Latent Varicella Zoster Virus Research Articles

Variable Gene Expression in Human Ganglia Latently Infected with Varicella-Zoster Virus.

Varicella-Zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (“chicken pox”) as a primary infection, following which it becomes latent in neuronal cells in human peripheral ganglia. It may then reactivate to cause herpes zoster (“shingles”). Defining the pattern of VZV gene expression during latency is an important issue, and four highly expressed VZV genes were first identified by Randall Cohrs in 1996 using cDNA libraries. Further studies from both his and other laboratories, including our own, have suggested that viral gene expression may be more widespread than previously thought, but a confounding factor has always been the possibility of viral reactivation after death in tissues obtained even at 24 h post-mortem. Recent important studies, which Randall Cohrs contributed to, have clarified this issue by studying human trigeminal ganglia at 6 h after death using RNA-Seq methodology when a novel spliced latency-associated VZV transcript (VLT) was found to be mapped antisense to the viral transactivator gene 61. Viral gene expression could be induced by a VLT-ORF 63 fusion transcript when VZV reactivated from latency. Prior detection by several groups of ORF63 in post-mortem-acquired TG is very likely to reflect detection of the VLT-ORF63 fusion and not canonical ORF63. The contributions to the VZV latency field by Randall Cohrs have been numerous and highly significant.

LNP-CpG ODN-adjuvanted varicella-zoster virus glycoprotein E induced comparable levels of immunity with Shingrix™ in VZV-primed mice

Latent varicella-zoster virus (VZV) may be reactivated to cause herpes zoster, which affects one in three people during their lifetime. The currently available subunit vaccine Shingrix™ is superior to the attenuated vaccine Zostavax® in terms of both safety and efficacy, but the supply of its key adjuvant component QS21 is limited. With ionizable lipid nanoparticles (LNPs) that were recently approved by the FDA for COVID-19 mRNA vaccines as carriers, and oligodeoxynucleotides containing CpG motifs (CpG ODNs) approved by the FDA for a subunit hepatitis B vaccine as immunostimulators, we developed a LNP vaccine encapsulating VZV-glycoprotein E (gE) and CpG ODN, and compared its immunogenicity with Shingrix™ in C57BL/6J mice. The results showed that the LNP vaccine induced comparable levels of gE-specific IgG antibodies to Shingrix™ as determined by enzyme-linked immunosorbent assay (ELISA). Most importantly, the LNP vaccine induced comparable levels of cell-mediated immunity (CMI) that plays decisive roles in the efficacy of zoster vaccines to Shingrix™ in a VZV-primed mouse model that was adopted for preclinical studies of Shingrix™. Number of IL-2 and IFN-γ secreting splenocytes and proportion of T helper 1 (Th1) cytokine-expressing CD4+ T cells in LNP-CpG-adjuvanted VZV-gE vaccinated mice were similar to that of Shingrix™ boosted mice. All of the components in this LNP vaccine can be artificially and economically synthesized in large quantities, indicating the potential of LNP-CpG-adjuvanted VZV-gE as a more cost-effective zoster vaccine.

Immunogenicity of Varicella Zoster Virus DNA Vaccines Encoding Glycoprotein E and Immediate Early Protein 63 in Mice.

Herpes zoster (HZ) is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia due to aging or immunosuppression. Glycoprotein E (gE) is a widely used vaccine antigen for specific humoral and cellular immune responses. Immediate early protein 63 (IE63) is expressed during latency, suggesting that it is a potential antigen against HZ reactivation. In this study, HZ DNA vaccines encoding gE, IE63, IE63-2A-gE (where 2A is a self-cleaving sequence), or IE63-linker-gE were developed and investigated for immunogenicity in mice. The results showed that each HZ DNA vaccine induced VZV-specific antibody production. The neutralizing antibody titer elicited by IE63-2A-gE was comparable to that elicited by gE or live attenuated HZ vaccine (LAV). IE63-2A-gE-induced gE or IE63-specific INF-γ+ T cell frequencies in splenocytes were comparable to those of LAV. Furthermore, IE63-2A-gE, gE, or IE63 led to a significant increase in IFN-γ (IE63 stimulation) and IL-2 (gE stimulation) secretion compared to LAV, showing a Th1-biased immune response. Moreover, IE63-2A-gE and gE induced cytotoxic activity of CD8+ T cells compared to that of LAV. This study elucidates that the IE63-2A-gE DNA vaccine can induce both humoral and cell-mediated immune responses, which provides a candidate for the development of an HZ vaccine.

