Live Attenuated Varicella-zoster Virus Research Articles

A Synergistic Lipid Nanoparticle Encapsulating mRNA Shingles Vaccine Induces Potent Immune Responses and Protects Guinea Pigs from Viral Challenges.

Shingles is caused by the reactivation of varicella zoster virus (VZV) and manifests as painful skin rashes. While the recombinant protein-based vaccine proves highly effective, it encounters supply chain challenges due to a shortage of the necessary adjuvant. Messenger RNA (mRNA)-based vaccines can be rapidly produced on a large scale, but their effectiveness relies on efficient delivery and sequence design. Here, an mRNA-based VZV vaccine using a synergistic lipid nanoparticle (Syn-LNP) containing two different ionizable lipids is developed. Syn-LNP shows superior mRNA expression compared to LNPs formulated with either type of ionizable lipid and to a commercialized LNP. After encapsulating VZV glycoprotein E (gE)-encoding mRNA, mgE@Syn-LNP induces robust humoral and cellular immune responses in two strains of mice. The magnitude of these responses is similar to that induced by adjuvanted recombinant gE proteins and significantly higher than that observed with live-attenuated VZV. mgE@Syn-LNP exhibits durable humoral responses for over 7 months without obvious adverse effects. In addition, mgE@Syn-LNP protects vaccinated guinea pigs against live VZV challenges. Preliminary studies on the mRNA antigen design reveal that the removal of glycosylation sites of gE greatly reduces its immune responses. Collectively, Syn-LNP encapsulating gE-encoded mRNA holds great promise as a shingles vaccine.

Investigation of the safety of live attenuated varicella-zoster virus vaccination in patients with relapse-remitting multiple sclerosis treated with natalizumab: A case series and review of the literature.

It is generally recommended to avoid live attenuated vaccines in patients treated with high efficacy disease-modifying treatment (DMT). However, a delay in starting DMT in highly active or aggressive multiple sclerosis (MS) might lead to a significant disability. We aimed to report a case series of 16 highly active RRMS patients who received the live-attenuated varicella-zoster virus (VZV) vaccine during treatment with natalizumab. This retrospective case series was conducted between September 2015 and February 2022 at the MS Research Center of Sina and Qaem hospital, Tehran, Mashhad, Iran, to identify the outcome of highly active MS patients who received the live-attenuated VZV vaccine on natalizumab. Two males and 14 females were included in this study, with a mean age of 25.5±8.4-year-old. 10 patients were naïve cases of highly active MS, and six were escalated to natalizumab. The patients received two doses of live attenuated VZV vaccine after a mean of 6.72 cycles of natalizumab treatment. Except for the one who experienced mild chickenpox infection, no serious adverse event or disease activity was evident after vaccination. While our data do not confirm the safety of the live attenuated VZV vaccine in natalizumab recipients, it highlights the importance of case-by-case decision-making in MS management based on the risk-benefit assessment.

Assessment of attenuation of varicella-zoster virus vaccines based on genomic comparison.

Live attenuated varicella-zoster virus (VZV) vaccines are used to prevent chickenpox and shingles. Single nucleotide polymorphisms (SNPs) that occur during the attenuation of parental strains are critical indicators of vaccine safety. To assess the attenuation of commercial VZV vaccines, genetic variants were comprehensively examined through high-throughput sequencing of viral DNA isolated from four VZV vaccines (Barycela, VarilRix, VariVax, and SKY Varicella). Whole-genome comparison of the four vaccines with the wild-type strain (Dumas) revealed that the sequences are highly conserved on a genome-wide scale. Among the 196 common variants across the four vaccines, 195 were already present in the genome of the parental strain (pOka), indicating that the variants occurred during the generation of the parental strain from the Dumas strain. Compared to the pOka genome, the vaccines exhibited distinct variant frequencies on a genome-wide and within an attenuation-related open reading frame. In particular, attenuation-associated 42 SNPs showed that Barycela, VarilRix, VariVax, and SKY Varicella are in ascending order regarding similarity with pOka-like genotypes, which in turn, might provide genomic evidence for the levels of attenuation. Finally, the phylogenetic network analysis demonstrated that genetic distances from the parental strain correlated with the attenuation levels of the vaccines.

