Varicella-zoster Virus Vaccine Research Articles

Variable Clinical Courses of Varicella Zoster Virus Infection-related or Vaccination-related Bone Marrow Failure.

We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.

Abstract LB353: Repurposing varicella zoster virus and human papillomavirus vaccines for local immunotherapy against solid tumors

Abstract Local immunotherapy against solid tumors is considered a viable approach to stimulate the tumor microenvironment (TME) and anti-tumor immunity. We assessed in situ vaccination with licensed subunit vaccines to leverage preexisting anti-vaccine immunity in the TC-1 tumor model expressing HPV16 viral oncogenes E6 and E7. We chose Shingrix, a VZV vaccine containing the glycoprotein E (gE), and Gardasil-9, an HPV vaccine containing L1 virus-like particles (VLP), to preferentially induce CD4 and CD8 T cell responses, respectively. Intratumoral (IT) injection of Shingrix in Shingrix prevaccinated mice led to complete regression in 20% to 50% of treated mice and elicited CD8 T cell responses against the viral oncoprotein E7. IT injection of an MHC-II-restricted gE peptide with polyI:C also led to durable remission, suggesting that gE-specific CD4 T cells played a significant role in tumor control. In contrast, IT injection of Gardasil-9 in Gardasi-9 prevaccinated animals did not delay tumor growth. However, IT injection of an MHC-I-restricted L1 peptide with Shingrix consistently led to complete remissions perhaps by overcoming preexisting antibodies against native HPV VLP which appeared to inhibit the cross-presentation of VLP derived antigens. TME analysis showed that IT injection of Shingrix with Gardasil-derived peptide induced IFN-gamma, TNF-alpha and CXCL9. This treatment also dramatically reshaped the immune cell infiltrate causing the recruitment of T cells and neutrophils and the decrease of tumor-associated macrophage and eosinophils. We are investigating now how these changes may contribute to tumor clearance and epitope spreading against tumor-derived antigens. Finally, IT injection of Shingrix and a E7 viral neoantigen peptide led to the eradication of all primary injected and abscopal tumors. Our results indicate that the ability of Shingrix to induce exceptionally strong Th1 responses makes it a versatile component for in-situ vaccination which can be combined with peptides derived from licensed vaccines or tumor antigens. Because this approach relies on relatively low cost existing vaccines and inexpensively manufactured minimal CD8 restricted peptides, it has the potential for a broadly applicable cancer immunotherapy strategy for use in resource-constrained settings. The approach is currently being evaluated in a phase I clinical trial in companion dogs with spontaneously arising cancers. Citation Format: Nicolas Cuburu, Shiv K. Sethi, Claire E. Bradley, Lukas Bialkowski, Cynthia D. Thompson, Douglas R. Lowy, John T. Schiller. Repurposing varicella zoster virus and human papillomavirus vaccines for local immunotherapy against solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB353.

Baculovirus Vector-Based Varicella-Zoster Virus Vaccine as a Promising Alternative with Enhanced Safety and Therapeutic Functions.

Varicella-zoster virus (VZV) poses lifelong risks, causing varicella and herpes zoster (HZ, shingles). Currently, varicella and HZ vaccines are predominantly live attenuated vaccines or adjuvanted subunit vaccines utilizing VZV glycoprotein E (gE). Here, we propose our vaccine candidates involving a comparative analysis between recombinant baculoviral vector vaccines (AcHERV) and a live attenuated vaccine strain, vOka. AcHERV vaccine candidates were categorized into groups encoding gE only, VZV glycoprotein B (gB) only, or both gE and gB (gE-gB) as AcHERV-gE, AcHERV-gB, and AcHERV-gE-gB, respectively. Humoral immune responses were evaluated by analyzing total IgG, IgG1, IgG2a, and neutralizing antibodies. Cell-mediated immunity (CMI) responses were evaluated by enzyme-linked immunospot (ELISPOT) assay and Th1/Th2/Th17 cytokine profiling. In the mouse model, AcHERV-gE-gB elicited similar or higher total IgG, IgG2a, and neutralizing antibody levels than vOka and showed robust VZV-specific CMI responses. From the perspective of antigens encoded in vaccines and their relationship with CMI response, both AcHERV-gB and AcHERV-gE-gB demonstrated results equal to or superior to AcHERV-gE, encoding only gE. Taken together, these results suggest that AcHERV-gE-gB can be a novel candidate for alleviating risks of live attenuated vaccine-induced latency and effectively preventing varicella during early stages of life while providing strong CMI for effective resistance against HZ and therapeutic potential in later stages of life.

Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR’HIV): a multicenter, international, non-randomized clinical trial study protocol

BackgroundThe burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH – even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR’HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls.MethodsWe will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls.DiscussionThe SHINGR’HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population.Trial registrationClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).

Abstract TMP8: Varicella Zoster Virus Infection in Children With Arterial Ischemic Stroke: The Chicken or the Egg?

Introduction: Serologic evidence of varicella zoster virus (VZV) infection has been associated with childhood arterial ischemic stroke (AIS). Questions of causality persist: does VZV infection cause AIS, or does AIS reactivate VZV? The Vascular effects of Infection in Pediatric Stroke (VIPS II) study aimed to examine this relationship. Methods: This North American 22-center prospective cohort study enrolled 205 children (28 days-18 years) with AIS (2017-2022). Blood samples were hyperacute (≤72hrs; n=194), acute (4-7 days; n=180) and convalescent (1-6 weeks; n=73). A virology research lab used ELISA to measure VZV IgM and IgG titers. A pediatric virologist (CG) interpreted the results and classified the evidence of infection. Low-level IgG seropositivity is consistent with prior vaccination/infection. Highly elevated IgM in hyperacute/acute samples indicated reactivation coincident with stroke . Rising IgG titers between hyperacute and convalescent samples, occasionally with a high IgM in convalescent sample, indicated reactivation after the stroke . Results: Median age (IQR) was 11.6 years (5.3, 15.6). All 205 cases were low-level IgG positive; 160 (78%) reported prior VZV vaccination and 3 reported remote chicken pox. Serologies for 15 (7.3%; 95% CI 4.1, 11.8%) indicated VZV reactivation coincident with stroke; prior VZV vaccination reported in 14 and unknown in one. Stroke etiology amongst these 15 was definite arteriopathy in 4 (27%), possible arteriopathy in 4 (27%), cardioembolic in 5 (33%), and idiopathic in 2 (13%) (compared to 37%, 37%, 10%, 14%, respectively, for the other 190). Among 73 with convalescent samples, 17 (23%) had VZV reactivation after stroke. All cases of VZV reactivation were asymptomatic zoster sine herpete (herpes zoster without rash). Conclusions: While stroke triggered VZV reactivation in 23% of cases, 7.3% had evidence of zoster sine herpete at the time of their stroke, implying a causal role. We could not distinguish antibodies to vaccine virus versus wild-type; these zoster cases could represent reactivation of vaccine virus or a break-through wild-type varicella infection. Either scenario would be unexpected in this current era of routine childhood VZV vaccination and low rates of pediatric chicken pox or zoster.

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

Varicella Seroprevalence among Healthcare Workers: A Pilot Study from a Tertiary Care Centre in Northern India

