Varicella zoster virus vaccines: potential complications and possible improvements

Varicella zoster virus(VZV) is the causative agent of varicella(chicken pox) and herpes zoster(shingles). After primary infection, the virus remains latent in sensory ganglia, and reactivates upon weakening of the cellular immune system due to various conditions, erupting from sensory neurons and infecting the corresponding skin tissue. The current varicella vaccine(v-Oka) is highly attenuated in the skin, yet retains its neurovirulence and may reactivate and damage sensory neurons. The reactivation is sometimes associated with postherpetic neuralgia(PHN), a severe pain along the affected sensory nerves that can linger for years, even after the herpetic rash resolves. In addition to the older population that develops a secondary infection resulting in herpes zoster, childhood breakthrough herpes zoster affects a small population of vaccinated children. There is a great need for a neuro-attenuated vaccine that would prevent not only the varicella manifestation, but, more importantly, any establishment of latency, and therefore herpes zoster. The development of a genetically-defined live-attenuated VZV vaccine that prevents neuronal and latent infection, in addition to primary varicella, is imperative for eventual eradication of VZV, and, if fully understood, has vast implications for many related herpesviruses and other viruses with similar pathogenic mechanisms.

Microbiology laboratory and the management of motherchild varicella-zoster virus infection

Varicella-zoster virus, which is responsible for varicella(chickenpox) and herpes zoster(shingles), is ubiquitous and causes an acute infection among children, especially those aged less than six years. As 90% of adults have had varicella in childhood, it is unusual to encounter an infected pregnant woman but, if the disease does appear, it can lead to complications for both the mother and fetus or newborn. The major maternal complications include pneumonia, which can lead to death if not treated. If the virus passes to the fetus, congenital varicella syndrome, neonatal varicella(particularly serious if maternal rash appears in the days immediately before or after childbirth) or herpes zoster in the early years of life may occur depending on the time of infection. A Microbiology laboratory can help in the diagnosis and management of mother-child infection at four main times:(1) when a pregnant woman has been exposed to varicella or herpes zoster, a prompt search for specific antibodies can determine whether she is susceptible to, or protected against infection;(2) when a pregnant woman develops clinical symptoms consistent with varicella, the diagnosis is usually clinical, but a laboratory can be crucial if the symptoms are doubtful or otherwise unclear(atypical patterns in immunocompromised subjects, patients with post-vaccination varicella, or subjects who have received immunoglobulins), or if there is a need for a differential diagnosis between varicella and other types of dermatoses with vesicle formation;(3) when a prenatal diagnosis of uterine infection is required in order to detect cases of congenital varicella syndrome after the onset of varicella in the mother; and(4) when the baby is born and it is necessary to confirm a diagnosis of varicella(and its complications), make a differential diagnosis between varicella and other diseases with similar symptoms, or confirm a causal relationship between maternal varicella and malformations in a newborn.

Review of varicella-zoster virus infections in pregnant women and neonates

Even though varicella is rare in pregnancy, the disease can lead occasionally to disastrous illnesses for both the mother and her neonate. By contrast, normal zoster is not associated with special problems during pregnancy and peri- natal period. Pregnant women, who contract varicella, are at risk of varicella pneumonia which must be regarded as medical emergency. At any stage during pregnancy, chickenpox may cause intrauterine infection. The consequences for the fetus depend on the time of maternal disease. During the first two trimesters, maternal varicella may result in congenital varicella syndrome which may occur in nearly 2%. Typical symptoms are skin lesions in dermatomal distribution, neurological defects, eye diseases, and skeletal anomalies. Maternal infection near term is associated with a substantial risk of intrauterine acquired neonatal chickenpox in the neonate. If the mother develops varicella rash between day 4 (5) ante partum and day 2 post partum, generalized neonatal varicella leading to death in about 20% of the cases has to be expected. The present paper reviews the clinical consequences and the currently available concepts of prevention, diagnosis, and therapy of varicella-zoster virus infections during pregnancy.

Detection of Varicella Zoster Virus DNA within Lesions and Healed Skin Lesions of Herpes Zoster by PCR

Varicella zoster virus(VZV) DNA in blister lesions and skin biopsies obtained from healed skin lesions in 16 patients with herpes zoster was detected using polymerase chain reaction. A 385 bp VZV DNA fragment was found in all the blister lesions and in two of six biopsies from the skin lesions healed within two months by PCR. No VZV DNA was found in the skin lesions more than two months after healing in 10 cases of herpes zoster. VZV DNA may be detected at the sites of resolved herpes zoster lesions within short duration.

