RESUMEN
Background: Currently, evidence regarding the causal relationship between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome is limited and inconsistent. Therefore, this study employs Mendelian randomization (MR) methodology to investigate the causal relationship between the two. Methods: This study selected 110 single-nucleotide polymorphisms (SNPs) of primary immunodeficiency-related genes as instrumental variables (IVs). Genetic associations of primary immunodeficiency-related genes were derived from recent genome-wide association studies (GWAS) data on human plasma protein levels and circulating immune cells. Data on genes associated with varicella-zoster virus reactivation syndrome were obtained from the GWAS Catalog and FINNGEN database, primarily analyzed using inverse variance weighting (IVW) and sensitivity analysis. Results: Through MR analysis, we identified 9 primary immunodeficiency-related genes causally associated with herpes zoster and its subsequent neuralgia; determined causal associations of 20 primary immunodeficiency-related genes with three vascular lesions (stroke, cerebral aneurysm, giant cell arteritis); revealed causal associations of 10 primary immunodeficiency-related genes with two ocular diseases (retinopathy, keratitis); additionally, three primary immunodeficiency-related genes each were associated with encephalitis, cranial nerve palsy, and gastrointestinal infections. Conclusions: This study discovers a certain association between primary immunodeficiency-related genes and varicella-zoster virus reactivation syndrome, yet further investigations are warranted to explore the specific mechanisms underlying these connections.
Asunto(s)
Estudio de Asociación del Genoma Completo , Herpesvirus Humano 3 , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Humanos , Herpesvirus Humano 3/inmunología , Herpes Zóster/genética , Herpes Zóster/inmunología , Herpes Zóster/virología , Activación Viral , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Predisposición Genética a la Enfermedad , Infección por el Virus de la Varicela-Zóster/genética , Infección por el Virus de la Varicela-Zóster/inmunología , Síndromes de Inmunodeficiencia/genéticaRESUMEN
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.
Asunto(s)
Herpesvirus Humano 3 , Células T Invariantes Asociadas a Mucosa , Humanos , Células T Invariantes Asociadas a Mucosa/inmunología , Herpesvirus Humano 3/inmunología , Activación de Linfocitos/inmunología , Citocinas/metabolismo , Citocinas/inmunología , Riboflavina/inmunología , Infección por el Virus de la Varicela-Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/virología , Evasión Inmune/inmunología , Herpes Zóster/inmunología , Herpes Zóster/virologíaRESUMEN
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.
Asunto(s)
Anticuerpos Antivirales , Encefalitis por Herpes Simple , Herpesvirus Humano 1 , Inmunoglobulina G , Humanos , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Femenino , Masculino , Encefalitis por Herpes Simple/líquido cefalorraquídeo , Encefalitis por Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Anciano , Anticuerpos Antivirales/líquido cefalorraquídeo , Anticuerpos Antivirales/sangre , Adulto Joven , Adolescente , Herpesvirus Humano 3/inmunología , Reacción en Cadena de la Polimerasa , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/sangre , Anciano de 80 o más Años , Niño , Líquido Cefalorraquídeo/virología , Líquido Cefalorraquídeo/inmunologíaRESUMEN
mRNA platform holds promise for next-generation Varicella-zoster Virus (VZV) vaccine development due to its high potency at inducing strong T-cell response. Built upon the design of our 1st-generation VZV mRNA vaccine that encodes for full-length gE antigen, in this study we reported on a novel combinatorial strategy to further optimize the gE-encoding mRNA sequence through signal peptide replacement, C-terminal modification, and insertion of mRNA-stabilizing motif, which collectively contributed to significantly improved vaccine immunogenicity. In adult mice, aged mice, and immunocompromised mice, this optimized VZV mRNA vaccine showed strong superiority in multiple aspects including the induction of gE-specific antibodies, specific memory B-cell response, as well as Th1-type T-cell response.
