Varicella Zoster Virus disrupts MAIT cell polyfunctional effector responses.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells that respond to riboflavin biosynthesis and cytokines through TCR-dependent and -independent pathways, respectively. MAIT cell activation plays an immunoprotective role against several pathogens, however the functional capacity of MAIT cells following direct infection or exposure to infectious agents remains poorly defined. We investigated the impact of Varicella Zoster Virus (VZV) on blood-derived MAIT cells and report virus-mediated impairment of activation, cytokine production, and altered transcription factor expression by VZV infected (antigen+) and VZV exposed (antigen-) MAIT cells in response to TCR-dependent and -independent stimulation. Furthermore, we reveal that suppression of VZV exposed (antigen-) MAIT cells is not mediated by a soluble factor from neighbouring VZV infected (antigen+) MAIT cells. Finally, we demonstrate that VZV impairs the cytolytic potential of MAIT cells in response to riboflavin synthesising bacteria. In summary, we report a virus-mediated immune-evasion strategy that disarms MAIT cell responses.

Heterologous Prime-Boost Immunization Strategies Using Varicella-Zoster Virus gE mRNA Vaccine and Adjuvanted Protein Subunit Vaccine Triggered Superior Cell Immune Response in Middle-Aged Mice.

Purpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.

Utilization of multiplex polymerase chain reaction for simultaneous and rapid detection of viral infections from different ocular structures.

The impact of viral keratitis (VK) on individuals and society is notable. Early diagnosis and treatment are crucial in managing viral keratitis effectively. Timely intervention with antiviral medications and supportive care can help mitigate the severity of the infection and improve visual outcomes. We examined the prevalence of varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), adenovirus (AdV) and herpes simplex virus type 2 (HSV-2) in patients suspected for ocular infections. Patients included in the study exhibited various clinical manifestations indicative of ocular pathology, such as infectious keratitis, corneal scar, endogenous endophthalmitis, panuveitis, endothelitis, stromal edema, and other relevant conditions. Four different types of tear fluid, corneal samples epithelium, aqueous humor and vitreous humor were taken. After genome extraction, multiplex real-time PCR was used for diagnosis of viruses. 48 (29.6%) out of the total of 162 (100%) eye specimen were positive. The dominant prevalence was VZV (12.3%) and HSV-1 (11.7%) followed by AdV (4.9%) and HSV-2 (0.6%). There were 4 (8.3%) coinfections within the samples (HSV-1 and VZV). Aqueous humor samples demonstrated superior virus detection ability and our only HSV-2 positive sample was from aqueous humor. The utilization of multiplex real-time PCR assays in differential diagnosis of VK holds promise for expeditious diagnoses while also preventing unwarranted antibiotic prescriptions. Moreover, the aqueous humor appears to be a more sensitive site for detecting viral keratitis.

Population immunity to varicella in Canada: A Canadian Immunization Research Network (CIRN) study.

INTRODUCTION: The incidence of varicella in Canada has decreased by almost 99% since vaccination was introduced. However, variation in the timing and eligibility of vaccination programs across the country has resulted in some cohorts being under-vaccinated and therefore potentially susceptible to infection. METHODS: We used nationally representative specimens from the Biobank of Statistics Canada's Canadian Health Measures Survey (CHMS) as well as residual specimens from Ontario collected between 2009-2014 to estimate population immunity across age-groups and geography, and identify any groups at increased risk of varicella infection. RESULTS: The weighted proportion of specimens with antibody levels above the threshold of protection was 93.6% (95% CI: 92.4, 95.0). Protection was lowest among those aged 3-5 years (54.3%; 95% CI: 47.3, 61.4), but increased with age. Individuals born outside Canada had more than twice the odds of varicella susceptibility than those born in Canada (aOR: 2.7; 95% CI: 1.4, 5.0; p = 0.004). There were no differences by sex or geography within Canada, and there were no statistically significant differences when Ontario CHMS sera were compared to Ontario residual sera, apart from in participants aged 12-19 year age-group, for whom the CHMS estimate (91.2%; 95% CI: 86.7, 95.7) was significantly higher (p = 0.03) than that from residual specimens (85.9%, 95% CI: 81.1, 90.8). DISCUSSION: Varicella immunity in Canada is changing. Children appear to have low population immunity, placing them at greater risk of infection and at increased risk of severe disease as they age. Our results underscore the importance of performing periodic serosurveys to monitor further population immunity changes as the proportion of vaccine-eligible birth-cohorts increases, and to continually assess the risk of outbreaks.