Transverse myelitis after infection with varicella zoster virus in patient with normal immunity: A case report

BACKGROUND Varicella zoster virus(VZV)is a human neurotropic and double-stranded DNA alpha-herpes virus.Primary infection with VZV usually occurs during childhood,manifesting as chickenpox.Reactivation of latent VZV can lead to various neurological complications,including transverse myelitis(TM);although cases of the latter are very rare,particularly in newly active VZV infection.CASE SUMMARY We report here an unusual case of TM in a middle-aged adult immunocompetent patient that developed concomitant to an active VZV infection.The 46-year-old male presented with painful vesicular eruption on his left chest that had steadily progressed to involvement of his back over a 3-d period.Cerebrospinal fluid testing was denied,but findings from magnetic resonance imaging and collective symptomology indicated TM.He was administered antiviral drugs and corticosteroids immediately but his symptom improvement waxed and waned,necessitating multiple hospital admissions.After about a month of repeated treatments,he was deemed sufficiently improved for hospital discharge to home.CONCLUSION VZV myelitis should be suspected when a patient visits the outpatient pain clinic with herpes zoster showing neurological symptoms.

Varicella-zoster virus meningitis after spinal anesthesia:A case report

BACKGROUND Headache is a common complication of regional anesthesia.The treatment of post spinal anesthesia headache varies depending on the cause.Although meningitis is rare,it can cause significant harm to the patient.Post dural puncture headache and septic meningitis are the most commonly suspected causes of post spinal anesthesia headache;however,other causes should also be considered.CASE SUMMARY A 69-year-old woman was scheduled for varicose vein stripping surgery under spinal anesthesia.The procedure was performed aseptically,and surgery was completed without any complications.After 4 d,the patient visited the emergency room with complaints of headache,nausea,and anorexia.Clinical examination revealed that the patient was afebrile.Considering the history of spinal anesthesia,post dural puncture headache and septic meningitis was initially suspected,and the patient was treated with empirical antibiotics.Subsequently,varicella-zoster virus PCR test result was positive,and all other test results were negative.The patient was diagnosed with meningitis caused by varicella-zoster virus and was treated with acyclovir for 5 d.The headache improved,and the patient was discharged without any problems.CONCLUSION Viral meningitis due to virus reactivation may cause headache after regional anesthesia.Therefore,clinicians should consider multiple etiologies of headache.

Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease

Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal-CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy.

Regulation of Wnt/β-catenin signaling by herpesviruses

The Wnt/β-catenin signaling pathway is instrumental in successful differentiation and proliferation of mammalian cells. It is therefore not surprising that the herpesvirus family has developed mechanisms to interact with and manipulate this pathway. Successful coexistence with the host requires that herpesviruses establish a lifelong infection that includes periods of latency and reactivation or persistence. Many herpesviruses establish latency in progenitor cells and viral reactivation is linked to host-cell proliferation and differentiation status. Importantly, Wnt/β-catenin is tightly connected to stem/progenitor cell maintenance and differentiation. Numerous studies have linked Wnt/β-catenin signaling to a variety of cancers, emphasizing the importance of Wnt/β-catenin pathways in development, tissue homeostasis and disease. This review details how the alpha-, beta-, and gammaherpesviruses interact and manipulate the Wnt/β-catenin pathway to promote a virus-centric agenda.

Severe autoimmune hepatitis triggered by varicella zoster infection

Autoimmune hepatitis (AIH) is a chronic disease of unknown etiology that is characterized by the presence of circulatory autoantibodies and inflammatory histological changes in the liver. Although the pathogenesis of AIH is not known, it is thought that, in a genetically predisposed individual, environmental factors such as viruses can trigger the autoimmune process. Herpes simplex virus, Epstein-Barr virus, measles virus, and hepatitis viruses are thought to play a role in the etiology of AIH. Proteins belonging to these viruses may be similar to the amino acid chains of different autoantigens in the liver, this causes immune cross reactions and liver tissue damage. We report a case of severe AIH following varicella zoster infection in a 23-year-old man, and speculate that, based on the molecular mimicry hypothesis, the liver damage was caused by an immune cross reaction to the viral proteins. Varicella-zoster-induced AIH has not been reported previously.