Introduction: Susceptible Healthcare Workers (HCWs) lacking immunity to Varicella Zoster Virus (VZV) can get infected and spread the infection to their patients. Effective screening can help in early vaccination to limit nosocomial transmission of VZV. Aim: To assess the seroprevalence of VZV among HCWs. Materials and Methods: This was a hospital-based pilot study where serum samples were collected from 201 HCWs working in different departments of the Government Medical College, Srinagar, Jammu and Kashmir, India and its eight associated hospitals over a period from January 2021 to February 2021, after obtaining their consent to participate in the study. Samples were tested for VZV Immunoglobulin G (IgG) antibodies using the Enzyme Linked Immuno Sorbent Assay (ELISA) method (NovaLisaVZVIgG, ELISA Kit). Variables including age, sex, professional category, history of varicella infection, and VZV vaccination were collected in a proforma. Statistical analysis was done using Open Epi version 3.01. Results: The overall prevalence of antibodies to varicella was 150/196 (76.53%). HCWs had equivocal results in 4 (2.04%) cases. An age-related increase in seroprevalence was observed. Only 6/196 (3.06%) participants were vaccinated against VZV, and 38/196 (19.39%) participants had a history of VZV infection in the past. Conclusion: The present study found a significant proportion of HCWs susceptible to VZV, making them potentially at risk of acquiring and transmitting the infection. This reinforces the need for screening HCWs against VZV and vaccinating them whenever necessary to protect the patients.

Varicella zoster virus outbreak in a long-term care unit of a tertiary care hospital in northern India.

Nosocomial outbreak of varicella zoster virus (VZV) has been reported when susceptible individuals encounter a case of chicken pox or shingles. A suspected VZV outbreak was investigated in a 50-bedded in-patient facility of Physical Medicine and Rehabilitation in a tertiary care multispecialty hospital. A 30-year-old female patient admitted with Pott's spine was clinically diagnosed with chicken pox on 31 December 2022. The following week, four more cases were identified in the same ward. All cases were diagnosed as laboratory-confirmed varicella zoster infection by PCR. Primary case was a housekeeping staff who was clinically diagnosed with chicken pox 3weeks prior (9 December 2022). He returned to work on eighth day of infection (17 December 2022) after apparent clinical recovery but before the lesions had crusted over. Thirty-one HCWs were identified as contacts a and three had no evidence of immunity. Two of these susceptible HCWs had onset of chickenpox shortly after first dose of VZV vaccination was inoculated. All cases recovered after treatment with no reported complications. VZV infection is highly contagious in healthcare settings with susceptible populations. Prompt identification of cases and implementation of infection prevention and control measures like patient isolation and vaccination are essential for the containment of outbreaks.

A retrospective cohort study evaluating the incidence of herpes zoster and postherpetic neuralgia after a live attenuated Oka-strain herpes zoster vaccine in a real-world setting in Japan

BackgroundIn Japan, freeze-dried live attenuated Oka-strain varicella-zoster virus vaccine, VVL (BIKEN), is available for adults aged ≥50 years to prevent herpes zoster (HZ). Although an increase in the antibody titer and cellular immune response has been demonstrated following vaccination with VVL (BIKEN), to date, no clinical studies have shown that the vaccine decreases the incidence of HZ and postherpetic neuralgia (PHN). This study investigated the incidence of HZ and PHN among adults aged ≥50 years who received a single dose of VVL (BIKEN) to prevent HZ. MethodsThis retrospective cohort study investigated the incidence of HZ and PHN among adults aged ≥50 years who received a single dose of VVL (BIKEN) at a large hospital and affiliated clinics in Japan. A dispensing database and electronic medical records were used to identify vaccine recipients and cases of HZ and PHN. The end date of the follow-up period and the reason to end the follow-up were defined to avoid underestimating the incidence. The analysis was stratified according to age, sex, immunocompromising conditions, and use of immunosuppressant therapy. Vaccine effectiveness was estimated using published estimates of the incidence of HZ and PHN in the unvaccinated population in Japan. ResultsA total of 1175 patients were enrolled in the study. During a median follow-up period of 3.36 years, HZ was diagnosed in 27 participants (15 men [2.8%] and 12 women [1.9%]). The incidence of HZ among VVL (BIKEN) recipients was 7.67/1000 person-years. The incidence of PHN was 0.82/1000 person-years. The vaccine effectiveness was estimated as 27.8% [95% confidence interval (CI), −29.8 to 63.9%] and 73.8% [95% CI, 38.6–100%] against HZ and PHN, respectively. ConclusionsThe VVL (BIKEN) had limited effectiveness at preventing HZ, but relatively good effectiveness at preventing PHN. VVL (BIKEN) might have a role as an affordable alternative.

