Varicella Virus Vaccination in the United States.

Varicella zoster virus (VZV) is the cause of chickenpox (varicella) and shingles (zoster), and was once responsible for over 4 million infections in the United States annually. The development of a live attenuated VZV vaccine was initially viewed with extreme skepticism. Nonetheless, a VZV vaccine was developed in the 1970s by Takahashi and his colleagues in Japan and was eventually licensed in the US. It is now known to be one of the safest and most effective vaccines available and is administered worldwide. Here are described important factors that contributed to the successful research and licensure of the highly successful VZV vaccine.

Varicella and herpes zoster vaccine development: lessons learned.

INTRODUCTION: Before vaccination, varicella zoster virus (VZV), which is endemic worldwide, led to almost universal infection. This neurotropic virus persists lifelong by establishing latency in sensory ganglia, where its reactivation is controlled by VZV-specific T-cell immunity. Lifetime risk of VZV reactivation (zoster) is around 30%. Vaccine development was galvanised by the economic and societal burden of VZV, including debilitating zoster complications that largely affect older individuals. Areas covered: We describe the story of development, licensing and implementation of live attenuated vaccines against varicella and zoster. We consider the complex backdrop of VZV virology, pathogenesis and immune responses in the absence of suitable animal models and examine the changing epidemiology of VZV disease. We review the vaccines' efficacy, safety, effectiveness and coverage using evidence from trials, observational studies from large routine health datasets and clinical post-marketing surveillance studies and outline newer developments in subunit and inactivated vaccines. Expert commentary: Safe and effective, varicella and zoster vaccines have already made major inroads into reducing the burden of VZV disease globally. As these live vaccines have the potential to reactivate and cause clinical disease, developing alternatives that do not establish latency is an attractive prospect but will require better understanding of latency mechanisms.

Varicela por virus vacunal en un paciente en tratamiento con metotrexato / Post-vaccination varicella in a patient receiving methotrexate

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Efectividad de la vacuna de la varicela en el contexto de brotes escolares en una zona semiurbana / Varicella vaccine effectiveness in schoolchildren in outbreaks in a semi-urban area

OBJETIVO: Calcular la efectividad de la vacuna de la varicela en brotes escolares durante el curso académico 2009-2010. MATERIAL Y MÉTODO: Estudio de cohortes retrospectivo realizado en guarderías y/o colegios de educación infantil o primaria públicos de un municipio de la Región de Murcia, España. Los participantes fueron el alumnado de 1 a 12 años que acudía a la misma aula donde se produjo un brote de varicela. Las mediciones principales fueron: datos sociodemográficos, antecedentes clínicos y de vacunación y variables relacionadas con la enfermedad varicelosa obtenidos a través de un cuestionario autocumplimentado por padres y/o tutores y del registro regional informatizado de vacunas (VACUSAN). RESULTADOS: Se detectaron 51 brotes de varicela, con una mediana de 3 casos por brote en ambos niveles educativos. La cobertura vacunal global fue del 10,7% (IC del 95%, 8,63-13,18), siendo siempre muy superior en el alumnado de nacionalidad española frente al de nacionalidad extranjera (OR = 21,21; IC del 95%, 2,92-153,92; p < 0,001). Encontramos discrepancias entre los datos vacunales del cuestionario y el programa informatizado de vacunaciones (kappa=0,50 [IC del 95%, 0,43-0,58), p < 0,001). La tasa de ataque global según VACUSAN fue de 59,7 (IC del 95%, 55,82-63,43) en no vacunados y de 6,5 (IC del 95%, 2,54-15,45) en vacunados. Obtuvimos una efectividad global del 89,1% (IC del 95%, 74,55-95,35) y 100% para una y 2 dosis de vacuna, respectivamente. CONCLUSIONES: Elevada efectividad de la vacuna de la varicela y muy especialmente en un esquema de vacunación de 2 dosis. Se han detectado discrepancias entre la información aportada por los padres y los registros informatizados regionales, así como una diferencia en la cobertura de vacunación en función de la nacionalidad