Live attenuated VZV vaccination induces antitumor immunity in ATLL patients

Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C–C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.

Immunogenicity of varicella-zoster virus vaccine by different routes of administration: Comparable vaccination efficacy of one-fifth dose intradermal vaccination to conventional subcutaneous vaccination

BackgroundThe live attenuated varicella-zoster virus (VZV) vaccine is used for the prevention of chickenpox and herpes zoster; however, there have been few studies on the immunogenicity of intradermal vaccination. ObjectiveTo compare the immunogenicity between subcutaneous and intradermal VZV vaccination. MethodsThirty healthy participants aged 50–75 who developed erythema less than 10 mm in diameter in VZV skin test were examined. Thirteen participants received full dose of VZV vaccine subcutaneously and 17 participants received one-fifth dose of vaccine intradermally. Immunogenicity to VZV was determined by VZV skin test reaction, proliferation of VZV-specific memory T cells, levels of VZV-specific serum antibody, and cytokine production from peripheral blood cells. ResultsVZV skin test reaction was similar between two groups. VZV-specific memory T cells were significantly increased only in the intradermal injection group. The increase of VZV-specific memory T cells correlated with Th1, Th2 and Th17 cytokines and cytotoxic molecules. No serious adverse events were observed in either group after vaccination. ConclusionIntradermal injection with one-fifth dose VZV vaccine showed a similar or greater effect on VZV-specific cellular immunostimulation than conventional subcutaneous injection. These findings suggest that one-fifth dose intradermal vaccination may have a comparable preventive effect to conventional subcutaneous injection.

Herpes Zoster Vaccines.

Herpes zoster (HZ) affects approximately 1 in 3 persons in their lifetime, and the risk of HZ increases with increasing age. The most common, debilitating complication of HZ is the chronic neuropathic pain of postherpetic neuralgia (PHN). Two herpes zoster vaccines, a live-attenuated varicella-zoster virus (VZV) vaccine (zoster vaccine live [ZVL]; ZOSTAVAX [Merck]) and an adjuvanted VZV glycoprotein E (gE) subunit vaccine (recombinant zoster vaccine [RZV]; SHINGRIX [GlaxoSmithKline]) are licensed for the prevention of HZ and PHN in healthy older adults. The safety and efficacy of both vaccines has been demonstrated in clinical trials in immunocompetent adults and in selected immunocompromised persons and persons with immune-mediated diseases. Numerous real-world effectiveness studies have confirmed the safety and effectiveness of both ZVL and RZV. Recombinant zoster vaccine (RZV) is more effective for prevention of HZ than ZVL. Recombinant zoster vaccine is nonreplicating and is thus safe in immunocompromised persons. Additional zoster vaccines are in different stages of development. Wider distribution of safe and effective zoster vaccines will improve the health and well being of the rapidly growing population of older adults around the world.

Intratracheal inoculation of human varicella zoster virus (VZV; MAV strain) vaccine successfully induced VZV IgG antibodies in rhesus monkeys

BackgroundThe objective of this study was to investigate whether the use of live attenuated varicella zoster virus (VZV) MAV vaccination can efficiently induce VZV antibody production in naive rhesus monkeys as an approach to prevent simian varicella virus (SVV) reactivation in animals immunosuppressed for transplantation studies.ResultsClinically available human VZV vaccine was used to induce the production of anti-VZV antibodies in rhesus monkeys. A vial of the vaccine was subcutaneously injected at 0 week, and the second and third vaccination was performed at 5 and 6 weeks by intratracheal inoculation. The titer of anti-VZV IgG was assessed at 0, 2, 4, 6, and 7 weeks. At 2 weeks, 3/16 were seropositive for VZV IgG. At 6 weeks, 9/16 were shown to be seropositive. At 7 weeks, 16/16 were found to be seropositive.ConclusionsThe VZV vaccine via intratrachael inoculation was shown to induce VZV IgG humoral immunity in rhesus monkeys and may be important immunosuppressed macaques for transplantation studies. Although the humoral immunity produced is an important finding, further studies will be necessary to confirm possible protection and it could protect probably against SVV infection in rhesus monkey.