Herpes zoster in the era of COVID 19: A prospective observational study to probe the association of herpes zoster with COVID 19 infection and vaccination.

Herpes zoster (HZ) is caused by reactivation of the latent varicella zoster virus (VZV) following decline in cell‐mediated immunity. All over the world, in the past couple of years, the Corona Virus 2019 (COVID‐19) has emerged as a viral cause of severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) infection. Based on the current limited evidence, co‐infection of COVID‐19 with VZV or reactivation of VZV after COVID‐19 vaccination has been sporadically reported. All patients diagnosed with HZ, in Farwaniya Hospital in Kuwait, from March 2020 to July 2021, having either (A) a positive COVID‐19 polymerase chain reaction (PCR) test, or (B) been vaccinated against SARS‐CoV‐2 were enrolled in the study. All patients' demographic information, medical history, laboratory findings, and vaccination status was documented. All statistical analyses were performed using SPSS Statistics version 21.0 software. Twelve cases infected with COVID‐19 with a positive PCR (group 1) and five cases vaccinated against SARS‐CoV‐2 (group 2) were documented. Out of the 12 COVID‐19 infected patients (group 1), only two patients (16.67%) required hospitalization, while the remaining 10 patients had mild/moderate lymphopenia. Furthermore, amongst the 12 positive COVID‐19 cases, four patients with HZ were diagnosed within the first week of COVID‐19, while the remaining eight cases were diagnosed within 8 weeks of COVID‐19. Thoracic segments were affected in five cases (41.67%), cervical in one case (8.33%), cranial in two cases (16.67%), lumbar in three cases (25%) and sacral in one case (8.33%). In group 2, three patients presented with HZ within 4 weeks of having received the first dose of the vaccine and two patients after the second dose. Blood investigations for all five vaccinated patients did not show any abnormalities. Cervical segments were affected in two patients (40%), and cranial, thoracic, and lumbar segment in the remaining patients respectively (20%). Experts must be aware of the probable increased risk of HZ during the COVID 19 pandemic. We propose appropriate curative and preventive measures against HZ infection, including a systematic follow‐up of these patients to ensure that they stick to extreme safety measures till the diagnosis of COVID‐19 is omitted.

An adjuvanted zoster vaccine elicits potent cellular immune responses in mice without QS21

Herpes zoster (HZ) is caused by reactivation of latent varicella-zoster virus (VZV) when VZV-specific cellular immunity is insufficient to control reactivation. Currently, Shingrix, which contains the VZV gE protein and GSK’s AS01B adjuvant composed of liposomes formulated with cholesterol, monophosphoryl lipid A (MPL) and QS21, is used for prevention of HZ. However, reactogenicity to Shingrix is common leading to poor patient compliance in receiving one or both shots. Here, we evaluated the immunogenicity of a newly formulated gE protein-based HZ vaccine containing Second-generation Lipid Adjuvant (SLA), a synthetic TLR4 ligand, formulated in an oil-in-water emulsion (SLA-SE) without QS21 (gE/SLA-SE). In VZV-primed mouse models, gE/SLA-SE-induced gE-specific humoral and cellular immune responses at comparable levels to those elicited by Shingrix in young mice, as both gE/SLA-SE and Shingrix induce polyfunctional CD4+ T-cell responses. In aged mice, gE/SLA-SE elicited more robust gE-specific T-cell responses than Shingrix. Furthermore, gE/SLA-SE-induced T-cell responses were sustained until 5 months after immunization. Thus, QS21-free, gE/SLA-SE is a promising candidate for development of gE-based HZ vaccines with high immunogenicity—particularly when targeting an older population.

Fraternal Twins: The Enigmatic Role of the Immune System in Alphaherpesvirus Pathogenesis and Latency and Its Impacts on Vaccine Efficacy.