OBJECTIVE: To estimate the effectiveness of the varicella vaccine in school outbreaks during the academic year 2009-2010. MATERIAL AND METHOD: Retrospective cohort study in public day-care centers and/or schools in an area in the region of Murcia. Spain. The participants were all children of 1 to 12 years who were in the same classroom where there was an outbreak of varicella. The main measurements were the sociodemographic, clinical and vaccination data, as well as variables related to varicella disease obtained through a questionnaire self-completed by parents, and from the computerized regional immunization registry (VACUSAN). RESULTS: A total of 51 varicella outbreaks were detected, with a median of 3 cases per outbreak at both educational levels. The overall vaccination coverage was 10.7% (95% CI 8.63 to 13.18), always being higher in Spanish schoolchildren versus foreign (OR: 21.21, 95% CI: 2.92 to 153.92, P<.001). Discrepancies were found between the vaccine questionnaire data and vaccination program (kappa=0.50, 95% CI: 0.43 to 0.58, P<.001). According to VACUSAN, the overall attack rate was 59.7 (95% CI: 55.82 to 63.43) in unvaccinated and 6.5 (95% CI: 2.54 to 15.45) in vaccinated children. An overall effectiveness of 89.1% (95% CI: 74.55 to 95.35) and 100% was obtained for 1 and 2 doses of vaccine, respectively. CONCLUSIONS: There is a high effectiveness of varicella vaccine, emphasizing that the administration of two doses of vaccine produces an adequate and optimal protection against varicella disease. A discrepancy was found between the information provided by parents and official records. Finally, there was a lower vaccination coverage in the immigrant community

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.

Novel polyvalent live vaccine against varicella-zoster and mumps virus infections.

The varicella-zoster virus (VZV) Oka vaccine strain (vOka) is a highly immunogenic and safe live vaccine that has long been used worldwide. Because its genome is large, making it suitable for inserting foreign genes, vOka is considered a candidate vector for novel polyvalent vaccines. Previously, a recombinant vOka, rvOka-HN, that expresses mumps virus (MuV) hemagglutinin-neuraminidase (HN) was generated by the present team. rvOka-HN induces production of neutralizing antibodies against MuV in guinea pigs. MuV also expresses fusion (F) protein, which is important for inducing neutralizing antibodies, in its viral envelope. To induce a more robust immune response against MuV than that obtained with rvOka-HN, here an rvOka expressing both HN and F (rvOka-HN-F) was generated. However, co-expression of HN and F caused the infected cells to form syncytia, which reduced virus titers. To reduce the amount of cell fusion, an rvOka expressing HN and a mutant F, F(S195Y) were generated. Almost no syncytia formed among the rvOka-HN-F(S195Y)-infected cells and the growth of rvOka-HN-F(S195Y) was similar to that of the original vOka clone. Moreover, replacement of serine 195 with tyrosine had no effect on the immunogenicity of F in mice and guinea pigs. Although obvious augmentation of neutralizing antibody production was not observed after adding F protein to vOka-HN, the anti-F antibodies did have neutralizing activity. These data suggest that F protein contributes to induction of immune protection against MuV. Therefore this recombinant virus is a promising candidate vaccine for polyvalent protection against both VZV and MuV.

Differentiation between vaccine and wild-type varicella-zoster virus genotypes by high-resolution melt analysis of single nucleotide polymorphisms.

BACKGROUND: The analysis of single nucleotide polymorphisms (SNPs) of varicella-zoster virus (VZV) has enabled differentiation between wild-type genotypes from the Oka vaccine strain (V-Oka). OBJECTIVES: To genotype VZV strains in Australia using high-resolution melt (HRM) analysis of SNPs in five gene targets. STUDY DESIGN: Extracted DNA from 78 samples obtained from patients with chickenpox and zoster were genotyped by HRM analysis of SNPs in five open reading frames (ORFs): 1 (685 G>A), 21 (33725 C>T), 37 (66288 G>A), 60 (101464 C>A) and 62 (106262 T>C) using a double-stranded (ds) DNA saturating dye, LC Green Plus. RESULTS: For each genotype, melt curve temperature (Tm) shifts differentiated the nucleotide present at that locus (P<0.0001) with melting curve shifts between alleles ranging from 0.56 degrees C (ORF 37) to 3.34 degrees C (ORF 62). The most common genotypes detected were the European Type C (59%) and B (18%) strains. This was followed by the African/Asian Type A (14%) and Japanese J1 (9%), strains, both prevalent in the Northern Territory and Western Australia. CONCLUSIONS: HRM analysis of SNPs showed that the European B and C genotypes were most prevalent in Australia, with genotypes A and J strains also present. HRM analysis using a dsDNA dye provides a useful tool in classifying varicella-zoster viruses.

