The Varicella-Zoster Virus (VZV), also known as varicella-zoster virus, can cause two different diseases in humans at various stages of life, namely chickenpox and shingles. Chickenpox is the primary infection caused by VZV, characterized by widespread rashes or blisters, and it primarily occurs in infants and children. After the initial recovery from the virus, VZV remains latent in areas like the spinal nerve ganglia in the human body. With age and a decline in the immune system, VZV can reactivate, leading to clusters of blisters and localized nerve pain, known as shingles. According to the Frost & Sullivan report, the global incidence rate of shingles in the general population is 3-5 cases per 1,000 person-years. At the age of 60, the incidence rate rises to 6-8 cases per 1,000 person-years, and by the age of 80, it can reach 8-12 cases per 1,000 person-years. According to data from the Centers for Disease Control and Prevention (CDC) in the United States, it is estimated that one-third of people in the United States will experience shingles in their lifetime, with nearly a million cases occurring each year(sources from

    Currently, there are approved vaccines for shingles on the market, with different technological approaches including live attenuated vaccines and recombinant subunit vaccines. However, the existing shingles vaccines have certain limitations. Live attenuated vaccines are less effective for older patients and are not suitable for immunocompromised individuals. Recombinant subunit vaccines are more effective for older individuals but may have higher reactogenicity due to the AS01B adjuvant component, resulting in more significant side effects. Therefore, there is a pressing need for a shingles vaccine with fewer side effects and superior immunogenicity. mRNA technology, as a new generation vaccine platform, has the potential to be a breakthrough in the development of the next generation of shingles vaccines due to its rapid development capabilities and platform-based production processes.

    I. Brief Overview of Herpesviruses Structure

    Herpesviruses belong to a large family of DNA viruses and can be classified into three subfamilies: α-herpesviruses, β-herpesviruses, and γ-herpesviruses. There are nine known human herpesviruses, with five of them being widely spread among the human population. These include herpes simplex viruses (HSV1 and HSV2), both of which can cause oral and genital herpes, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), which primarily infects B lymphocytes, and human cytomegalovirus (HCMV), leading to the formation of nuclear and cytoplasmic inclusions and cell swelling after infection.

    Different types of herpesviruses share a similar structure, characterized by four distinct layers:

    Core: The core consists of a single linear double-stranded DNA molecule, encoding 100-200 genes.

    Capsid: Surrounding the core is an icosahedral capsid with a diameter of approximately 100 nm, composed of 162 capsomers.

    Tegument: The tegument is an amorphous structure located between the capsid and the envelope. Tegument proteins are further categorized into outer tegument proteins and inner tegument proteins, forming a compact viral particle depending on their positions on the virus particle.

    Envelope: The envelope constitutes the outermost layer of the virus and is composed of host cell membranes and various unique glycoproteins. It exhibits spherical to pleomorphic shapes with a diameter ranging from 150 to 200 nm, and it follows a T=16 icosahedral symmetry. Notably, herpesviruses contain 11 glycoproteins in their envelope, including gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM. The VZV glycoproteins, in particular, are associated with host cell invasion and serve as target antigens for herpesvirus vaccine development.

    II. Marketed Shingles Vaccines

    Zostavax, a live attenuated vaccine for shingles produced by Merck & Co., was approved by the FDA on May 25, 2006, for the prevention of shingles in individuals aged 50 and over. Key Phase III study data showed that compared to a placebo, Zostavax reduced the risk of shingles by nearly 70% in adults aged 50 to 59(quotes from Zostavax was indicated for the prevention of shingles in individuals aged 50 and over. However, it was not suitable for the treatment of shingles or postherpetic neuralgia (PHN), nor could it be used for preventing chickenpox. As of November 18, 2020, Zostavax ceased production in the United States.

    On October 20, 2017, the FDA approved Shingrix, manufactured by GSK, for the prevention of shingles in adults aged 50 and over. Shingrix is a recombinant subunit vaccine with gE protein as its primary component, combined with the AS01B adjuvant, and administered as a two-dose intramuscular injection. The approval of Shingrix was based on comprehensive Phase III clinical trials, which assessed its safety and immunogenicity in over 38,000 participants. Summarized data analysis indicated that Shingrix demonstrated efficacy in preventing shingles exceeding 90% across all age groups, with sustained effectiveness over a follow-up period of 4 years. By preventing shingles, Shingrix also reduced the overall incidence of postherpetic neuralgia (PHN).

    The currently available shingles vaccines have several shortcomings: live attenuated vaccines are less effective in elderly patients and cannot be used in immunocompromised individuals, while subunit vaccines show better efficacy in the elderly but may be associated with higher reactogenicity and greater side effects due to the AS01B adjuvant component. Therefore, there is an urgent need for a shingles vaccine with fewer side effects and superior immunogenicity. Cell-mediated immunity (CMI) responses are crucial for preventing and controlling initial VZV infections and the reactivation of latent infections. Clinical evidence suggests that higher levels of VZV-specific CMI responses are associated with reduced rates and severity of shingles. Hence, this aspect must be considered in the rational development of the next generation of VZV vaccines.

    One significant feature of mRNA vaccines is their ability to effectively induce T-cell responses. mRNA vaccines elicit higher levels of CD4(+) and CD8(+) T-cell responses compared to recombinant protein vaccines. With the tremendous success of mRNA technology in COVID-19 vaccines, there is a natural expectation that mRNA technology can make a breakthrough in the development of shingles vaccines. In fact, aside from shingles virus mRNA vaccines, Moderna has already laid out multiple pipelines for herpes virus mRNA vaccines, including HSV vaccines, EBV vaccines, and CMV vaccines.

    In 2021, Merck and Moderna collaborated on research published in Vaccine titled “Immunogenicity generated by mRNA vaccine encoding VZV gE antigen is comparable to adjuvanted subunit vaccine and better than live attenuated vaccine in nonhuman primates.” They selected a truncated form of VZV gE, with a C-terminal truncation and a Y569 mutation, as the target encoded protein for the mRNA vaccine. This C-terminal truncation and mutation were used to regulate the protein’s folding and expression within cells. In the rhesus monkey model, they found that a single dose of 100-200 μg of VZV gE-mRNA vaccine or two doses of 50 μg each of VZV gE-mRNA vaccine generated immune responses that were comparable to two doses of 50 μg recombinant protein subunit vaccine (VZV gE protein/adjuvant). This indicates that the VZV gE mRNA/LNP platform is capable of inducing a robust immune response, significantly stronger than the live attenuated shingles vaccine.