuvants may induce autoimmune/inflammatory syndrome induced by adjuvants (ASIA). RZV may also exacerbate immune-mediated disease. Nevertheless, reports of these occurrences are limited. Given the risk–benefit balance, RZV can be considered an effective preventive measure, particularly for individuals at high risk for HZ and its associated complications.