Although the establishment, maintenance and reactivation from alphaherpesvirus latency is far from fully understood, some things are now manifestly clear: Alphaherpesvirus latency occurs in neurons of the peripheral nervous system and control of the process is multifactorial and complex. This includes components of the immune system, contributions from non-neuronal cells surrounding neurons in ganglia, specialized nucleic acids and modifications to the viral DNA to name some of the most important. Efficacious vaccines have been developed to control both acute varicella and zoster, the outcome of reactivation, but despite considerable effort vaccines for acute herpes simplex virus (HSV) infection or reactivated lesions have thus far failed to materialize despite considerable effort. Given the relevance of the immune system to establish and maintain HSV latency, a vaccine designed to tailor the HSV response to maximize the activity of components most critical for controlling reactivated infection might limit the severity of recurrences and hence reduce viral transmission. In this review, we discuss the current understanding of immunological factors that contribute to HSV and VZV latency, identify differences between varicella-zoster virus (VZV) and HSV that could explain why vaccines have been valuable at controlling VZV disease but not HSV, and finish by outlining possible strategies for developing effective HSV vaccines.

The untapped potential of herpes zoster vaccination

Herpes zoster infection corresponds to the reactivation of latent varicella-zoster virus, and is characterised by a vesicular dermatomal rash, which usually spontaneously resolves, but can result in persistent (>3 months) debilitating pain, known as postherpetic neuralgia. Two vaccines are available against herpes zoster, namely zoster vaccine live (ZVL) and a newer, recombinant zoster vaccine (RZV), available since 2017.

Enhanced Potency and Persistence of Immunity to Varicella-Zoster Virus Glycoprotein E in Mice by Addition of a Novel BC02 Compound Adjuvant

Herpes zoster (HZ) is one of two distinct syndromes caused by Varicella-zoster virus (VZV). A primary infection with VZV causes varicella in susceptible young children. After resolution of the primary infection, VZV establishes a lifelong latency within the cranial or dorsal root ganglia. With increasing age, family history of shingles, immunosuppression or other risk factors, there is a decline in the virus-specific T-cell-mediated immune (CMI) response which allows reactivation of latent VZV in the root ganglia resulting in HZ. There are currently two vaccines that have been approved to prevent HZ and postherpetic neuralgia (PHN) but one is a live attenuated vaccine, the protective effect of which is considered to decrease significantly with the age of the recipient. However, a recombinant subunit vaccine may provide targeted VZV-specific cellular and humoral immunity, giving it a more potent and longer-lasting protective effect against HZ. The current study reports the development of a novel adjuvant, BC02 (BCG CpG DNA compound adjuvants system 02), composed of Al(OH)3 inorganic salt adjuvant and BC01 (BCG CpG DNA compound adjuvants system 01), a Toll-like receptor 9 (TLR9) agonist. Immunogenicity and compatibility with recombinant VZV glycoprotein E (gE) in mice were studied. The BC02-adjuvanted gE experimental vaccine was highly effective in eliciting both humoral and cellular immune responses to the recombinant gE glycoprotein and VZV-Oka in a mouse model. The efficient production and long-term persistence of gE and VZV-Oka-specific IFN-γ, IL-2-specific T cells and memory B cells in the early (1W), middle (7W), middle-late (15W), and final (27W) immune stages were established. Results of fluorescent antibody to membrane antigen (FAMA) and serum antibody plaque reduction tests also showed that the BC02 adjuvanted-gE experimental vaccine induced mice to secrete neutralizing antibodies against clinically isolated VZV strains. In combination, the current data suggest that the BC02 compound adjuvant offers a strategy to induce an appropriately strong cellular and humoral immunity against the VZV gE protein subunit to improve vaccine efficacy.

Research progress on the incidence and economic burden of herpes zoster disease in immunocompromised population

With the increase of age or the impairment of immune function, the specific cellular immune level against varicella zoster virus (VZV) in the body decreases, and the latent VZV in the ganglion can be reactivated to cause herpes zoster (HZ). HZ and its main complication postherpetic neuralgia (PHN) can seriously affect the quality of life of patients. The immunocompromised (IC) population is more prone to HZ than the immunocompetent population due to diseases and therapeutic drugs. This paper reviews the incidence, risk factor and economic burden of HZ in IC population with special health status, to provide ideas for research and adjustment of immunization strategies in the future.

