- Efficacy of varicella (VZV) vaccination: an update for the clinician. [Journal Article]
- Ther Adv Vaccines 2016 Jan; 4(1-2):20-31.
Varicella-zoster virus (VZV) infection causes two distinct clinical conditions. Primary varicella infection results in chickenpox, a contagious rash illness typically seen among children. VZV can reactivate years after the initial infection to cause herpes zoster (HZ) and lead to post-herpetic neuralgia, a common complication resulting in persistent pain that may last for years after the zoster rash resolves. A person's risk of having longer lasting and more severe pain associated with HZ increases with age. Since the introduction of VZV vaccines, the rates of infection, hospitalizations, and mortality have declined. In this review, we discuss in detail current VZV vaccines available for the prevention of VZV and HZ infections. Varilrix (GSK Biologicals, UK), Varivax (Merck, USA) and the combined measles, mumps, rubella, and varicella (MMRV) vaccine contain the live attenuated Oka strain of VZV for routine varicella vaccination. While Zostavax is the only HZ vaccine currently approved for use in the United States and the European Union [EMEA, 2011], a subunit vaccine candidate called HZ/su has recently shown improved efficacy for zoster prevention in two clinical trial phase III studies. VariZIG, a post-exposure prophylactic, uses zoster immune globulin to prevent VZV infection in those who have recently been in contact with VZV but lack evidence of varicella immunity and are contraindicated to receive the varicella vaccine. Further, we discuss the skin tropic and neurotropic factor VZV ORF7 gene and its involvement in varicella infection, reactivation and latency in ganglia. Ultimately, these studies can contribute to the development of a neuroattenuated vaccine candidate against varicella or a vector for delivery of other virus antigens.
- Varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia. [JOURNAL ARTICLE]
- J Infect Chemother 2016 Aug 2.
Abdominal pain may precede the characteristic varicella skin lesions in immunocompromised patients with visceral varicella. The absence of skin lesions may delay timely diagnosis and treatment of varicella for those patients. Furthermore, abdominal imaging findings to provide information to diagnose visceral varicella have rarely been reported. Varicella was diagnosed in a 5-year-old boy with acute lymphoblastic leukemia complaining of fever and abdominal pain followed by papulovesicular skin lesions. Later, the patient was found to have rapidly progressive acute hepatitis, and abdominal computed tomography showed multiple hypodense hepatic nodules. The patient was treated with intravenous acyclovir, intravenous immunoglobulin, and empirical antibiotic and antifungal therapy. However, his fever and abdominal pain persisted, and a laparoscopic liver biopsy was performed to differentiate other causes of the persisting symptoms. Eventually, the patient was diagnosed with visceral varicella based on histopathologic findings. In conclusion, visceral varicella should be considered in immunocompromised patients with abdominal pain and multiple hypodense hepatic nodules on abdominal imaging studies. However, bacteria, fungi, and tuberculosis can produce similar imaging findings; therefore, a biopsy may be necessary in patients not responding to antiviral therapy.
- Deep-sequencing of distinct preparations of the live-attenuated VZV vaccine reveals a conserved core of attenuating SNPs. [JOURNAL ARTICLE]
- J Virol 2016 Jul 20.
The continued success of the live-attenuated varicella zoster virus vaccine in preventing varicella and herpes zoster is well documented, as are many of the mutations that contribute to the attenuation of the vOka virus for replication in skin. At least three different preparations of vOKa are marketed. Here, we show using deep sequencing of seven batches of vOka vaccine (including ZostaVax, VariVax, VarilRix and the Oka/Biken working seed) from three different manufacturers (VariVax, GSK and Biken) that 137 SNP mutations are present in all vaccine batches. This includes six sites at which the vaccine allele is fixed or near-fixation which we speculate are likely to be important for attenuation. We additionally show that despite differences in the vaccine populations between preparations, batch to batch variation is minimal, as is the number and frequency of mutations unique to individual batches. This suggests that the vaccine manufacturing processes are not introducing new mutations and notwithstanding the mixture of variants present, VZV live vaccines are extremely stable.The continued success of vaccinations to prevent chickenpox and shingles, combined with the extremely low incidence of adverse reactions, is testament to the quality of these vaccines. The vaccine itself is comprised of a heterogeneous live-attenuated virus population and thus requires deep sequencing technologies to explore the differences and similarities in the virus populations between different preparations and batches of the vaccines. Our data demonstrate minimal variation between batches, an important safety feature, and provide new insights into the extent of the mutations present in this attenuated virus.
- Analysis of single nucleotide polymorphism among Varicella-Zoster Virus and identification of vaccine-specific sites. [Journal Article]
- Virology 2016 Sep.:277-86.