LNP-CpG ODN-adjuvanted varicella-zoster virus glycoprotein E induced comparable levels of immunity with Shingrix^(TM) 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^(TM) 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^(TM) in C57BL/6J mice.The results showed that the LNP vaccine induced comparable levels of gE-specific IgG antibodies to Shingrix^(TM) as determined by enzymelinked immunosorbent assay(ELISA).Most importantly,the LNP vaccine induced comparable levels of cellmediated immunity(CMI)that plays decisive roles in the efficacy of zoster vaccines to Shingrix^(TM) in a VZVprimed mouse model that was adopted for preclinical studies of Shingrix^(TM) .Number of IL-2 and IFN-γsecreting 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^(TM) boosted mice.All of the components in this LNP vaccine can be artificially and economically synthesized in large quantities,indicating the potential of LNP-CpGadjuvanted VZV-gE as a more cost-effective zoster vaccine.

黄芪对感染VZV小鼠T、MФ细胞功能的影响

目的 观察黄芪对感染VZV小鼠T、MФ细胞功能的影响 ,探讨黄芪在病毒感染治疗方面的作用及机理。方法 制备感染VZV小鼠模型 ,检测血液淋巴细胞转化功能、腹腔巨噬细胞吞噬功能和血清溶血素。结果 感染服药组与对照组比较 ,淋巴细胞转化率、巨噬细胞吞噬率和吞噬指数及血清溶血素均有明显回升 (P <0 .0 1和P <0 .0 5 )。结论 黄芪具有改善VZV感染小鼠体液免疫和细胞免疫功能的作用。

我国水痘-带状疱疹病毒VZV84-7减毒株基因特征研究

目的 建立水痘 带状疱疹病毒 (VZV)毒株的特异性鉴定方法 ,研究我国分离的VZV84 7减毒株(VZV84 7株 )基因特征。方法 利用PCR分别扩增VZV84 7株和Oka株R2和R5可变区基因 ,比较两者串联重复单位拷贝数 ;用PCR结合限制性片段长度多态性 (PCR RFLP)分析VZV84 7株和Oka株基因的BglI、PstI酶切位点突变 ;并对gpI编码区基因进行序列分析。结果 VZV84 7株R2、R5区PCR产物分别为 4 2 5bp和 2 5 5bp ,对应的串联重复单位拷贝数分别为 7和 1;Oka株R2、R5区PCR产物分别为 4 2 5bp和 36 7bp ,对应的串联重复单位拷贝数分别为 7和 2。VZV84 7株基因存在PstI酶切位点 ,而Oka株无PstI酶切位点 ;两者均存在BglI酶切位点。基因序列分析显示 ,VZV84 7株与Oka株在gpI区存在 4个碱基差异 ,并导致 1个编码氨基酸不同 ,氨基酸序列同源性为99 8%。结论 所建立的PCR和PCR RFLP方法简便、特异 ;VZV84 7株的基因特征与Oka株存在一定差异 。

VZV糖蛋白E基因胞外域的原核表达及其兔抗血清的制备

目的采用原核表达系统表达水痘-带状疱疹病毒(VZV)糖蛋白E(g E)基因的胞外域,将纯化后的目的蛋白免疫新西兰家兔,制备该蛋白特异性抗血清。方法构建原核表达质粒g E-p ET-32a(+),测序后将其转化至E.coli BL21,以异丙基硫代β-D-半乳糖苷(IPTG)诱导,获得VZV g E融合蛋白。采用SDS-PAGE电泳、Western blot法鉴定其特异性,利用Ni2+-NTA柱对g E蛋白进行纯化,复性后免疫新西兰家兔,获得兔抗VZV g E血清;采用间接免疫荧光、Western blot法和ELISA法检测该血清的特异性和效价。结果成功诱导表达出VZV g E融合蛋白,SDS-PAGE鉴定提示其主要为包涵体表达,浓度约为3.01 mg/ml。蛋白经Ni2+-NTA柱纯化后,纯度约为90%。Western blot法显示,经变性、复性后的该融合蛋白有良好的免疫反应性。用该蛋白免疫新西兰家兔后获得兔抗VZV g E血清。ELISA分析显示,该兔抗血清的效价为1∶6 400。结论成功构建了高效表达VZV g E蛋白的原核表达系统,获得较高纯度的g E蛋白,可以作为VZV亚单位疫苗的候选抗原,制备了特异性及效价均较高的兔抗VZV g E多克隆抗体,为VZV感染的临床诊断及治疗提供了重要的实验工具。