A Synergistic Lipid Nanoparticle Encapsulating mRNA Shingles Vaccine Induces Potent Immune Responses and Protects Guinea Pigs from Viral Challenges.

Shingles is caused by the reactivation of varicella zoster virus (VZV) and manifests as painful skin rashes. While the recombinant protein-based vaccine proves highly effective, it encounters supply chain challenges due to a shortage of the necessary adjuvant. Messenger RNA (mRNA)-based vaccines can be rapidly produced on a large scale, but their effectiveness relies on efficient delivery and sequence design. Here, an mRNA-based VZV vaccine using a synergistic lipid nanoparticle (Syn-LNP) containing two different ionizable lipids is developed. Syn-LNP shows superior mRNA expression compared to LNPs formulated with either type of ionizable lipid and to a commercialized LNP. After encapsulating VZV glycoprotein E (gE)-encoding mRNA, mgE@Syn-LNP induces robust humoral and cellular immune responses in two strains of mice. The magnitude of these responses is similar to that induced by adjuvanted recombinant gE proteins and significantly higher than that observed with live-attenuated VZV. mgE@Syn-LNP exhibits durable humoral responses for over 7 months without obvious adverse effects. In addition, mgE@Syn-LNP protects vaccinated guinea pigs against live VZV challenges. Preliminary studies on the mRNA antigen design reveal that the removal of glycosylation sites of gE greatly reduces its immune responses. Collectively, Syn-LNP encapsulating gE-encoded mRNA holds great promise as a shingles vaccine.

Is the level of varicella-zoster virus IgG associated with symptomatic status of genital herpes simplex virus infection? A case-control study.

Herpes simplex virus (HSV) is a common infection, affecting the majority of the population by age of 50. Recurrent symptomatic outbreaks, experienced by a minority, have significant psychological and psychosexual effects. The varicella zoster virus (VZV), resembling HSV, shows potential for a functional cure via vaccination. This study seeks to investigate if there is an association between low VZV antibody levels and recurrent HSV outbreaks. A total of 110 patients with symptomatic and asymptomatic HSV were recruited during their sexual health screen. Serum samples were collected between Aug 2019 - July 2022; breaks in the study occurred due to COVID. The primary outcome measure was the serological status of HSV and VZV IgG titre level. The average age was 37.3years (range 21-65years). For people with asymptomatic genital HSV2 the average VZV IgG titre was 2373.9IU/mL (n = 17); and 1219.0IU/mL for the symptomatic group (n = 67); p ≤ 0.00001), with similar results for HSV1. There is a strong association between average higher varicella-zoster virus (VZV) IgG level and being an asymptomatic carrier of herpes simplex sirus (HSV)1&2. A feasibility study to assess the use of the VZV vaccine as a treatment of HSV is planned.

Genomic sequencing revealed recombination event between clade 1 and clade 2 occurs in circulating varicella-zoster virus in China.

Varicella-zoster virus (VZV), a member of the Alphaherpesvirinae subfamily, causes varicella in primary infections and establishing a latent stage in sensory ganglia. Upon reactivation, VZV causes herpes zoster with severe neuralgia, especially in elderly patients. The mutation rate for VZV is comparatively lower than the other members of other alpha herpesviruses. Due to geographic isolation, different genotypes of VZV are circulating on separate continents. Here, we successfully isolated a VZV from the vesicular fluid of a youth zoster patient. Based on the single-nucleotide polymorphism profiles of different open reading frames that define the genotype, this newly isolated VZV primarily represents genotype clade 2 but also has characteristics of genotype clade 1. The next-generation sequencing provided a nearly full-length sequence, and further phylogenetic analysis revealed that this VZV isolate is distinct from clades 1 and 2. The Recombination Detection Program indicates that a possible recombinant event may occur between the VZV isolate and clade 1. In summary, we found that there is a circulating VZV isolate in China that may represent a recombinant between clade 1 and clade 2, providing new concerns that need to be considered in the future VZV vaccination program.