Varicella-zoster virus (VZV) is a causative agent for chickenpox and zoster. Live attenuated vaccines have been developed based on Oka and MAV/06 strains. In order to understand the molecular mechanisms of attenuation, complete genome sequences of vaccine and wild-type strains were compared and single nucleotide polymorphism (SNP) was analyzed. ORF22 and ORF62 contained the highest number of SNPs. The detailed analysis of the SNPs suggested 24 potential vaccine-specific sites. All the mutational events found in vaccine-specific sites were transitional, and most of them were substitution of AT to GC pair. Interestingly, 18 of the vaccine-specific sites of the vaccine strains appeared to be genetically heterogeneous. The probability of a single genome of vaccine strain to contain all 24 vaccine-type sequences was calculated to be less than 4%. The average codon adaptation index (CAI) value of the vaccine strains was significantly lower than the CAI value of the clinical strains.
- Preparing to introduce the varicella vaccine into the Italian immunisation programme: varicella-related hospitalisations in Tuscany, 2004-2012. [Journal Article]
- Euro Surveill 2016 Jun 16; 21(24)
A universal immunisation programme against varicella in the form of the measles-mumps-rubella-varicella (MMRV) vaccine for toddlers aged 13-15 months was introduced in Tuscany in July 2008. An assessment of the impact of this programme on varicella-related hospitalisations 4 years after its introduction could further support its adoption at a national level. The hospitalisation data were analysed in two periods: pre-vaccination (2004-2007) and vaccination period (2009-2012). The high coverage of the vaccines (84% in 2012) resulted in a significant decline in notifications, from 33,114 (2004-2007) to 13,184 cases (2009-2012), and also of hospitalisations, from 584 (pre-vaccination period) to 325 (vaccination period). The hospitalisation rate was 4.1 per 100,000 (95% confidence intervals (CI): 3.4-4.7) before the introduction of vaccination, which dropped to 2.2 per 100,000 (95% CI: 1.7-2.7) in the vaccination period (hospitalisation risk ratios: 0.54; 95% CI: 0.472-0.619). The reduction was most significant in the youngest age groups. The introduction of universal vaccination has already led to a significant decline in hospitalisations due to varicella after just 4 years of implementation. Hospitalisation rates fell noticeably among younger individuals involved in the vaccination programme. The decrease in hospitalisation rate in the older age groups suggests a possible indirect protection.
- [Measles and chickenpox susceptibility among immigrants]. [English Abstract, Journal Article]
- Rev Med Suisse 2016 May 4; 12(517):882-4.
Exposure of immigrants to infectious diseases in their country of origin influences their susceptibility to infections later in life. Susceptibility to certain infections may significantly differs between immigrants depending on their regions of origin. Both measles and chickenpox (varicella) are conditions for which the level of exposure in the country of origin influences the preventive measures that immigrant health providers should propose. Through these two illustrative examples, this article summarizes the practical implications for clinicians who care for immigrants originating from southern countries.
- Varicella Vaccination of Children with Leukemia without Interruption of Maintenance Therapy - A Danish Experience. [JOURNAL ARTICLE]
- Pediatr Infect Dis J 2016 Jun 10.
Varicella zoster virus (VZV) can be fatal or cause severe complications in children with acute lymphoblastic leukemia (ALL). This analysis set out to investigate the morbidity and mortality of VZV vaccination without interruption of maintenance therapy in children with ALL.Files of 73 seronegative children with ALL were examined for data regarding VZV vaccination and infection, and long-term seroconversion was measured. Criteria prior to VZV-vaccination were: 1) seronegative; 2) in complete remission; 3) age ≥ 1.0 year; 4) lymphocyte count ≥ 0.6 x 10/l at time of vaccination; and 5) receiving maintenance therapy.Forty-five children were vaccinated. No child died or experienced serious adverse events due to VZV-vaccination. Nine children developed late chickenpox despite vaccination. Long-term protection was found in 86% of children not receiving acyclovir and 78 % of the entire population. Long-term seroconversion was found in 52% of the children. There were no severe cases of varicella infection. Acyclovir prophylaxis post-vaccination was associated with an increased risk of late chickenpox (HR=5.40,[1.43; 20.41],p=0.01). In contrast, a vaccine-induced rash reduced the risk of late chickenpox (HR=0.08, [0.01; 0.66] p = 0.02). No child had interruption of maintenance therapy at the time of vaccination, but 33% experienced discontinuation of therapy due to vaccine-induced rash. Dexamethasone was associated with an increased risk of vaccine-induced rash (HR=2.9 [1.21; 6.90], p = 0.02).This analysis indicates that VZV-vaccination is feasible and justified in seronegative children with ALL, in countries where VZV-vaccination is not part of the national vaccination program.