甲钴胺对VZV病毒感染施万细胞中朊蛋白和TNF-α转换酶表达的影响

目的:探究感染水痘-带状疱疹病毒(VZV)对人施万细胞(hSC)朊蛋白(PrP^(C))、肿瘤坏死因子-α转换酶(TACE)和肿瘤坏死因子-α受体1(TNFR1)表达的影响,及甲钴胺(MCbl)的调节作用。方法:将传代培养的hSC分为:空白对照组、VZV感染组、VZV感染加MCbl干预组、VZV感染PrP^(C)基因(Prnp)siRNA转染细胞组、VZV感染Prnp-siRNA转染细胞加MCbl干预组。设计合成Prnp的siRNA序列转染hSC,构建PrP^(C)表达下调的hSC模型。以感染复数为1.0的VZV分别感染后4组细胞3 d后,加药组分别加入250μg/ml的MCbl干预。感染7 d后采用CCK-8法评估细胞活力,real time RT-PCR检测Prnp mRNA表达,Western Blot分析PrP^(C)糖基化的变化,免疫荧光双染检测TACE和TNFR1的表达,TACE试剂盒检测其酶活性的变化,酶联免疫吸附试验(ELISA)测定细胞上清液中可溶性TNFR1(sTNFR1)的浓度。结果:与对照组比较,感染组细胞活力明显下降(P<0.05)。感染组细胞Prnp的mRNA表达与对照组相比上调了2.7倍,PrP^(C)的单糖基化条带密度明显增加。TACE染色颗粒明显变小,TACE活性为对照组的36%,TNFR1表达与对照组比较明显增多,sTNFR1含量为(16.77±4.57)pg/ml。感染加药组Prnp mRNA表达上调3.7倍,显著高于感染组,PrP^(C)向单糖基化迁移的比例较感染组明显减少。TACE染色颗粒变大,且TACE的活性为对照组的76%,TNFR1表达较感染组减少,sTNFR1水平达到(231.23±41.04)pg/ml,较感染组明显增加。Prnp-siRNA转染细胞感染VZV后,TACE和TNFR1等表达及活性与VZV感染组比较无明显差异,sTNFR1含量与感染组比较无明显差异。Prnp-siRNA转染细胞感染VZV加药组对TACE和TNFR1的表达及活性调节作用不明显,sTNFR1含量与感染组比较无明显差异。结论:VZV可诱导hSC中PrP^(C)稳定性下降,TACE活性降低。而MCbl可稳定PrP^(C),调节TACE活性,促进TNFR1的脱落,从而增强hSC的抗TNF-α神经毒性能力。

18例成人重症水痘临床分析

目的:分析成人重症水痘患者的临床特征,提高对该病的认识。方法:回顾性分析我院重症二科2018年1月至2024年3月收治的18例成人重症水痘患者的临床资料。结果:18例患者中男12例、女6例,平均年龄32.1岁(18~50岁),9例(50.0%)因器官移植、类风湿关节炎等基础疾病长期使用免疫抑制药物。异常实验室结果主要包括血小板计数降低12例(66.7%)、肝酶升高15例(83.3%)、心肌酶升高18例(100%)、N氨基末端脑钠肽升高15例(83.3%)、D-二聚体升高16例(88.9%)、降钙素原升高14例(77.8%)。6例(33.3%)因治疗效果不佳自动出院(3例)或死亡(3例)。15例(83.3%)合并肺部感染,其中11例合并Ⅰ型呼吸衰竭。结论:成人重症水痘患者以男性居多,死亡率较高。免疫抑制个体是成人重症水痘的高发人群。成人重症水痘合并肺部感染患者Ⅰ型呼吸衰竭发生率高。

VZV和钩端感染者谷丙转氨酶的检测

目的:探讨水痘-带状疱疹病毒(varicellazostervirus,VZV)和钩端螺旋体感染者血清转氨酶水平及其意义。方法:应用速率法检测VZV和钩端螺旋体感染者血清转氨酶水平。结果:40例VZV感染者中有23例血清谷丙转氨酶值升高,32例钩端螺旋体感染者中有21例GPT值升高,GPT异常率分别达57.5%和65.63%。结论:GPT值在VZV和钩端螺旋体感染者中异常率较高,在此类疾病中具有诊断和判断病情的意义。

Varicella-zoster virus as a causative agent of acute retinal necrosis in younger patients