Asunto(s)
Anticuerpos Antivirales , Herpesvirus Humano 3 , Proteínas del Envoltorio Viral , Animales , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/genética , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/genética , Ratones , Anticuerpos Antivirales/inmunología , Humanos , Vacunas de ARNm , ARN Mensajero/genética , ARN Mensajero/inmunología , Femenino , Desarrollo de Vacunas , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Inmunogenicidad Vacunal , Vacuna contra la Varicela/inmunología , Vacuna contra la Varicela/administración & dosificación , Vacuna contra la Varicela/genética , Linfocitos B/inmunología , Ratones Endogámicos BALB C , Células TH1/inmunologíaRESUMEN
The incidence of herpes zoster (HZ) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is significantly higher than that of the general public. Although routine antiviral prophylaxis is recommended, late-onset HZ has been highlighted, yet limited information is known about its clinical features and predictors. Here, we conducted a retrospective nested case-control study to identify patients with late-onset HZ, defined as a diagnosis of HZ after 1 year of transplantation, among allo-HSCT recipients between 2012 and 2017 at Peking University People's Hospital. Three controls were matched for each patient. A total of 201 patients developed late-onset HZ. Age over 20 years, absence of neutrophil engraftment by 14 days, mental disorders, immunosuppressant use at 1 year, and a peripheral CD4+/CD8+ ratio ≥0.5 at 1 year were independent risk factors, among which the CD4+/CD8+ ratio demonstrated good discriminative power for predicting late-onset HZ. For patients with a CD4+/CD8+ ratio <0.5, patient age, neutrophil engraftment time, mental disorders, and immunosuppressant use were potential risk factors. A stratification algorithm was accordingly established, classifying the transplant recipients into three risk groups. Whether the algorithm could facilitate the administration of posttransplant antiviral prophylaxis merits further validation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Herpes Zóster , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpes Zóster/virología , Herpes Zóster/epidemiología , Herpes Zóster/diagnóstico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Estudios de Casos y Controles , Trasplante Homólogo/efectos adversos , Adulto Joven , Medición de Riesgo , Antivirales/uso terapéutico , Incidencia , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Relación CD4-CD8 , Adolescente , Factores de Tiempo , Anciano , Herpesvirus Humano 3/inmunologíaRESUMEN
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.
Asunto(s)
Adyuvantes Inmunológicos , Inmunidad Celular , Ratones Endogámicos C57BL , Nanopartículas , Vacunas de Subunidad , Animales , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/administración & dosificación , Nanopartículas/química , Adyuvantes Inmunológicos/administración & dosificación , Femenino , Vacunas de ARNm , Ratones , Herpesvirus Humano 3/inmunología , Anticuerpos Antivirales/sangre , Inmunización Secundaria/métodos , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/administración & dosificación , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/administración & dosificación , LiposomasRESUMEN
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.
Asunto(s)
Varicela , Humanos , Varicela/epidemiología , Varicela/inmunología , Varicela/prevención & control , Adolescente , Niño , Preescolar , Femenino , Masculino , Canadá/epidemiología , Adulto , Adulto Joven , Persona de Mediana Edad , Lactante , Vacuna contra la Varicela/inmunología , Vacunación , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Herpesvirus Humano 3/inmunologíaRESUMEN
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.
Asunto(s)
Herpesvirus Humano 3 , Interferón gamma , Humanos , Niño , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Masculino , Femenino , Interferón gamma/metabolismo , Preescolar , Adolescente , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Médula Ósea , Células T de Memoria/inmunologíaRESUMEN
Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that causes neurological manifestations either as a complication of primary infection or reactivation. VZV induced neurological diseases have a good prognosis when confirmed early and treated with anti-viral therapy. Myelitis, encephalitis, ventriculitis or meningitis can occur without a telltale rash in immunocompetent and immunocompromised individuals making the diagnosis difficult. We analyzed CSF and serum samples from 30 unvaccinated study participants (17 male and 13 female) to determine the presence of VZV DNA by PCR in CSF and to estimate serum and CSF anti-VZV IgG and albumin levels in participants with neurological manifestations with/without rash. Anti-VZV IgG was detected in CSF (n = 22, [73%]) and serum (n = 29, [97%]) of pediatric and adult participants. Anti-VZV IgG were detected in CSF of participants with varied clinical presentation altered sensorium (n = 8, [36%]), meningitis (n = 4, [18%]), acute febrile illness (n = 3, [14%], encephalopathy/meningoencephalitis (n = 2, [9%]), irritability (n = 2, [9%]) and each patient from cerebrovascular stroke, demyelinating disorder and febrile seizure (n = 1, [4.5%]). VZV DNA was detected from one participant and CSF serum albumin levels were elevated in 53% of study participants. VZV DNA is present up to 1-2 weeks post onset of disease, after which anti-VZV antibody may be the only indicator of disease and therefore both VZV DNA and anti-VZV IgG need to be tested for in CSF. As VZV DNA and VZV IgG antibody are both good indicators of VZV reactivation, routine testing would result in reduced morbidity and mortality by early detection of disease and antiviral treatment.