Throwing out old dogma: time for introduction of universal VZV vaccination in the UK

There has been a reticence to introduce universal varicella zoster virus (VZV) vaccines in the UK because of a theoretical concern of increased herpes zoster infections. However, this has not been borne out in real-world data. Here, I argue that, in reality, many parents are vaccinating their children privately and, thus, we do not know the degree of inequity that this creates. The fairest option going forward is to introduce universal VZV vaccination in the UK.

Seroprevalence of VZV and HSV-2 Antibodies among Women of Childbearing Age Referring to Health Centres of Mashhad, Iran: The Need for Consideration of VZV Vaccination Program.

Infections with herpes simplex virus type 2 (HSV-2) and varicella-zoster virus (VZV) are associated with serious maternal and neonatal health consequences. The literature review reveals a research gap regarding the seroprevalence of HSV-2 and VZV among women of reproductive age in Mashhad, Northeast of Iran. The present study aims to evaluate the seroprevalence of these viruses among a group of women in Mashhad, Iran. Sera were collected by health center personnel using a cluster sampling method from healthy women with specific age characteristics residing in three distinct socioeconomic regions of the city. The participants, aged 20-35, were divided into three groups (20-25, 26-30, and 31-35 years). The levels of VZV and HSV-2 IgG antibodies were evaluated using commercial ELISA kits. Subsequently, the results were analyzed using SPSS software. A total of 93 women were included in the study. Anti-HSV-2 IgG antibody was detected in 3 out of 93 participants (7.5%), while anti-VZV IgG antibody was found positive in 80 out of 93 individuals (83.3%). The HSV-2 positive cases were concurrently positive for the VZV antibody. There was no significant difference in the positivity of anti-HSV-2 and anti-VZV antibody positivity within age groups or socioeconomic status (P > 0.05). The high seroprevalence of VZV among nonvaccinated participants indicates a widespread presence of the virus and underscores its potentially serious impact on community health. Therefore, it is recommended that a VZV vaccination program be considered by the health system. Furthermore, the reactivation of latent HSV-2, whether symptomatic or asymptomatic, during pregnancy should not be disregarded as a life-threatening threat.

Ocular Inflammation Post-Vaccination.

The association between vaccines and ocular disorders has attracted significant attention in scientific research. Numerous mainstream vaccines are associated with a range of uveitis types, including anterior, intermediate, and posterior uveitis. Additionally, they are associated with distinct ocular diseases such as multifocal choroiditis, Vogt-Koyanagi-Harada (VKH) disease, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), and multiple evanescent white dot syndrome (MEWDS). These ocular conditions are often transient, with a vast majority of patients experiencing improvement after steroid intervention. To date, numerous cases of vaccine-induced uveitis have been reported. This study analyzed the correlation between antiviral vaccines, including the hepatitis B virus (HBV), human papillomavirus (HPV), measles-mumps-rubella (MMR), varicella zoster virus (VZV), and influenza vaccines, and different manifestations of uveitis. This is the first comprehensive study to offer a detailed analysis of uveitis types induced by antiviral vaccines. Through an extensive database search, we found a particularly strong link between influenza vaccines, followed by VZV and HPV vaccines. While anterior uveitis is common, conditions such as APMPPE, MEWDS, and VKH are particularly notable and merit careful consideration in clinical practice. Corticosteroid treatment was effective; however, half of the observed patients did not achieve full recovery, indicating potentially prolonged effects of the vaccine.

Mutations in Coding and Non-Coding Regions in Varicella-Zoster Virus Causing Fatal Hemorrhagic Fever Without Rash in an Immunocompetent Patient: Case Report.