Occurrence of Herpes Viruses in Morphologically Normal Corneas.

The purpose of this study was to detect the occurrence of herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV) DNA in transplanted corneas using polymerase chain reaction (PCR) and to determine the relationship between latent HSV and VZV and herpetic eye disease in recipients. This was a retrospective, interventional case series. Samples from 88 donor corneoscleral buttons (CSBs) were collected from the conjunctiva, iris, and endothelium and tested for HSV-1, HSV-2, and VZV DNA using PCR. All transplanted eyes were evaluated and followed up. The main outcome measures were HSV-1, HSV-2, and VZV DNA positivity rates in donor CSBs and the occurrence of herpetic eye disease or graft failure in recipients of positive corneas. HSV-1 DNA was detected in 5 (5.7%) of 88 CSBs. HSV-2 was not detected in any CSBs, and VZV was found in 1 (1.2%) of the 82 examined CSBs. One recipient (16.7%) developed dendritic epitheliopathy and keratouveitis typical of HSV 12 months after transplantation, although the graft remained clear after treatment. One cornea was used for a tectonic graft and stayed edematous at the 20-month follow-up. The remaining corneas remained clear. Morphologically normal donor corneas may be PCR-positive for herpes viruses, especially HSV-1. Recipients of herpes-positive corneal grafts could be at risk for herpetic eye disease. Further studies using viral RNA by reverse transcriptase PCR are needed to provide more information on HSV and VZV latency and active replication in donor corneas.

P402 Incidence and outcomes of herpes zoster in the ozanimod phase, 3 ulcerative colitis and relapsing multiple sclerosis clinical program

Abstract Background Patients with ulcerative colitis (UC) and patients with multiple sclerosis (MS) have an elevated risk of developing herpes zoster (HZ), caused by reactivation of latent varicella zoster virus (VZV). Increased incidence of HZ has been reported with sphingosine, 1-phosphatase (S1P) receptor modulators. This analysis examined the number of patients who failed screening due to a lack of demonstrated VZV immunity and the incidence of HZ from completed phase, 3 ozanimod clinical trials. Methods Safety results were included from True North (52-week trial) in patients with UC, and SUNBEAM (12-month trial), and RADIANCE (24-month trial) in patients with MS. All patients were required to have had a positive VZV IgG antibody status or completed VZV vaccination ≥30 days prior to randomization based on known effects of S1P modulators. Patients with a negative VZV antibody titer could choose to receive the VZV vaccination to qualify for the trial. Number of pre-screen failures because of lack of demonstrated immunity, occurrence of HZ, and association between HZ cases and lymphopenia were analyzed. Results Of, 1831 patients with UC screened for VZV immunity, 104 (5.7%) failed screening due to lack of documentation of VZV antibody or VZV vaccination ≥30 days before randomization;, 22% (23/104) subsequently received varicella vaccination and were rescreened and enrolled. Of, 3332 MS patients tested for VZV immunity, 309 (9.3%) tested negative and, 32% (98/309) of these patients were vaccinated prior to randomization. In the UC and MS trials, the incidence of HZ cases was low in ozanimod-treated patients (8 cases [1.0%] and, 5 cases [0.6%], respectively; Table, 1). All cases were distributed across a single dermatome, did not result in a complication of HZ, and were treated with oral antivirals while patients remained on ozanimod. None of the patients discontinued ozanimod because of HZ and none of the HZ cases were associated with grade, 4 lymphopenia (defined as an absolute lymphocyte count <0.2 x, 109/L). Conclusion In the ozanimod phase, 3 UC and MS trials, 5%–10% of patients screened did not have demonstrated VZV immunity;, 22%–32% of these patients received varicella vaccination, were rescreened and enrolled. The overall HZ incidence in clinical trials was low (≤1% of patients), all cases were distributed across a single dermatome, and no serious or complicated cases occurred in ozanimod-treated patients with VZV immunity. Additional studies are warranted to evaluate the incidence of HZ in clinical practice.