Asunto(s)
Anticuerpos Antivirales , Herpesvirus Humano 3 , Inmunoglobulina G , Humanos , Masculino , Femenino , Herpesvirus Humano 3/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Adolescente , Persona de Mediana Edad , Niño , Preescolar , ADN Viral/sangre , ADN Viral/líquido cefalorraquídeo , Adulto Joven , Anciano , Varicela/virología , Varicela/inmunología , Varicela/diagnóstico , Varicela/sangre , LactanteRESUMEN
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.
Asunto(s)
Vesículas Extracelulares , Herpesvirus Humano 3 , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/virología , Humanos , Herpes Zóster/virología , Herpes Zóster/inmunología , Animales , MicroARNs/metabolismo , MicroARNs/genética , Células Receptoras Sensoriales/virología , Infección por el Virus de la Varicela-Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/virología , Proteínas Virales/metabolismo , Activación ViralAsunto(s)
Herpes Zóster Oftálmico , Vacuna contra el Herpes Zóster , Recurrencia , Humanos , Herpes Zóster Oftálmico/diagnóstico , Herpes Zóster Oftálmico/tratamiento farmacológico , Vacuna contra el Herpes Zóster/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Herpesvirus Humano 3/inmunologíaRESUMEN
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.
Asunto(s)
Vacuna contra la Varicela , Herpesvirus Humano 3 , Trasplante de Órganos , Humanos , Estudios Retrospectivos , Femenino , Masculino , Preescolar , Niño , Lactante , Vacuna contra la Varicela/administración & dosificación , Vacuna contra la Varicela/inmunología , Trasplante de Órganos/efectos adversos , Adolescente , Herpesvirus Humano 3/inmunología , Varicela/prevención & control , Vacunación , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Infección por el Virus de la Varicela-Zóster/inmunologíaRESUMEN
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.
Asunto(s)
Vacuna contra el Herpes Zóster , Herpesvirus Humano 3 , Inmunidad Celular , Nanopartículas , Proteínas del Envoltorio Viral , Animales , Ratones , Herpesvirus Humano 3/inmunología , Proteínas del Envoltorio Viral/inmunología , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/administración & dosificación , Macaca mulatta , Herpes Zóster/prevención & control , Herpes Zóster/inmunología , Femenino , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Adyuvantes Inmunológicos/administración & dosificación , Humanos , Antígenos Virales/inmunología , Inmunogenicidad Vacunal , Ratones Endogámicos BALB C , NanovacunasRESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes , Vacuna contra el Herpes Zóster , Herpes Zóster , Herpesvirus Humano 3 , Humanos , Herpesvirus Humano 3/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/virología , Vacuna contra el Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/uso terapéutico , Herpes Zóster/prevención & control , Herpes Zóster/inmunología , Herpes Zóster/virología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Inmunosupresores/uso terapéutico , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/prevención & controlRESUMEN
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.
Asunto(s)
Anticuerpos Antivirales , COVID-19 , Herpesvirus Humano 3 , Humanos , Estudios Seroepidemiológicos , Tailandia/epidemiología , Adolescente , Niño , Adulto Joven , Adulto , Anticuerpos Antivirales/sangre , Masculino , Femenino , Preescolar , Herpesvirus Humano 3/inmunología , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/prevención & control , Persona de Mediana Edad , Anciano , Varicela/epidemiología , Varicela/inmunología , Varicela/prevención & control , Lactante , Vacunación/estadística & datos numéricosRESUMEN
BACKGROUND: Reactivation of the latent varicella-zoster virus can cause herpes zoster (HZ) infection, and renal transplant recipients undergoing immunosuppressive therapy are particularly susceptible to this condition. This study aims to evaluate the potential increase in HZ incidence following influenza vaccination among this specific patient population. METHODS: This study was a population-based, retrospective, self-controlled case series. Data were retrieved from Taiwan's National Health Insurance Research Database spanning the years 2008 to 2017. Patients diagnosed with HZ within a 6-month period before and after receiving the influenza vaccine were eligible for inclusion. Two distinct time intervals were defined for analysis: the initial 15 days and 30 days following vaccination were categorized as risk intervals, while all other periods served as control intervals. Incidence rate ratios (IRRs) were computed to compare HZ incidence during the risk intervals with that during the control intervals. RESULTS: This study encompassed a cohort of 4,222 renal transplant recipients who had received the influenza vaccine. Among this group, 67 recipients were subsequently diagnosed with HZ. The IRR during both the initial 15 days (IRR = 0.63; 95 % CI, 0.23-1.89) and the first 30 days (IRR = 1.50; 95 % CI, 0.71-3.16) following influenza vaccination did not demonstrate a statistically significant increase when compared to the post-exposure observation times. Comparable results were also observed when comparing these IRR values to the pre-exposure observation times. The subgroup analysis, stratified by age, sex, and underlying medical conditions (including cancer and autoimmune diseases), revealed that the IRRs did not exhibit statistically significant differences. CONCLUSIONS: No significant association between the influenza vaccine and an elevated risk of HZ was detected. The administration of annual influenza vaccines appears to be a reasonable practice for renal transplant recipients.