We report the case of a fatal hemorrhagic varicella primary infection in an immunocompetent man and whole-genome characterization of the virus for the investigation of biomarkers of virulence. A 38-year-old patient born in Nigeria presented to the emergency department with abdominal pain and subsequently developed fatal hemorrhagic disease without skin rash. Extensive laboratory tests including serology and PCR for arenaviruses, bunyaviruses and ebolaviruses were negative. Varicella-zoster virus (VZV) PCR of sera, liver and spleen tissue samples from autopsy revealed the presence of VZV DNA. Primary infection by varicella-zoster virus with hemorrhagic manifestations was diagnosed after virological testing. The VZV genome was sequenced using a mWGS approach. Bioinformatic analysis showed 53 mutations across the genome, 33 of them producing non-synonymous variants affecting up to 14 genes. Some of them, such as ORF11 and ORF 62, encoded for essential functions related to skin or neurotropism. To our knowledge, the mutations reported here have never been described in a VZV causing such a devastating outcome. In immunocompetent patients, viral factors should be considered in patients with uncommon symptoms or severe diseases. Some relevant mutations revealed by using whole genome sequencing (WGS) directly from clinical samples may be involved in this case and deserves further investigation. Differential diagnosis of varicella-zoster virus in immunocompetent adults should be considered among patients with suspected VHF, even if the expected vesicular rash is not present at admission and does not arise thereafter. Whole genome sequencing of strains causing uncommon symptoms and/or mortality is needed for epidemiological surveillance and further characterization of putative markers of virulence. Additionally, this report highlights the recommendation for a VZV vaccination policy in non-immunized migrants from developing countries.

Evaluation of the Immunological Efficacy of an LNP-mRNA Vaccine Prepared from Varicella Zoster Virus Glycoprotein gE with a Double-Mutated Carboxyl Terminus in Different Untranslated Regions in Mice.

Cell-mediated immunity (CMI) plays a key role in the effectiveness of varicella zoster virus (VZV) vaccines, and mRNA vaccines have an innate advantage in inducing CMI. Glycoprotein E (gE) has been used widely as an antigen for VZV vaccines, and carboxyl-terminal mutations of gE are associated with VZV titer and infectivity. In addition, the untranslated regions (UTRs) of mRNA affect the stability and half-life of mRNA in the cell and are crucial for protein expression and antigenic translational efficiency. In this study, three UTRs were designed and connected to the nucleic acid sequence of gE-M, which is double mutated in the extracellular region of gE. Then, mRNA with different nucleic acids was encapsulated in lipid nanoparticles (LNPs), forming three LNP-mRNA VZV vaccines, named gE-M-Z, gE-M-M, and gE-M-P. The immune response elicited by these vaccines in mice was evaluated at intervals of 4 weeks, and the mice were sacrificed 2 weeks after the final immunization. In the results, the gE-M-P group, which retains the nucleic acid sequence of gE-M and is connected to Pfizer/BioNTech's BNT162b2 UTRs, induced the strongest humoral immune response and CMI. Because CMI is crucial for protection against VZV and for the design of VZV vaccines, this study provides a feasible strategy for improving the effectiveness and economy of future VZV vaccines.

Investigation of the safety of live attenuated varicella-zoster virus vaccination in patients with relapse-remitting multiple sclerosis treated with natalizumab: A case series and review of the literature.

It is generally recommended to avoid live attenuated vaccines in patients treated with high efficacy disease-modifying treatment (DMT). However, a delay in starting DMT in highly active or aggressive multiple sclerosis (MS) might lead to a significant disability. We aimed to report a case series of 16 highly active RRMS patients who received the live-attenuated varicella-zoster virus (VZV) vaccine during treatment with natalizumab. This retrospective case series was conducted between September 2015 and February 2022 at the MS Research Center of Sina and Qaem hospital, Tehran, Mashhad, Iran, to identify the outcome of highly active MS patients who received the live-attenuated VZV vaccine on natalizumab. Two males and 14 females were included in this study, with a mean age of 25.5±8.4-year-old. 10 patients were naïve cases of highly active MS, and six were escalated to natalizumab. The patients received two doses of live attenuated VZV vaccine after a mean of 6.72 cycles of natalizumab treatment. Except for the one who experienced mild chickenpox infection, no serious adverse event or disease activity was evident after vaccination. While our data do not confirm the safety of the live attenuated VZV vaccine in natalizumab recipients, it highlights the importance of case-by-case decision-making in MS management based on the risk-benefit assessment.