Decline in hospitalization rates for herpes zoster in Italy (2003-2018): reduction in the burden of disease or changing of hospitalization criteria?

Herpes Zoster (HZ) is a very demanding disease caused by the reactivation of latent Varicella Zoster Virus. The main aim of this study was to estimate the burden of the HZ hospitalizations in Italy from 2003 to 2018 evaluating temporal trends. Retrospective population-based study analyzing Hospital Discharge Records. Hospitalization records reporting the ICD-9 CM 053.X code in the principal diagnosis or in any of the five secondary diagnoses were considered as cases. Trends of hospitalization rates have been evaluated by Joinpoint analyses. Overall, 99,036 patients were hospitalized with HZ in the 16-year period of the study, and 83,720 (84.5%) of these patients were over 50years. Hospitalization rate was 10.4 per 100,000 persons/year with a significant decreasing trend from 13.9 in 2003-2006 to 7.8 in 2015-2018 (p < 0.001). Hospitalization rates showed a 20-fold higher risk among subjects aged over 80years and 11-fold higher risk among 70-79-year-old subjects with respect to those aged less than 50years. Over time, a statistically significant increase was observed for the case fatality rate (from 1.2 to 1.7%; p < 0.001) and the median length of stay (from 7 to 8days; p < 0.001). Zoster is a disease that causes hospitalization as relatively frequent complication and the observed reduced trend over time could be due to a restriction in hospitalization criteria instead of a reduced burden of disease. The decreasing trend should be carefully interpreted, since it could have an impact on promoting herpes zoster vaccination.

A rare case of herpes zoster in a child involving dermatomes V1 and V2

Herpes zoster (HZ) is rarely found in healthy children but may be attributed to immunocompromised children. Latent varicella-zoster virus (VZV) might have source from intrauterine exposure, chicken pox vaccination, or exposure to wild VZV. A 2 ½-year-old healthy boy presented with a painful red vesicular rashes with blisters on the right upper cheek, periorbital area, temporal and nasal area extending over the dermatomes V1 and V2 of 3 days' duration. There was an involvement of the right eye causing conjunctivitis. He had persistent frontal and temporal headache on the day 10 of the disease. Computed tomography scan of the brain reveals no abnormality. The child responded well to symptomatic management and routine skin care. Medications such as cetrizine, sup acyclovir, and local acyclovir ointment and emollients were given. Acyclovir was used orally in a dose of 20 mg/kg body weight every 6 hourly for 7 days. The patient recovered well in 10 days of treatment. HZ is a rare presentation in healthy children and needs a high index of suspicion to diagnose in cases with vesicular eruptions. In our case, the intrauterine infection is the source of latent VZV. HZ may not indicate that the child is immunocompromised.

Case Report of Herpes Zoster in the 17-year-old Boy

Herpes zoster has been caused because of the reactivation of latent Varicella-Zoster virus. It is a proportionally uncommon condition in the young population, as compared with adults. After taking consent from the legal guardian of the patient, we report a 17-year-old boy with a history of varicella, who came to us with the complaint of very severe painful vesicular lesions on the right side T1 and T2 dermatomal distribution of the chest, arm, and dorsal side of the trunk. Ultimately, the patient was diagnosed with herpes zoster. We focus to highlight that herpes zoster could occur in the healthy and immunocompetent young population and this may be due to the previous subclinical infection or vaccine strain reactivation.

Complications and cost estimations in herpes zoster - a retrospective analysis at a Swiss tertiary dermatology clinic.