Detection and differentiation of wild-type and vaccine mutant varicella-zoster viruses using an Invader Plus method.

We report the use of a prototype Invader Plus method (Third Wave Technologies, Inc., Madison, WI) for the qualitative detection of varicella-zoster virus (VZV) and differentiation of wild-type and Oka vaccine VZV. The analytical sensitivity of the VZV Invader Plus reagents is at 10 copies per reaction. A total of 174 skin and mucous swab specimens were used to validate the assay's performance. The sensitivity and specificity were 98.3% and 98.1%, respectively, in comparison to a PCR-EIA assay. A perfect 100% agreement was obtained when VZV wild-type and vaccine differentiation was performed on 54 VZV-positive swab specimens against an allele-specific FRET real-time assay. The Invader Plus method provides another reliable tool for qualitative detection of VZV and differentiation of wild-type and vaccine virus.

DNA sequence variability in isolates recovered from patients with postvaccination rash or herpes zoster caused by Oka varicella vaccine.

Little is known about the pathogenic potential of individual strains in the varicella vaccine. We analyzed genomic variation among specimens obtained from vaccine recipients with postvaccination rash or herpes zoster (HZ), focusing on polymorphisms between live attenuated varicella vaccine virus and wild-type varicella-zoster virus. Eleven of 18 postvaccination HZ specimens contained >1 strain, and 7 of 18 appeared to be clonal. All 21 postvaccination rash specimens contained mixtures of vaccine strains. Four single-nucleotide polymorphisms (SNPs) consistently occurred in every isolate; all were polymorphisms in open-reading frame (ORF) 62, and 2 confer amino acid substitutions in the immediate-early protein 62. Four wild-type SNPs occurred in every isolate: one each occurred in ORF 10, ORF 21, ORF 62, and a noncoding region upstream of ORF 64. The frequencies of the remaining wild-type SNPs were variable, with the SNPs uniformly expressed (even in mixtures) in 20.5%-97.4% of isolates (mean frequency, 67.7%). No 2 clinical isolates had identical SNP profiles; as such, vaccine latency usually involves >1 strain.

Vaccine Oka varicella-zoster virus genotypes are monomorphic in single vesicles and polymorphic in respiratory tract secretions.

We previously found that, after immunization with vaccine Oka varicella-zoster virus, virus obtained from a single vesicle were monomorphic, and virus obtained from different individuals were heterogeneous. Here we show that virus obtained from the lungs of a patient were a mixture of vaccine Oka variants. We hypothesize that complications after immunization are unlikely to be caused by expansion of a single, biologically more virulent clone of virus that either pre-exists in the vaccine or develops after random mutation of different clones. We hypothesize that some clones are more trophic than others for skin.

Molecular diagnosis of zoster post varicella vaccination.

BACKGROUND: Herpes zoster can be caused by endogenous reactivation of both wild-type virus or vaccine varicella-zoster virus (VZV) becoming latent within sensory ganglia after natural primary infection or varicella vaccination. OBJECTIVES: To demonstrate molecular biological methods for reliable discrimination between wild-type VZV and vaccine strain Oka by an example of zoster in a vaccinated girl. STUDY DESIGN: VZV was isolated from zoster occurring 16 months after varicella vaccination in a 2-year-old infant. Including VZV wild-type and different Oka strains as controls, viral DNA fragments located in the open reading frames (ORF) 38, 54, 62 and the R5 variable repeat region were characterized by amplification and restriction fragment length polymorphisms (RFLP) analysis. RESULTS: VZV vaccine strain Oka was definitely proven to be the causative virus in this case of zoster post vaccination. CONCLUSIONS: Molecular procedures for characterization of ORF 38 allow reliable discrimination between Oka-like and wild-type VZV outside Japan and Japanese communities. To distinguish Oka vaccine virus from Oka-like wild strains, analysis of DNA fragments located in the ORF 62 should be included.