Background: Herpes virus is considered to be the pathogen of acute retinal necrosis (ARN) infection. Previous studies have that patients with ARN caused by the varicella-zoster virus (VZV) are often older, and patients with herpes simplex virus (HSV) induced ARN are considerably younger. However, in our clinical work, we find that VZV is also a pathogen in younger ARN patients. We, therefore, aimed to analyze the common etiology of younger ARN patients. Methods: A retrospective analysis was made of 20 eyes (18 patients) diagnosed as having ARN in the Department of Ophthalmology of Peking Union Medical College Hospital from 2014 to 2016. All patients were reviewed for demographic data, clinical course, clinical manifestations, time from onset to initial physician visit, duration of follow-up, visual acuity at both presentation and final visit, and treatment strategies. A paired t test was used to compare visual acuity between the presenting vision and those of final follow-up. Vitreous or aqueous specimens from 18 eyes of 18 patients were analyzed with multiplex polymerase chain reaction (mPCR)/quantitative PCR (qPCR) and xTAG-liquid chip technology (xTAG-LCT) to determine the causative virus of ARN. Results: Final best visual acuity (BCVA) improved significantly from 1.36±0.95 (median 20/400) to 0.95±0.82 (median 20/100)￠=2.714, P = 0.015) after systemic and intravitreal antiviral treatment combined with or without pars plana vitrectomy. PCR and xTAG-LCT results showed four of the five samples in the younger group (32.2±5.2 years) and 12 of the 13 samples in the senior group (53.6±4.9 years) were positive for VZV, and two of the five samples in the younger group were positive for HSV-1. Conclusions: This study demonstrates that VZV is also a common causative virus for ARN in younger patients. Considering this finding, a systemic antiviral treatment protocol should be immediately changed to intravenous ganciclovir when the patient does not respond to acyclovir before determining the causative virus, especially in younger patients.

Insights into the function of tegument proteins from the varicella zoster virus

Chickenpox(varicella) is caused by primary infection with varicella zoster virus(VZV), which can establish long-term latency in the host ganglion. Once reactivated, the virus can cause shingles(zoster) in the host. VZV has a typical herpesvirus virion structure consisting of an inner DNA core, a capsid, a tegument, and an outer envelope. The tegument is an amorphous layer enclosed between the nucleocapsid and the envelope, which contains a variety of proteins. However, the types and functions of VZV tegument proteins have not yet been completely determined. In this review, we describe the current knowledge on the multiple roles played by VZV tegument proteins during viral infection. Moreover, we discuss the VZV tegument protein-protein interactions and their impact on viral tissue tropism in SCID-hu mice. This will help us develop a better understanding of how the tegument proteins aid viral DNA replication, evasion of host immune response, and pathogenesis.

Complete recovery of herpes zoster radiculopathy based on electrodiagnostic study:A case report

BACKGROUND Herpes zoster is a painful infectious disease caused by the varicella zoster virus.Herpes zoster radiculopathy,which is a type of segmental zoster paresis,can complicate the disease and cause motor weakness.This complication should be considered when a patient with a rash complains of acute-onset motor weakness,and the diagnosis can be verified via electrodiagnostic study.CASE SUMMARY A 64-year-old female with a history of asthma presented to the emergency department with stabbing pain,an itching sensation,and a rash on the right anterior shoulder that had begun 5 d prior.Physical examination revealed multiple erythematous grouped vesicles in the right C4-5 and T1 dermatome regions.Because herpes zoster was suspected,the patient immediately received intravenous acyclovir.On the third hospital day,she complained of motor weakness in the right upper extremity.Magnetic resonance imaging of the cervical spine revealed mild intervertebral disc herniation at C4-C5 without evidence of nerve root compression.On the 12th hospital day,electrodiagnostic study revealed right cervical radiculopathy,mainly in the C5/6 roots.Six months later,monoparesis resolved,and follow-up electrodiagnostic study was normal.CONCLUSION This case emphasizes that clinicians should consider the possibility of postherpetic paresis,such as herpes zoster radiculopathy,and that electrodiagnostic study is useful for diagnosis and follow-up.

Acute pancreatitis associated with herpes zoster:Case report and literature review

Varicella-zoster virus(VZV)is a type of herpes virus known to cause varicella,mainly in young children,and herpes zoster in adults.Although generally non-lethal,VZV infection can be associated with serious complications,particularly in adults.Acute pancreatitis caused by VZV infection is a rare event,with reports primarily concerning immunocompromised individuals.Here we report a 44-year-old immunocompetent female who developed acute pancreatitis associated with VZV infection.The patient presented with vomiting and persistent pain in the upper quadrant less than one week after diagnosis and treatment for a herpes zoster-related rash with stabbing pain on the abdomen and dorsal right trunk side.A diagnosis of acute pancreatitis was confirmed based on abdominal pain,elevated levels of urine and serum amylase,and findings of peri-pancreatic exudation and effusions by computed tomography and magnetic resonance cholangiopancreatography.This case highlights that,though rare,acute pancreatitis should be considered in VZV patients who complain of abdominal pain,especially in the epigastric area.Early detection and proper treatment are needed to prevent the condition from deteriorating further and to minimize mortality.