Herpes zoster is the common reactivation of latent varicella zoster virus infection and is associated with substantial morbidity and costs. Age, immunosuppression, diabetes and active cancer are important risk factors for developing herpes zoster. The recombinant herpes zoster vaccine is highly effective in preventing this infection. To inform cost-effectiveness analyses of vaccination in risk groups, it is important to define the rates of complications, mortality, and hospitalisation and its costs. In this single-centre, investigator-initiated, retrospective study we analysed herpes zoster patients treated in our tertiary dermatology referral centre between 2005 and 2019. Case costs were calculated using health insurance invoices and by estimating the drug-related costs. The associations between patients' characteristics and complications were assessed using logistic regression models. A total of 355 herpes zoster patients were analysed (mean age 61.5 ± 18.8 years; 56.6% women). The complication rate was 30.1% (n = 107) with post-herpetic neuralgia being the most frequent (37/355, 10.4%). The herpes zoster-related hospitalisation rate was 19.2% (n = 68), the herpes zoster-related mortality rate 0.85% (n = 3). Of all patients, 22.8% (n = 81) had herpes zoster risk factors. The odds ratio for complications (multivariate analysis) was 2.5 (95% confidence interval [CI] 1.12-5.72) in cancer patients and 1.04 (1.02-1.05) for each additional year of age (1.41 for 10 years). The cost ratio (median) of in- vs outpatient treatment was 26.9 (CHF/case 9029 vs 335), of all complicated vs non-complicated herpes zoster patients 6.6 (CHF/case 2203 vs 332) and of complicated vs non-complicated herpes zoster outpatients 4.3 (CHF/case 1331 vs 306). In this herpes zoster population at a university hospital, one in three patients was affected by herpes zoster-related complications. Age and cancer were independently associated with a high complication rate, suggesting a need to vaccinate cancer patients. Herpes zoster-related complications and the need for inpatient treatment escalated the costs per case.

The adjuvanted recombinant zoster vaccine co-administered with the 13-valent pneumococcal conjugate vaccine in adults aged ≥50 years: A randomized trial

BackgroundHerpes zoster (HZ) results from reactivation of latent varicella-zoster virus. Adults at increased risk of HZ (due to immunocompromising conditions or older age) are also at risk of pneumococcal disease, both of which are preventable by vaccination. We evaluated simultaneous versus sequential administration of the adjuvanted recombinant zoster vaccine (RZV) and the 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ≥50 years. MethodsIn this phase IIIB multinational trial (NCT03439657), participants were randomized 1:1 to receive either the first RZV dose and PCV13 simultaneously followed by the second RZV dose two months later (Co-Ad, N = 449), or at two-month intervals, PCV13, the first RZV dose, and the second RZV dose sequentially (Control, N = 463). Objectives were to demonstrate that immune responses to both vaccines are non-inferior when co-administered compared to sequential administration and to evaluate the safety of their co-administration. ResultsThe RZV vaccine response rate (VRR) in the Co-Ad group was 99.1% (95% confidence interval [CI]: 97.6–99.7), meeting the VRR success criterion. Non-inferiority criteria for the Co-Ad versus Control group were also met for anti-glycoprotein E antibodies (adjusted geometric mean concentration Control/Co-Ad ratio 1.07 [95%CI: 0.99–1.16]) and all PCV13 serotypes (adjusted antibody geometric mean titer Control/Co-Ad ratios 1.02 [95%CI: 0.86–1.22] to 1.36 [95%CI: 1.07–1.73]). Upon co-administration, the frequency of solicited local adverse events was consistent with the known safety profile of each individual vaccine, whereas solicited general adverse events were within the same range as for RZV alone. ConclusionsRZV co-administered with PCV13 had an acceptable safety profile. Humoral immune responses to both vaccines were non-inferior when co-administered compared to sequential administration. These results suggest that adults may benefit from receiving RZV and a PCV at the same healthcare visit.

Ramsay Hunt Syndrome in a Patient with Ulcerative Colitis Treated with Infliximab.

Ramsay Hunt syndrome is a rare complication of herpes zoster that results from reactivation of varicella-zoster virus in the geniculate ganglion of the VII cranial nerve. Immunosuppression can lead to reactivation of latent varicella-zoster virus, resulting in herpes zoster. Here, we present a case of Ramsay Hunt syndrome in a patient with ulcerative colitis under treatment with infliximab.LEARNING POINTSRamsay Hunt syndrome is a rare form of herpes zoster and characterized by the presence of otalgia, facial palsy, vertigo and vesicular rash in the external ear or on the oropharynx.Treatment with TNF inhibitors increases the risk of its development.Although not generally recommended, vaccination may reduce the risk of herpes zoster recurrence during TNF inhibitor therapy.

