Accurant Mini Workshop: Shingles Vaccine Research - Clinical Research Progress and Bioanalytical Strategies

Introduction

Herpes Zoster (HZ) is an infectious skin disease caused by the reactivation of the Varicella Zoster Virus (VZV), which remains latent in the dorsal root ganglia of the spinal cord or cranial nerve ganglia. The primary clinical symptoms include skin lesions and neuropathic pain [1].

Overview of the Varicella Zoster Virus (VZV)

Varicella Zoster Virus (VZV) is an enveloped virus with a double-stranded DNA genome, belonging to the alpha subfamily of human herpesviruses, and classified as human herpesvirus type 3 (HHV-3). The VZV virion is spherical, measuring 180–200 nm in diameter, and is composed of glycoproteins, an envelope, a tegument, a capsid, and DNA from the outside to the inside (Figure 1) [2]. The virus is encased in a lipid envelope surrounding a 100 nm nucleocapsid structure made up of 162 hexamer and pentamer capsomers arranged in an icosahedral shape. The glycoproteins on the surface of the VZV virion are crucial for the im[KK1]?mune response, as they interact with antigen-presenting cells and enhance the likelihood of antibody production. There are 8 types of VZV glycoproteins: gB, gC, gE, gH, gI, gK, gL, and gM, each with unique physiological roles. Among these gE, gB, gH, and gI are the primary proteins response for inducing the production of specific antibodies. Gglycoprotein gE, in particular, is the most studied and is the leading candidate antigen for vaccine development.

Pathogenesis and Epidemiology of Herpes Zoster

VZV can be transmitted through droplets or direct contact and presents primarily as skin lesions and neuropathic pain. Clinically, VZV leads to two distinct disease forms (Figure 2) [2]: Varicella (Chickenpox), typically a primary infection in individuals without prior immunity, and herpes zoster (shingles), which occurs when the virus reactivates after remaining dormant. The initial VZV infection known as chickenpox, is characterized by a widespread vesicular rash. During this phase, the virus spreads through the bloodstream and infects numerous nerve cells (ganglia) in the spinal cord and cranial nerves, where it remains latent. If the body’s immune system becomes weakened, the latent VZV can reactivate, leading to the development of shingles, which is marked by clustered vesicular skin lesions and localized nerve pain.

Humans are highly susceptible to VZV, with serological evidence indicating that the infection rate of VZV in adults exceeds 90%. Therefore, the general population is at risk of developing shingles. The incidence rate of shingles in the general population worldwide is 3–5 per 1,000 person-years, and in the Asia-Pacific region, it is 3–10 per 1,000 person-years, with an annual increase of 2.5%–5.0%. Among individuals aged 50 and older, the global incidence rate of shingles rises to 5.23–10.9 per 1,000 person-years. Besides age, factors such as hematologic malignancies, HIV infection, and treatment with JAK inhibitors further elevate the risk of shingles.

Postherpetic neuralgia (PHN) is the most common complication of shingles, occurring in 9%–34% of shingles patients, particularly in elderly individuals or those with weakened immune systems. Other complications, such as corneal perforation and necrotizing retinitis, can lead to blindness. In rare cases, shingles may cause visceral damage, manifesting as pneumonia, hepatitis, or encephalitis [1]. Shingles also imposes a significant economic burden on patients and severely impacts their quality of life.

Treatment for Herpes Zoster

The treatment of shingles primarily involves antiviral and analgesic therapies, aiming to promote the resolution of skin lesions, relieve pain, and improve the patient's quality of life [1]. Currently approved systemic antiviral drugs (Table 1) include acyclovir, valacyclovir, famciclovir, brivudine, and foscarnet. Analgesic medications (Table 2) include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), ion channel modulators such as gabapentin and pregabalin, tricyclic antidepressants such as amitriptyline, or, if needed, opioid medications such as morphine or oxycodone.

Overview of Herpes Zoster Vaccine

Vaccination against shingles is an effective strategy to prevent th[KK1]?e reactivation of VZV, thereby reducing the risk of shingles, postherpetic neuralgia (PHN), and other complications. According to Evaluate Pharma, four shingles vaccines have been approved globally: Zostavax (Merck), Shingrix (GSK), SkyZoster (SK Chemicals), and Ganwei (BCHT Biotech). Among these, Shingrix is currently the only option available in the US Market ]?with Zostavax have bee[KK4?n removed from the market.