The frequency of interleukin-1β-producing monocytes is significantly associated with varicella-zoster responses of nursing home residents.

Previous studies have demonstrated that the status of the T cell compartment and inflammation-related factors are associated with the immunogenicity of the varicella-zoster virus (VZV) vaccine in older adults; however, little is known about the roles of other immune cell subsets known to influence the generation and maintenance of immunological memory. Responses to a live-attenuated VZV vaccine were studied in relation to peripheral blood mononuclear cell (PBMC) composition and function in a sample of 30 nursing home residents (aged 80-99 years). Interferon-gamma enzyme-linked immunospot (ELISPOT) was used to measure VZV responses at baseline and 6weeks following vaccination, and associations were sought with the frequencies of monocytes and T, B and natural killer (NK) cells and the production and secretion of cytokines following their ex-vivo stimulation with different agents. While only the frequency of interleukin (IL)-6+ CD14+ monocytes was inversely associated with post-vaccination VZV response, amounts of IL-1β, IL-10, IL-17A and tumour necrosis factor (TNF) secreted by PBMCs and the frequency of IL-1β+ CD14+ monocytes was positively correlated with pre-vaccination VZV response. Furthermore, both bivariate correlation and causal mediation analyses supported the notion that IL-1β+ CD14+ monocytes were significant mediators of the associations between IL-1β and TNF secretion by PBMCs and pre-vaccination VZV responses. Our findings implicate a strong cytokine response mediated by inflammatory IL-1β+ monocytes in coordinating responses of long-lived VZV-reactive memory T cells, but with an opposing effect of IL-6+ CD14+ monocytes. Whether monocyte status promotes or inhibits the induction and/or maintenance of these memory T cells later in life has yet to be determined.

Twelve Children with Varicella Vaccine Meningitis: Neuropathogenesis of Reactivated Live Attenuated Varicella Vaccine Virus.

Varicella vaccine is a live attenuated varicella-zoster virus (VZV). Like its parental strain called VZV pOka, the vaccine virus vOka retains some neurotropic properties. To better understand vOka neuropathogenesis, we reassessed 12 published cases of vOka meningitis that occurred in once-immunized and twice-immunized children, all of whom had bouts of herpes zoster preceding the central nervous system infection. Eight of the 12 meningitis cases occurred in children who had received only one immunization. There was no pattern to the time interval between varicella vaccination and the onset of herpes zoster with meningitis. Four of the meningitis cases occurred in children who had received two immunizations. Since all four children were 14 years old when meningitis was diagnosed, there was a strong pattern to the interval between the first vaccination at age 1 year and onset of meningitis, namely, 13 years. Knowledge of pathogenesis requires knowledge of the location of herpes zoster; the majority of dermatomal rashes occurred at sites of primary immunization on the arm or thigh, while herpes zoster ophthalmicus was uncommon. Based on this literature review, currently there is no consensus as to the cause of varicella vaccine meningitis in twice-immunized children.