A booster administration of the OKA/SK strain causes fatal disseminated varicellain an immunocompetent child.

Live varicella vaccines are known to provide robust immunity against varicella zoster virus (VZV) infections. However, problems with viral attenuation have led to pathogenic VZV vaccine strains causing varicella-like rash and herpes zoster in immunocompetent children after immunization. We report the first fatal case of VZV infection caused by OKA/SK strain contained in the vaccine administrated as a booster shot in an immunocompetent child,which has been independently developed from any currently available varicella vaccines that are OKA strain or MAV/06 strain based. The patient died due to sudden pulmonary alveolar hemorrhage as a secondary complication of VZV pneumonitis. Sequencing of the four SNPs unique to the OKA/SK strain (SNP loci 14 035T; 32 626C; 58 777G; 70 319G) enabled discrimination of the strain responsible for the disseminated infection. OKA/SK strain does not have any SNPs in ORF62 postulated to be responsible for the attenuation of varicella vaccines which have been safely and effectively used world-wide or locally, and exclusively enriches a virulent factor in ORF31 identified in parental OKA strain, thus possibly resulting in disseminated VZV infection leading to mortality. Therefore, actions need to be taken to prevent vaccine related morbidity and mortality in children.

P76 Management of aciclovir-resistant mucocutaneous herpes simplex virus infection: a systematic review

Abstract Aciclovir resistance results in immunocompromised hosts due to long-term antiviral therapy and ongoing viral replication. Aciclovir resistance in herpes simplex virus (HSV) poses a major concern, as this can lead to chronic and recalcitrant infection that significantly impacts on the quality of life. While different treatment options exist, there are currently no standardized clinical treatment guidelines for mucocutaneous aciclovir-resistant (ACV-R) HSV infection. This systematic review seeks to identify safe and effective treatments for mucocutaneous ACV-R HSV infection. For this systematic review, PubMed/MEDLINE and Embase were searched in September 2022 for all articles published between 1 January 1980 and 1 September 2022. Studies were included if they described the use of a medication for the treatment of mucocutaneous ACV-R HSV infection. From the initial search that yielded 1066 studies, 86 met the inclusion criteria and were selected. Of the 86 studies, 6 were clinical trials and 80 were case reports/series. A total of 318 patients were included in our review. Foscarnet [intravenous (IV) and topical] was studied in 5 clinical trials and 25 case reports/series, leading to complete response in most patients, with adverse effects including renal toxicity and electrolyte abnormalities. Vidarabine (IV) was found to be inferior to foscarnet in a clinical trial and reported in two case reports. Common side-effects included nausea, anaemia and renal impairment. Trifluridine (topical) was studied in a clinical trial and a case report, showing complete response in some patients. Cidofovir (IV, topical, intralesional) was studied in 21 case reports/series, showing complete response in most patients, with renal impairment as the most common adverse effect. Imiquimod (topical) was studied in eight case reports/series, showing complete response and no side-effects. Pritelivir (oral) was reported in two case reports/series, showing complete response and no side-effects. Combination treatment was reported in 10 case reports/series with variable clinical response. Our review also identified reports of less widely used treatments. These include artesunate, zidovudine, varicella-zoster virus vaccine, leflunomide and surgical excision, which achieved variable response rates but have not been widely studied. While foscarnet and cidofovir have the most robust evidence, IV administration of these agents is associated with significant side-effects and may be limiting. Intralesional and topical formulations of cidofovir, trifluridine and imiquimod are alternative options appropriate for outpatient management. Pritelivir is a novel and promising treatment of mucocutaneous ACV-R HSV infection.