- The burden of hospitalisation for varicella and herpes zoster in England from 2004 to 2013. [Journal Article]
- J Infect 2016 Sep; 73(3):241-53.
We aimed to determine the hospital burden of varicella-zoster virus infection (VZV) in England during 2004-2013 to support a future cost-effectiveness analysis of a childhood varicella vaccination programme.We analysed the incidence, duration, outcome and costs of hospitalisations for VZV using the Hospital Episode Statistics (HES) database for the general and immunocompetent population. Mortality in HES was validated using data from the Office for National Statistics (ONS).The average annual incidences of admissions due to varicella and herpes zoster were 7.6 (7.3-7.9) and 8.8 (8.6-9.0) per 100,000, respectively. The immunocompetent population accounted for 93% and 82% of the admissions due to varicella and herpes zoster, respectively. The average yearly number of hospital days was 10,748 (10,227-11,234) for varicella and 41,780 (40,257-43,287) for herpes zoster. The average yearly hospital costs (£2013/14) were £6.8 million (6.4-7.2) for varicella and £13.0 million (12.8-13.4) for herpes zoster. The average annual numbers of deaths identified in HES due to varicella and herpes zoster were 18.5 (14.3-22.8) and 160 (147-172), respectively. Comparison with ONS mortality data indicated a high level of uncertainty.Most of the hospital burden due to VZV-virus in England occurs in the immunocompetent population and is potentially vaccine-preventable.
- Role for the αV Integrin Subunit in Varicella-Zoster Virus-Mediated Fusion and Infection. [Journal Article]
- J Virol 2016 Aug 15; 90(16):7567-78.
Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. Membrane fusion is essential for VZV entry and the distinctive syncytium formation in VZV-infected skin and neuronal tissue. Herpesvirus fusion is mediated by a complex of glycoproteins gB and gH-gL, which are necessary and sufficient for VZV to induce membrane fusion. However, the cellular requirements of fusion are poorly understood. Integrins have been implicated to facilitate entry of several human herpesviruses, but their role in VZV entry has not yet been explored. To determine the involvement of integrins in VZV fusion, a quantitative cell-cell fusion assay was developed using a VZV-permissive melanoma cell line. The cells constitutively expressed a reporter protein and short hairpin RNAs (shRNAs) to knock down the expression of integrin subunits shown to be expressed in these cells by RNA sequencing. The αV integrin subunit was identified as mediating VZV gB/gH-gL fusion, as its knockdown by shRNAs reduced fusion levels to 60% of that of control cells. A comparable reduction in fusion levels was observed when an anti-αV antibody specific to its extracellular domain was tested in the fusion assay, confirming that the domain was important for VZV fusion. In addition, reduced spread was observed in αV knockdown cells infected with the VZV pOka strain relative to that of the control cells. This was demonstrated by reductions in plaque size, replication kinetics, and virion entry in the αV subunit knockdown cells. Thus, the αV integrin subunit is important for VZV gB/gH-gL fusion and infection.Varicella-zoster virus (VZV) is a highly infectious pathogen that causes chickenpox and shingles. A common complication of shingles is the excruciating condition called postherpetic neuralgia, which has proven difficult to treat. While a vaccine is now available, it is not recommended for immunocompromised individuals and its efficacy decreases with the recipient's age. These limitations highlight the need for new therapies. This study examines the role of integrins in membrane fusion mediated by VZV glycoproteins gB and gH-gL, a required process for VZV infection. This knowledge will further the understanding of VZV entry and provide insight into the development of better therapies.
- [Chickenpox and shingles: one virus, two diseases and current vaccination recommendations in Switzerland]. [English Abstract, Journal Article]
- Ther Umsch 2016; 73(5):247-52.
Adults, pregnant women, premature babies and immunocompromised persons are at increased risk for varicella complications. Therefore the current Swiss vaccination recommendations against varicella include a general recommendation for 11 to 15 year old adolescents with a negative varicella history, as well as a specific recommendation for risk groups. The goal of both recommendations is to reduce varicella complications in persons most at risk. The vaccine is not universally recommended for all toddlers in Switzerland, while this is the case in some countries such as the United States. Pros and cons of different vaccination strategies, as well as possible short- and long-term effects on herpes zoster incidence are taken into account. In the United States, there was a marked decline in incidence and hospitalisations, but an increased herpes zoster incidence in the short term. Finally, public health aspects of herpes zoster, post-herpetic neuralgia and possible vaccination strategies are outlined.