Elevated cerebrospinal fluid IgG index in herpes simplex encephalitis post-HSV-1 clearance: A preliminary study.

Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.

Bone Marrow-Suppressive Treatment in Children Is Associated with Diminished IFN-γ Response from T Cells upon Polyclonal and Varicella Zoster Virus Peptide Stimulation.

Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children's memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic-haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4+ and CD8+ effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells.

Purpura fulminans secondary to varicella-zoster virus infection.

BACKGROUND: Purpura fulminans (PF) is a rare, life-threatening condition involving consumptive coagulopathy and intravascular thrombosis, causing purpura and necrosis in the skin and soft tissue. CASE REPORT: A 4-year-old Tajik girl with PF secondary to varicella-zoster virus (VZV) infection presented with purplish red, diffuse, painful lesions localized to the entire right leg. Her vaccination status was unknown, and she did not have concurrent chronic illness. Ten days before admission, the girl was admitted to another hospital in Tajikistan with a diagnosis of chickenpox and PF. She was then transferred to the hospital of the authors of the current report due to the enlargement of lesions to the gluteal region, a change in the color of lesions from red to black, and the detection of arterial thrombosis via Doppler ultrasonography. Multiple surgical debridements were performed to manage tissue necrosis, and the patient's right leg was amputated at the 18th week of admission. The patient was discharged after 26 weeks of hospitalization. CONCLUSION: Although VZV infections mostly cause mild and self-limiting eruptive disease, they can progress, with life-threatening complications, including PF. To prevent VZV infection and resulting complications, immunization with live attenuated vaccines and maintaining population immunity above a certain threshold are the most important strategies to prevent the circulation of the virus.

A nanoparticle vaccine displaying varicella-zoster virus gE antigen induces a superior cellular immune response than a licensed vaccine in mice and non-human primates.

Herpes zoster (HZ), also known as shingles, remains a significant global health issue and most commonly seen in elderly individuals with an early exposure history to varicella-zoster virus (VZV). Currently, the licensed vaccine Shingrix, which comprises a recombinant VZV glycoprotein E (gE) formulated with a potent adjuvant AS01B, is the most effective shingles vaccine on the market. However, undesired reactogenicity and increasing global demand causing vaccine shortage, prompting the development of novel shingles vaccines. Here, we developed novel vaccine candidates utilising multiple nanoparticle (NP) platforms to display the recombinant gE antigen, formulated in an MF59-biosimilar adjuvant. In naïve mice, all tested NP vaccines induced higher humoral and cellular immune responses than Shingrix, among which, the gEM candidate induced the highest cellular response. In live attenuated VZV (VZV LAV)-primed mouse and rhesus macaque models, the gEM candidate elicited superior cell-mediated immunity (CMI) over Shingrix. Collectively, we demonstrated that NP technology remains a suitable tool for developing shingles vaccine, and the reported gEM construct is a highly promising candidate in the next-generation shingles vaccine development.

Varicella-Zoster Virus Pretransplant Vaccination and Posttransplant Infections Among Pediatric Solid Organ Recipients in the Two-Dose Varicella Era: A Single-Center, Multi-Organ Retrospective Study.