Asunto(s)
Herpes Zóster , Vacunas contra la Influenza , Trasplante de Riñón , Humanos , Herpes Zóster/prevención & control , Herpes Zóster/epidemiología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Taiwán/epidemiología , Incidencia , Anciano , Adulto Joven , Receptores de Trasplantes/estadística & datos numéricos , Vacunación/efectos adversos , Gripe Humana/prevención & control , Herpesvirus Humano 3/inmunología , AdolescenteRESUMEN
The Varicella-zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV-associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune-mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune-mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV-induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV-related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV-induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.
Asunto(s)
Herpesvirus Humano 3 , Humanos , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Herpesvirus Humano 3/patogenicidad , Herpes Zóster/virología , Herpes Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/inmunología , Infección por el Virus de la Varicela-Zóster/virología , Enfermedades del Sistema Nervioso/virología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/etiología , Animales , Varicela/virología , Varicela/inmunología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/virologíaRESUMEN
Introduction: Varicella zoster virus (VZV) causes varicella and can reactivate as herpes zoster, and both diseases present a significant burden worldwide. However, the mechanisms by which VZV establishes latency in the sensory ganglia and disseminates to these sites remain unclear. Methods: We combined a single-cell sequencing approach and a well-established rhesus macaque experimental model using Simian varicella virus (SVV), which recapitulates the VZV infection in humans, to define the acute immune response to SVV in the lung as well as compare the transcriptome of infected and bystander lung-resident T cells and macrophages. Results and discussion: Our analysis showed a decrease in the frequency of alveolar macrophages concomitant with an increase in that of infiltrating macrophages expressing antiviral genes as well as proliferating T cells, effector CD8 T cells, and T cells expressing granzyme A (GZMA) shortly after infection. Moreover, infected T cells harbored higher numbers of viral transcripts compared to infected macrophages. Furthermore, genes associated with cellular metabolism (glycolysis and oxidative phosphorylation) showed differential expression in infected cells, suggesting adaptations to support viral replication. Overall, these data suggest that SVV infection remodels the transcriptome of bystander and infected lung-resident T cells and macrophages.
Asunto(s)
Pulmón , Macaca mulatta , Animales , Pulmón/inmunología , Pulmón/virología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/virología , Transcriptoma , Linfocitos T/inmunología , Varicellovirus/fisiología , Varicellovirus/inmunología , Macrófagos/inmunología , Macrófagos/virología , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Modelos Animales de Enfermedad , Análisis de la Célula IndividualRESUMEN
OBJECTIVE: This study aims to evaluate the safety and immunogenicity of the SKYVaricella vaccine in healthy Vietnamese children aged 12 months to 12 years. METHODS: This open-label, single-arm study involved 201 children divided into two groups: 60 children aged 12 months to 5 years and 141 children aged 6 to 12 years. Safety was assessed through immediate reactions, solicited adverse events within 7 days, and unsolicited events up to Day 42. Immunogenicity was evaluated by seroconversion rates (SCR) and geometric mean titer (GMT) increments using fluorescent antibody-to-membrane antigen (FAMA) on the day of vaccination (D0) and 42 days after vaccination (D42). RESULTS: All participants completed the follow-up. Immediate adverse events included pain (8.0%), redness (8.0%), and swelling (20.9%) at the injection site. Within 7 days, pain (17.9%) and swelling (12.4%) were mild and self-resolving. Unsolicited adverse events were infrequent and mild. Both age groups achieved 100% SCR. GMT of varicella-zoster virus antibodies increased from 1.37 (SD 1.97) at D0 to 18.02 (SD 2.22) at D42, a 13.12-fold rise. No Grade 3 adverse events were observed. CONCLUSION: The SKYVaricella vaccine shows a robust immunogenic response and favorable safety profile in Vietnamese children aged 12 months to 12 years. These findings endorse its potential inclusion in pediatric vaccination programs as a reliable preventive option against varicella.