Short-term immunogenicity and safety of hepatitis-A and varicella vaccines in HIV-exposed uninfected and HIV-unexposed South African children

BackgroundHIV-exposed uninfected (HEU) children have increased risk of infectious morbidity during early childhood. We evaluated the short-term immunogenicity and safety of single dose inactivated hepatitis-A virus (HAV) vaccine and live attenuated varicella zoster virus (VZV) vaccine in South African children. Methods195 HIV-unexposed and 64 HEU children received either one dose of HAV or VZV vaccine at 18 months of age. Blood samples were tested for hepatitis-A or VZV antibodies before and one month after vaccination by chemiluminescent microparticle immunoassay and enzyme-linked immunosorbent assay, respectively. All children were evaluated for solicited adverse events (AEs). ResultsOne-month post-vaccination, a similar percentage of HIV-unexposed (91.8%) and HEU (82.9%) children were seropositive for hepatitis-A (p = 0.144). VZV antibody geometric mean fold-rise was also similar in HIV-unexposed (5.6; 95%CI: 4.6–6.7) and HEU children (5.1; 95%CI: 3.7–7.2); however, only 44% HIV-unexposed and HEU seroconverted (titers > 50 mIU/ml). AEs occurred with similar frequency and severity between groups, except for more systemic AEs after VZV vaccination in HEU than HIV-unexposed children. ConclusionsSingle dose HAV and VZV vaccine was similarly immunogenic in HIV-unexposed and HEU children. We did not identify differences in short-term humoral immunity after administration of either a live attenuated or inactivated vaccine. Seroconversion rates after a single dose of VZV vaccine were, however, lower compared to reports from previous studies (85–89%).Clinical trials registration: NCT03330171.

Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Adult Hematopoietic Cell Transplant Recipients: A Single Center Study

<h3>Background</h3> Hematopoietic cell transplant (HCT) recipients are at high risk for Varicella zoster virus (VZV) reactivation. Shingrix, the adjuvanted recombinant zoster vaccine, is a new alternative to the live-attenuated VZV vaccine for immunocompromised individuals. Post-marketing data on its immunogenicity and safety in HCT is limited. <h3>Objectives</h3> To assess the safety and immunogenicity of Shingrix vaccine in HCT recipients. <h3>Methods</h3> Single center retrospective study of 134 consecutive adult allogenic and autologous HCT recipients who received the full series (two doses) of Shingrix vaccine. Primary study end points were safety and immunogenicity defined as either seroconversion in previously seronegative individuals or 4-fold increase from baseline VZV IgG titers in previously exposed patients. <h3>Results</h3> Among the 134 patients who completed vaccine series, 39 patients including 25 allogeneic and 14 autologous HCT recipients (Figure), had serological data available at baseline and after completion of vaccine series. The median age of patients at the time of HCT was 61 years (IQR, 53-67). The median time from HCT to first dose of Shingrix vaccine was 9 months (IQR, 7-14) for the entire cohort, but it was significantly shorter in autologous versus allogeneic HCT recipients: 7 (IQR, 6-8) vs. 12 (IQR, 9-16) months (P=0.003 by Mann Whitney test), respectively. Vaccine administration was very well tolerated, out of 134 patients only two (1.4%) had documented adverse events following Shingrix (and other vaccines co-administered), including injection site reaction after second dose and flu-like syndrome with fatigue and non-productive cough after the first dose (n=1 each). Both reactions occurred in autologous HCT recipients. The median time from the second Shingrix dose to post-vaccination VZV IgG titer assessment was 3.5 (IQR, 2-6) months. A total of 16 (41%) patients had documented humoral vaccine responses as measured by post vaccination VZV IgG levels including 8/14 (57%) autologous HCT recipients compared to 8/25 (32%) allogeneic HCT recipients (P=0.18 by Fisher's exact test). Among the 16 responders, the VZV IgG antibody concentration index increased from 179 (2.1-559) to 3,868 (2,232-4,000) (P<0.0001 by Wilcoxon matched-pairs signed rank test). Of interest, 100% of the patients who were seronegative prior to vaccination (n=8) seroconverted in response to Shingrix. <h3>Conclusions</h3> A 2-dose course of adjuvanted recombinant zoster vaccine was well tolerated among adult HCT recipients. Vaccine humoral responses occurred in less than half of the patients although vaccine seems to be more immunogenic following autologous HCT and among seronegative patients. Although Shingrix vaccine is currently only licensed for VZV seropositive patients, our data indicate that this recombinant vaccine may also be useful for primary VZV immunization. Larger studies are needed.