BACKGROUND: Varicella-zoster virus (VZV) pretransplant immunization rates, exposures, and posttransplant disease are poorly characterized among pediatric solid organ transplant (SOT) recipients in the two-dose varicella vaccine era. METHODS: A retrospective analysis of the electronic health records among children <18 years old who received SOT from January 1, 2011 through December 31, 2021, was performed at a single center to assess for missed pretransplant varicella vaccination opportunities, characterize VZV exposures, and describe posttransplant disease. RESULTS: Among 525 children, 444 were ≥6 months old (m.o.) at SOT with a documented VZV vaccine status. Eighty-five (19%) did not receive VZV Dose One; 30 out of 85 (35%) could have been immunized. Infants 6-11 m.o. accounted for 14 out of 30 (47%) missed opportunities. Among children ≥12 m.o. with documented Dose Two status (n = 383), 72 had missed vaccination opportunities; 57 out of 72 (79%) were children 1-4 years old. Most children had unclassifiable pre-SOT serostatus as varicella serology was either not obtained/documented (n = 171) or the possibility of passive antibodies was not excluded (n = 137). Of those with classified serology (n = 188), 69 were seroimmune. Forty-seven of 525 (9%) children had recorded VZV exposures; two developed varicella-neither had documented pre-SOT seroimmunity nor had received post-exposure prophylaxis. Nine additional children had medically attended disease: four primary varicella and five zoster. Of the 11 cases, 10 had cutaneous lesions without invasive disease; one had multi-dermatomal zoster with transaminitis. Seven (64%) received treatment exclusively outpatient. CONCLUSIONS: VZV exposure and disease still occur. Optimizing immunization among eligible candidates and ensuring patients have a defined VZV serostatus pretransplantation remain goals of care.

Seroprevalence of antibodies against varicella zoster virus across all age groups during the post-COVID-19 pandemic period in Chonburi Province, Thailand.

As of 2024, Thailand has not incorporated the varicella-zoster virus (VZV) vaccine into the Expanded Program on Immunization (EPI). This study aimed to evaluate VZV seroprevalence across all age groups in Chonburi Province, Thailand, during the post-COVID-19 era, and to support the development of a vaccination plan against VZV. A total of 950 participants were enrolled from October 2022 to January 2023. VZV antibody levels were measured using ELISA kits (EUROIMMUN, Lübeck, Germany), with seropositivity set at ≥110 IU/L. The overall VZV seropositivity rate was 64.8%, similar to rates in 1994 and 2014. However, seropositivity rates for the 5-9, 10-14, and 15-19 age groups were significantly higher in the 1994 study, and for the 10-14 and 15-19 age groups in the 2014 study, indicating a declining trend among young Thai individuals. The seropositivity rate increased with age, with a seroprevalence exceeding 80% in individuals aged 30 years and older. Our study found a significant association between the history of varicella and seropositivity. Thus, a positive history may indicate immunity. In conclusion, a significant portion of Thai adolescents are still vulnerable to varicella, highlighting the crucial role of vaccination in averting serious illness.

An adult with hemorrhagic varicella co-infects with cytomegalovirus: a case report.

BACKGROUND: Hemorrhagic varicella (HV) is a particular form of chicken pox.,with high mortality in adults. This form of the disease is rare, to date, approximately 4 cases have been reported. Occasional cases of HV have been documented in adults with hematologic disorders or other diseases. While there is one reported case of simultaneous reactivation of cytomegalovirus in an adult with chickenpox, there is a lack of information regarding changes in liver function indicators for such patients. This is unfortunate, as CMV reactivation can further exacerbate liver failure and increase mortality. In this report, we present a case of hemorrhagic varicella reactivation with cytomegalovirus and provide some relevant discussions. CASE PRESENTATION: We present the case of a 25-year-old male with HV, who had a history of nephrotic syndrome generally controlled with orally administered prednisone at a dosage of 50 mg per day for two months. The patient arrived at the emergency room with complaints of abdominal pain and the presence of hemorrhagic vesicles on his body for the past 3 days. Despite medical evaluation, a clear diagnosis was not immediately determined. Upon admission, the leukocyte count was recorded as 20.96 × 109/L on the first day, leading to the initiation of broad-spectrum antibiotic treatment. Despite the general interpretation that a positive IgG and a negative IgM indicate a previous infection, the patient's extraordinarily elevated IgG levels, coupled with a markedly increased CMV DNA quantification, prompted us to suspect a reactivation of the CMV virus. In light of these findings, we opted for the intravenous administration of ganciclovir as part of the treatment strategy. Unfortunately,,the patient succumbed to rapidly worsening symptoms and passed away. Within one week of the patient's demise, chickenpox gradually developed in the medical staff who had been in contact with him. In such instances, we speculate that the patient's diagnosis should be classified as a rare case of hemorrhagic varicella. CONCLUSION: Swift identification and timely administration of suitable treatment for adult HV are imperative to enhance prognosis.