Shingrix

Shingrix a recombinant subunit adjuvanted vaccine developed by GSK, which uses varicella-zoster virus glycoprotein E (gE) and the AS01B adjuvant. It is administered in two doses by intramuscular injection and induces a strong and long-lasting immune response. Shingrix was approved by the FDA in October 2017 for the prevention of shingles in individuals aged 50 and above. In July 2021, its indication was expanded to include individuals aged 18 and older who are at high risk due to immunodeficiency or immunosuppression. In May 2019, Shingrix was conditionally approved for market use in China, for the prevention of shingles in immunocompetent individuals aged 50 and above.

In global clinical trials conducted in 18 countries and regions (the ZOE-50/70 studies) [5-6], Shingrix demonstrated over 90% efficacy in preventing shingles, significantly reducing the risk of shingles in individuals aged 50 and above. The protective efficacy against shingles was 96.6%, 97.4%, and 91.3% for individuals aged 50–59, 60–69, and 70 and above, respectively. The efficacy in preventing postherpetic neuralgia (PHN) was 91.2% in those aged ≥50 and 88.8% in those aged ≥70. According to a long-term follow-up study in the U.S. (ZOE-LTFU) [7], Shingrix maintained ≥90% efficacy in preventing shingles within four years of vaccination. For participants followed for an average of 5.6 to 9.6 years after vaccination, efficacy was 81.6% (95% CI: 75.2%–86.6%).

Zostavax

Zostavax is a live attenuated herpes zoster vaccine (Zoster Vaccine Live, ZVL) based on the Oka strain. Its production process is similar to the traditional varicella live attenuated vaccine, but with a viral load of ≥19,400 PFU per dose, which is approximately 10 times higher than that of the varicella vaccine. Zostavax was the first shingles vaccine to be approved for the market, receiving FDA approval in 2006 for the prevention of shingles in individuals aged 60 and above, and its indication was expanded in 2011 to include individuals aged 50 and above, with a single-dose immunization regimen.

The efficacy of Zostavax in individuals aged ≥60 years is as follows: it reduces the incidence of shingles by 51% and postherpetic neuralgia (PHN) by 67% [9]. However, the protective efficacy of Zostavax declines significantly with age: the overall efficacy for preventing shingles in people aged 60–69 is 64%, but it drops to about 38% in those aged ≥70. Additionally, the protective efficacy of Zostavax decreases over time, with the incidence of shingles returning to near baseline levels by around the eighth-year post-vaccination. The protective efficacy against shingles drops from 66.9% in the fourth year to 47.7% in the seventh year, and to 37.9% in the eleventh year. The efficacy in preventing PHN also declines, from 60.7% in the fourth year to 11.5% in the eleventh year [10-11]. Due to low preventive efficacy and weak market competitiveness, Zostavax was discontinued in November 2020.

R&D Pipeline

Currently, there are multiple shingles vaccine candidates in R&D phase, utilizing various technological approaches, including recombinant protein vaccines, live attenuated vaccines, mRNA vaccines, and adenovirus vector vaccines. Among the recombinant protein vaccines, the candidates from Maxvax and Luzhu Biotech are progressing the fastest, currently in pivotal Phase III trials. In the live attenuated vaccine pipeline, the product from the Shanghai Institute of Biological Products is in Phase I/II clinical trials. The mRNA shingles vaccines from Moderna and BioNTech are both in Phase II clinical trials, while the mRNA vaccine from Innorna received IND (Investigational New Drug) approval in the U.S. in September 2023, and in China in July 2024. Immorna’s self-replicating RNA (srRNA) shingles vaccine, JCXH-105, is currently in Phase II clinical trials in the U.S. CanSino's shingles vaccine, which uses an adenovirus vector approach, has initiated Phase I clinical studies in Canada.

Summary

Accurant Biotech is an innovative contract research organization (CRO) specializing in providing PK/PD/Immunogenicity/Potency testing service for the clinical and pre-clinical development of innovative new drugs. With a strong global presence across North America and Asia, Accurant Biotech has collaborated with 200+ pharmaceutical and biotechnology companies worldwide. The company plays a pivotal role in advancing the development of novel therapies, including 80+ Cell-Gene Therapy, 60+ multi-specific antibody, and 20+ Antibody-Drug Conjugate products, and multiple Biologics License Application (BLA) approvals. By leveraging a team of over 300 scientists and state-of-the-art technology, Accurant Biotech delivers high-quality, reliable solutions that accelerate the development of life-changing treatments.

Note: This article is credited to Accurant Biotech China Team.

Reference:

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