Reduction in the Number of Varicella-Zoster Virus-Specific T-Cells in Immunocompromised Children with Varicella.

Varicella zoster virus (VZV) causes a life-threatening infection in immunocompromised hosts. The immune response to VZV of healthy subjects has been rigorously assessed, but little is known about that of immunocompromised individuals. This study aimed to clarify the primary response to VZV infection in immunocompromised children. This prospective study enrolled six immunocompromised children (median age, 33 months; range, 20-62) receiving steroids or immunosuppressants, and 10 immunocompetent children (median age, 32 months; range, 15-81) with varicella. The immunocompromised children were three patients with acute lymphoblastic leukemia, two recipients with liver transplantation and one patient with juvenile idiopathic arthritis. Interferon-γ-producing CD69+T-cells produced by VZV stimulation (VZV-specific T-cells) were studied during the acute or convalescent phase. To further address the direct effect of immunosuppressants, we analyzed the number of VZV-specific T-cells after stimulating peripheral blood mononuclear cells obtained from healthy adults with live-attenuated VZV with or without prednisolone, cyclosporine-A, or tacrolimus. The circulating numbers of lymphocytes in the convalescent stage but not acute stage were lower in immunocompromised children compared with immunocompetent children. In the acute stage, immunocompromised patients showed lower VZV-specific CD8+T-cell counts than immunocompetent subjects. In contrast, in the convalescent phase, immunocompromised patients had lower VZV-specific CD4+T-cell counts than immunocompetent hosts. The in vitro culture of activated lymphocytes with prednisolone or immunosuppressants significantly decreased the proportion of VZV-specific CD4+T-cells. In conclusion, the decreased numbers of VZV-specific CD8+T-cells during the acute phase and VZV-specific CD4+T-cells during the convalescent phase of disease may account for severe varicella in immunocompromised children.

Understanding the immunology of the Zostavax shingles vaccine.

Zostavax is a live-attenuated varicella zoster virus (VZV) vaccine recommended for use in adults >50 years of age to prevent shingles. The main risk factor for the development of shingles is age, which correlates with decreasing cell-mediated immunity. These data suggest a predominant role of T cell immunity in controlling VZV latency. However, other components of the immune system may also contribute. In this review, we will discuss how the immune system responds to Zostavax, focusing on recent studies examining innate immunity, transcriptomics, metabolomics, cellular, and humoral immunity.

Live attenuated varicella-zoster virus vaccine does not induce HIV target cell activation

Varicella-zoster virus (VZV) is under consideration as a promising recombinant viral vector to deliver foreign antigens including HIV. However, new vectors have come under increased scrutiny, since trials with adenovirus serotype 5-vectored (Ad5-vectored) HIV vaccine demonstrated increased HIV risk in individuals with pre-immunity to the vector that was thought to be associated with mucosal immune activation (IA). Therefore, given the prospect of developing an HIV/VZV chimeric vaccine, it is particularly important to define the impact of VZV vaccination on IA. Healthy VZV-seropositive Kenyan women (n = 44) were immunized with high-dose live attenuated VZV vaccine, and we assessed the expression on CD4+ T cells isolated from blood, cervix, and rectum of IA markers including CD38 and HLA-DR and of markers of cell migration and tissue retention, as well as the concentration of genital and intestinal cytokines. A delayed-start group (n = 22) was used to control for natural variations in these parameters. Although immunogenic, VZV vaccination did not result in significant difference in the frequency of cervical activated (HLA-DR+CD38+) CD4+ T cells (median 1.61%, IQR 0.93%-2.76%) at 12 weeks after vaccination when compared with baseline (median 1.58%, IQR 0.75%-3.04%), the primary outcome for this study. VZV vaccination also had no measurable effect on any of the IA parameters at 4, 8, and 12 weeks after vaccination. This study provides the first evidence to our knowledge about the effects of VZV vaccination on human mucosal IA status and supports further evaluation of VZV as a potential vector for an HIV vaccine. ClinicalTrials.gov NCT02514018. Primary support from the Canadian Institutes for Health Research (CIHR). For other sources, see Acknowledgments.