Suppression of the host antiviral response by non-infectious varicella zoster virus extracellular vesicles.

Varicella zoster virus (VZV) reactivates from ganglionic sensory neurons to produce herpes zoster (shingles) in a unilateral dermatomal distribution, typically in the thoracic region. Reactivation not only heightens the risk of stroke and other neurological complications but also increases susceptibility to co-infections with various viral and bacterial pathogens at sites distant from the original infection. The mechanism by which VZV results in complications remote from the initial foci remains unclear. Small extracellular vesicles (sEVs) are membranous signaling structures that can deliver proteins and nucleic acids to modify the function of distal cells and tissues during normal physiological conditions. Although viruses have been documented to exploit the sEV machinery to propagate infection, the role of non-infectious sEVs released from VZV-infected neurons in viral spread and disease has not been studied. Using multi-omic approaches, we characterized the content of sEVs released from VZV-infected human sensory neurons (VZV sEVs). One viral protein was detected (immediate-early 62), as well as numerous immunosuppressive and vascular disease-associated host proteins and miRNAs that were absent in sEVs from uninfected neurons. Notably, VZV sEVs are non-infectious yet transcriptionally altered primary human cells, suppressing the antiviral type 1 interferon response and promoting neuroinvasion of a secondary pathogen in vivo. These results challenge our understanding of VZV infection, proposing that the virus may contribute to distant pathologies through non-infectious sEVs beyond the primary infection site. Furthermore, this study provides a previously undescribed immune-evasion mechanism induced by VZV that highlights the significance of non-infectious sEVs in early VZV pathogenesis. IMPORTANCE: Varicella zoster virus (VZV) is a ubiquitous human virus that predominantly spreads by direct cell-cell contact and requires efficient and immediate host immune evasion strategies to spread. The mechanisms of immune evasion prior to virion entry have not been fully elucidated and represent a critical gap in our complete understanding of VZV pathogenesis. This study describes a previously unreported antiviral evasion strategy employed by VZV through the exploitation of the infected host cell's small extracellular vesicle (sEV) machinery. These findings suggest that non-infectious VZV sEVs could travel throughout the body, affecting cells remote from the site of infection and challenging the current understanding of VZV clinical disease, which has focused on local effects and direct infection. The significance of these sEVs in early VZV pathogenesis highlights the importance of further investigating their role in viral spread and secondary disease development to reduce systemic complications following VZV infections.

A Review of Atypical Cutaneous Histological Manifestations of Herpes Zoster.

The clinical and histopathological features of herpes zoster (HZ) are usually straightforward. Atypical histological presentations, in the absence of the classical viral cytopathic changes, are well documented and can make the diagnosis of HZ extremely difficult. Herein, we review the existing literature on atypical cutaneous histological manifestations of the disease, with emphasis on the subtle clues, use of immunohistochemistry, and potential pitfalls.

A unique case of double meningitis with enterovirus and reactivated varicella-zoster virus in a male teenager.

This paper presents a unique case of double meningitis with enterovirus and reactivated varicella-zoster virus without shingles in an immunocompetent male teenager, a case that offers many important medical lessons, all "gravitating" around physiopathological reasoning of any clinical case in general.