Mutagenesis of the Varicella-Zoster Virus Genome Demonstrates That VLT and VLT-ORF63 Proteins Are Dispensable for Lytic Infection.

Primary varicella-zoster virus (VZV) infection leads to varicella and the establishment of lifelong latency in sensory ganglion neurons. Reactivation of latent VZV causes herpes zoster, which is frequently associated with chronic pain. Latent viral gene expression is restricted to the VZV latency-associated transcript (VLT) and VLT-ORF63 (VLT63) fusion transcripts. Since VLT and VLT63 encode proteins that are expressed during lytic infection, we investigated whether pVLT and pVLT-ORF63 are essential for VZV replication by performing VZV genome mutagenesis using CRISPR/Cas9 and BAC technologies. We first established that CRISPR/Cas9 can efficiently mutate VZV genomes in lytically VZV-infected cells through targeting non-essential genes ORF8 and ORF11 and subsequently show recovery of viable mutant viruses. By contrast, the VLT region was markedly resistant to CRISPR/Cas9 editing. Whereas most mutants expressed wild-type or N-terminally altered versions of pVLT and pVLT-ORF63, only a minority of the resulting mutant viruses lacked pVLT and pVLT-ORF63 coding potential. Growth curve analysis showed that pVLT/pVLT-ORF63 negative viruses were viable, but impaired in growth in epithelial cells. We confirmed this phenotype independently using BAC-derived pVLT/pVLT-ORF63 negative and repaired viruses. Collectively, these data demonstrate that pVLT and/or pVLT-ORF63 are dispensable for lytic VZV replication but promote efficient VZV infection in epithelial cells.

The Pfizer-BNT162b2 mRNA-based vaccine against SARS-CoV-2 may be responsible for awakening the latency of herpes varicella-zoster virus

BackgroundTo prevent the invasion and transmission of SARS-CoV-2, mRNA-based vaccines, non-replicating viral vector vaccines, and inactivated vaccines have been developed. The European Medicines Agency (EMA) authorized the use of the anti-SARS-CoV-2 vaccine in January 2021, the date on which the vaccination program began in Spain and across Europe. The aim of this study is to monitor the safety of anti-SARS-CoV-2 vaccines and report any cases of undesirable effects that have occurred, that are not included in the health profile of mRNA-based vaccines for commercialisation in humans. Furthermore, a brief review is given of the mechanism of action of the anti-SARS-CoV-2 vaccine on the host's immune system in triggering the reactivation of the herpes varicella-zoster infection. MethodsFollow-up of patients under the care of the southern health district of Seville of the SAS (Andalusian Health Service) during the Spanish state of alarm over the COVID-19 pandemic. ResultsTwo patients, a 79-year-old man and a 56-year-old woman, are reported who, after 4 and 16 days respectively of receiving the Pfizer-BNT162b2 vaccine against SARS-CoV-2, presented a state of reactivation of herpes varicella-zoster virus (VZV). DiscussionThe immunosenescence of the reported patients, together with the immunomodulation generated by administering the anti-SARS-CoV-2 vaccines, that depress certain cell subpopulations, could explain the awakening of VZV latency.

Recent Issues in Varicella-Zoster Virus Latency.

Varicella-zoster virus (VZV) is a human herpes virus which causes varicella (chicken pox) as a primary infection, and, following a variable period of latency in neurons in the peripheral ganglia, may reactivate to cause herpes zoster (shingles) as well as a variety of neurological syndromes. In this overview we consider some recent issues in alphaherpesvirus latency with special focus on VZV ganglionic latency. A key question is the nature and extent of viral gene transcription during viral latency. While it is known that this is highly restricted, it is only recently that the very high degree of that restriction has been clarified, with both VZV gene 63-encoded transcripts and discovery of a novel VZV transcript (VLT) that maps antisense to the viral transactivator gene 61. It has also emerged in recent years that there is significant epigenetic regulation of VZV gene transcription, and the mechanisms underlying this are complex and being unraveled. The last few years has also seen an increased interest in the immunological aspects of VZV latency and reactivation, in particular from the perspective of inborn errors of host immunity that predispose to different VZV reactivation syndromes.