1956. Persistence of Immune Response and Safety of an Adjuvanted Recombinant Zoster Vaccine in Older Adults Previously Vaccinated with a Live-Attenuated Herpes Zoster Vaccine: End-of-Study Results of a Phase III, Group-Matched, Clinical Trial

BackgroundHerpes zoster (HZ), caused by reactivation of varicella-zoster virus (VZV), typically manifests as a dermatomal rash and can result in complications, such as postherpetic neuralgia. HZ risk increases with age due to age-related decline of immunity. At time of study start, Zoster Vaccine Live (ZVL), containing live-attenuated VZV was recommended for vaccination in adults ≥60 years of age. Efficacy of ZVL declines with time since vaccination and increasing age. We evaluated immunogenicity and safety of Adjuvanted Recombinant Zoster Vaccine (RZV) containing truncated form of VZV glycoprotein E (gE) in adults vaccinated with ZVL ≥5 years before (HZ-PreVac) and ZVL-naïve adults (HZ-NonVac). In October 2017, the Advisory Committee on Immunization Practices recommended revaccination of ZVL recipients with RZV, based on available data, including 1 month (M) post-dose 2 results of this study (M3). Here we present immunogenicity and safety results up to 12 months post-dose 2 (M14).MethodsIn this phase III, multi-center study (NCT02581410), open-label, 2 parallel groups of group-matched adults ≥65 years of age, HZ-PreVac and HZ-NonVac, received 2 RZV doses 2 months apart. Humoral and cellular immune responses were evaluated at various time points up to M14. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post each dose, respectively. Serious AEs (SAEs), HZ cases and potential immune-mediated diseases (pIMDs) were recorded throughout the study.Results215 participants were vaccinated in each group. No apparent differences, in pre-vaccination and persistence values of the anti-gE antibody GMCs (Figure 1) and CD4[2+] T-cell frequencies (Figure 2) were observed between HZ-PreVac and HZ-NonVac, up to M14. No clinically relevant differences in frequencies of solicited AEs, unsolicited AEs or SAEs between the two groups were observed. Six pIMDs (two in HZ-PreVac group and four in HZ-NonVac group), were reported up to M14 (Table 1). ConclusionIn both groups, RZV-induced humoral and cellular immune responses persisted above baseline up to M14 at similar levels, irrespective of previous ZVL administration. Safety profile was similar regardless of previous ZVL vaccination. Funding: GlaxoSmithKline Biologicals SA.Disclosures T. Mrkvan, GSK: Employee and Shareholder, Salary and shares and share options. L. Campora, GSK: Employee and Shareholder, Salary. G. Catteau, GSK: Board Member, Salary. M. Douha, GSK: Employee, Salary. K. Grupping, GSK: Employee, Salary. C. Herve, GSK: Employee, Salary. G. Kalema, GSK: Consultant, Consulting fee. T. Heineman, GSK: Consultant, Employee and Shareholder, Consulting fee and Salary. N. P. Klein, GSK: Investigator, Research support. sanofi pasteur: Investigator, Research support. Merck: Investigator, Research support. Pfizer: Investigator, Research support. Protein Science: Investigator, Research support. MedImmune: Investigator, Research support. Dynavax: Investigator, Research support. H. Lal, GSK: Shareholder, Salary. Pfizer: Shareholder, Salary. L. Oostvogels, GSK: Employee, Salary and stock and stock options. A. Schuind, GSK: Employee and Shareholder, Salary.

Varicella in Poland: economic burden in children 1\u201312\xa0years of age in Poland, 2010\u20132015

BackgroundThe safety and efficacy of live-attenuated varicella zoster virus (VZV) vaccines in preventing varicella and reducing associated morbidity and mortality in real-world have been previously shown. In Poland, VZV vaccination is only mandatory for certain high-risk individuals. Here, we have conducted an evaluation of the clinical and economic burden of varicella in Poland.MethodsMulticenter, retrospective chart review of varicella inpatients and outpatients aged 1–12 years with a primary diagnosis between 2010 and 2015. Varicella-related outcomes included the incidence of complications, the proportion of patients reporting healthcare resource utilization (HCRU), and frequency of HCRU. Direct costs were derived from per patient resource use multiplied by unit costs, and indirect costs were calculated as loss of revenue of caregivers reporting work days missed. The overall annual cost of varicella in Poland was estimated based on the calculated direct and indirect costs per case and the estimated number of varicella cases. All costs are presented in 2015 Polish złoty (PLN) / Euros (€).ResultsA total of 150 children with varicella were included, of which 75 were outpatients and 75 were inpatients with a mean (± SD) age of 3.9 (±2.6) and 4.2 (±2.3) years, respectively. Complications were experienced by 14.7% of outpatients and 82.7% of inpatients, of which the most common were skin and soft tissue infections and dehydration. The rate of HCRU was as follows: over-the-counter medications (80.0% outpatients, 81.3% inpatients), prescription medications (80.0% outpatients, 93.3% inpatients), tests/procedures (0.0% outpatients, 69.3% inpatients), and allied health professional consults (0.0% outpatients, 24.0% inpatients). Total (direct and indirect) cost per varicella case was 5013.3 PLN (€ 1198.1) for inpatients and 1027.2 PLN (€ 245.5) for outpatients, resulting in an estimated overall annual (2015) cost of varicella in Poland of 178,198,320 PLN (€ 42,588,385) among children aged 1–15 years.ConclusionsSignificant clinical and economic burden is associated with varicella in Poland. These results may be used to foster discussion related to the implications of implementing routine VZV vaccination in Poland.

Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults.

Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Blood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax) at middle age (N = 53, 50-65 years of age). VZV-specific IFNγ-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Robust short-term enhancement of the VZV-specific IFNγ-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFNγ-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFNγ-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFNγ-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFNγ-producing cells. These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFNγ-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.

UK experience of herpes zoster vaccination can inform varicella zoster virus policies

UK experience of herpes zoster vaccination can inform varicella zoster virus policies

Immunogenicity of Inactivated Varicella Zoster Vaccine (ZVIN) in Autologous Hematopoietic Stem Cell Transplant (auto-HSCT) Recipients

BackgroundRecipients of auto-HSCT have an increased risk of herpes zoster (HZ) infection; however, live attenuated varicella-zoster virus (VZV) vaccine is contraindicated in these patients. In this pivotal Phase III study (V212-001; NCT01229267) inactivated VZV vaccine (ZVIN) reduced the rate of HZ infection compared with placebo (estimated vaccine efficacy, 63.8%) and was well tolerated. Immunogenicity of ZVINin recipients of auto-HSCT was assessed in the Phase III study as an exploratory objective.MethodsAdults undergoing auto-HSCT were randomized to receive either ZVIN(n = 560) or placebo (n = 564), administered in a 4-dose regimen. Doses 1 through 4 were administered ~30 days before and ~30, ~60, and ~90 days following auto-HSCT. VZV-specific immune responses were measured at Day 1, ~28 days post-vaccinations 3 and 4, and annually until the end of the study. VZV-specific antibody responses were measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) in all patients; cell-mediated immune responses were measured by VZV interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay in a randomized subset of patients (n = 403).ResultsGeometric mean titers (GMT) were significantly higher and the ratios of the gpELISA and IFN-γ ELISPOT were significantly greater in the ZVINgroup compared with the placebo group (Tables 1 and 2).Table 1. GMT 28 days post-dose 4 (PD4) Vaccine Placebo gpELISA n = 102 n = 108 241.8 (95% CI: 186.2, 313.9)105.8 (95% CI: 84.6, 132.3) IFN-γ ELISPOT n = 102 n = 116 62.8 (95% CI: 45.8, 86.2)10.4 (95% CI: 7.9, 13.7)Table 2. Ratios of geometric mean fold rise between the vaccine and placebo groups (ZVIN/placebo) gpELISA (n = 764) IFN-γ ELISPOT (n = 339) Pre-vaccination and 28 days PD4 1.79 (95% CI: 1.39, 2.32)5.41 (95% CI: 3.60, 8.12) Pre-vaccination and 1 year PD4 1.30 (95% CI: 0.99, 1.71)4.12 (95% CI: 2.62, 6.47)ConclusionZVIN elicited higher VZV-specific humoral and cell-mediated responses in adult auto-HSCT recipients when compared with placebo ~28 days and ~1 year post-dose 4. These results indicate that ZVIN is immunogenic in these patients who are ineligible for live attenuated HZ vaccine, which is consistent with previously observed clinical efficacy.Disclosures M. Boeckh, Merck: Investigator, Research Contractor and Scientific Advisor, Consulting fee and Research support; GlaxoSmithKline: Research Contractor, Research support; A. Arvin, Merck: Scientific Advisor, Consulting fee; K. Mullane, Merck: Scientific Advisor, Grant recipient; D. J. Winston, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; J. Brown, Merck: Clinical adjudication and site investigator and Investigator, Consulting fee; Cellerant Therapeutics: Consultant, Cellerant developing and executing clinical trials of myeloid progenitor cells in neutropenia for which I hold the patent; S. Pergam, Merck: Consultant and Investigator, Consulting fee; K. Hurtado, Merck: Employee and Shareholder, Salary; L. Pang, Merck: Employee and Shareholder, Salary; I. Lee, Merck: Employee, Salary; Z. Popmihajlov, Merck & Co., Inc.: Employee and Shareholder, Salary

Economic burden of varicella in children 1\u201312\xa0Years of age in Hungary, 2011\u20132015

BackgroundAlthough live-attenuated varicella-zoster virus (VZV) vaccines have been proven to be safe and effective in preventing varicella and real-word evidence shows routine childhood immunization programs are effective in dramatically reducing varicella associated morbidity and mortality, varicella vaccine is not included in the National Immunization Program (NIP) in Hungary. The purpose of this study was to evaluate the clinical and economic burden associated with varicella in Hungary.MethodsThis was a multicenter, retrospective, chart review study of patients aged 1–12 years with a primary varicella diagnosis between 2011 and 2015. Healthcare resource utilization (HCRU) associated with varicella, unit costs, and work loss were used to estimate direct and indirect costs. All costs are presented in 2015 HUF / Euros (€).Results156 children with varicella were included (75 outpatients, 81 inpatients), with a mean age of 4.4 (SD: 2.0) and 3.7 (SD: 2.1) years, respectively. One or more complications were reported by 12.0% of outpatients and 92.6% of inpatients, the most common being dehydration, skin and soft tissue infections, pneumonia, keratoconjunctivitis, and cerebellitis. HCRU estimates included use of over-the-counter (OTC) medications (96.0% outpatients, 53.1% inpatients), prescription medications (9.3% outpatients, 70.4% inpatients), tests/procedures (4.0% outpatients, 97.5% inpatients), and consultation with allied health professionals (2.7% outpatients, 30.9% inpatients). The average duration of hospital stay (inpatients) was 3.6 (95% CI: 3.2, 4.1) days. The total combined direct and indirect cost per varicella case was 228,146.7 Hungarian Forint (HUF)/€ 736.0 for inpatients and 49,790.6 HUF/€ 106.6 for outpatients. The overall annual cost of varicella in Hungary for children aged <15 years in 2015 was estimated at 1,903,332,524.3 HUF/ € 6,139,980.4.ConclusionVaricella is associated with substantial clinical burden in Hungary, resulting in the utilization of a significant amount of healthcare resources. These results support the need for routine vaccination of all healthy children to reduce the varicella-associated disease burden.