Effect of high dose vitamin D supplementation on subsequent immune responses to administration of the live herpes zoster vaccine to long-term care residents.

Thirty-three long-term care residents (mean age 76.5 years), who were participating in a study in which they were randomized to receive either oral daily standard dose (400-1000 IU/day) 25-hydroxy vitamin D (vitamin D3) (SD) or high dose (3000-4000 IU/day) (HD) vitamin D3, were vaccinated with the live, attenuated herpes zoster vaccine. Blood was drawn at vaccination and three weeks later to determine varicella-zoster virus (VZV) antibody and T-cell mediated immune responses. ELISA and neutralizing antibodies increased significantly, but to the same extent, in both groups. The antibody avidity significantly increased from pre- to post-vaccination only in the HD group. VZV-CMI, as measured by FLUOROSPOT significantly increased post-vaccination in both groups, but the difference in interferon-γ spot-forming cells (SFC) and interleukin-2 SFC was lower in the HD than SD group. The increase in VZV-CMI correlated inversely with circulating regulatory T cells in the HD group. We conclude that pre-treatment with HD vitamin D3 does not appreciably enhance the antibody response to a live vaccine and that VZV-CMI responses were diminished in HD vitamin D3 recipients.

Crohn's Disease and Herpes Zoster: Being Mindful of Vaccination.

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract. Immunosuppressive therapy is the main treatment modality in Crohn's disease. Herpes zoster (HZ), caused by Varicella-zoster virus, is a relatively common albeit burdensome clinical picture mainly affecting adult population with immunosuppressive status. In this paper, we aimed to report a Crohn's disease patient with HZ to raise awareness on vaccination. There are commercially available vaccines that are shown to be safe and effective against HZ reactivation. Crohn's disease patients should be evaluated and informed about preventive options against HZ to prevent unwanted HZ-related complications.

Effectiveness of the live zoster vaccine during the 10 years following vaccination: real world cohort study using electronic health records.

OBJECTIVES: To assess the effectiveness of live zoster vaccine during more than 10 years after vaccination; and to describe methods for ascertaining vaccine effectiveness in the context of waning. DESIGN: Real world cohort study using electronic health records. SETTING: Kaiser Permanente Northern California, an integrated healthcare delivery system in the US, 1 January 2007 to 31 December 2018. POPULATION: More than 1.5 million people aged 50 years and older followed for almost 9.4 million person years. MAIN OUTCOME MEASURE: Vaccine effectiveness in preventing herpes zoster, postherpetic neuralgia, herpes zoster ophthalmicus, and admission to hospital for herpes zoster was assessed. Change in vaccine effectiveness by time since vaccination was examined using Cox regression with a calendar timeline. Time varying indicators were specified for each interval of time since vaccination (30 days to less than one year, one to less than two years, etc) and adjusted for covariates. RESULTS: Of 1 505 647 people, 507 444 (34%) were vaccinated with live zoster vaccine. Among 75 135 incident herpes zoster cases, 4982 (7%) developed postherpetic neuralgia, 4439 (6%) had herpes zoster ophthalmicus, and 556 (0.7%) were admitted to hospital for herpes zoster. For each outcome, vaccine effectiveness was highest in the first year after vaccination and decreased substantially over time. Against herpes zoster, vaccine effectiveness waned from 67% (95% confidence interval 65% to 69%) in the first year to 15% (5% to 24%) after 10 years. Against postherpetic neuralgia, vaccine effectiveness waned from 83% (78% to 87%) to 41% (17% to 59%) after 10 years. Against herpes zoster ophthalmicus, vaccine effectiveness waned from 71% (63% to 76%) to 29% (18% to 39%) during five to less than eight years. Against admission to hospital for herpes zoster, vaccine effectiveness waned from 90% (67% to 97%) to 53% (25% to 70%) during five to less than eight years. Across all follow-up time, overall vaccine effectiveness was 46% (45% to 47%) against herpes zoster, 62% (59% to 65%) against postherpetic neuralgia, 45% (40% to 49%) against herpes zoster ophthalmicus, and 66% (55% to 74%) against admission to hospital for herpes zoster. CONCLUSIONS: Live zoster vaccine was effective initially. Vaccine effectiveness waned substantially yet some protection remained 10 years after vaccination. After 10 years, protection was low against herpes zoster but higher against postherpetic neuralgia. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01600079; EU PAS register number EUPAS17502.

Cost-effectiveness of varicella and herpes zoster vaccination in Sweden: An economic evaluation using a dynamic transmission model.

OBJECTIVES: Comprehensive cost-effectiveness analyses of introducing varicella and/or herpes zoster vaccination in the Swedish national vaccination programme. DESIGN: Cost-effectiveness analyses based on epidemiological results from a specifically developed transmission model. SETTING: National vaccination programme in Sweden, over an 85- or 20-year time horizon depending on the vaccination strategy. PARTICIPANTS: Hypothetical cohorts of people aged 12 months and 65-years at baseline. INTERVENTIONS: Four alternative vaccination strategies; 1, not to vaccinate; 2, varicella vaccination with one dose of the live attenuated vaccine at age 12 months and a second dose at age 18 months; 3, herpes zoster vaccination with one dose of the live attenuated vaccine at 65 years of age; and 4, both vaccine against varicella and herpes zoster with the before-mentioned strategies. MAIN OUTCOME MEASURES: Accumulated cost and quality-adjusted life years (QALY) for each strategy, and incremental cost-effectiveness ratios (ICER). RESULTS: It would be cost-effective to vaccinate against varicella (dominant), but not to vaccinate against herpes zoster (ICER of EUR 200,000), assuming a cost-effectiveness threshold of EUR 50,000 per QALY. The incremental analysis between varicella vaccination only and the combined programme results in a cost per gained QALY of almost EUR 1.6 million. CONCLUSIONS: The results from this study are central components for policy-relevant decision-making, and suggest that it was cost-effective to introduce varicella vaccination in Sweden, whereas herpes zoster vaccination with the live attenuated vaccine for the elderly was not cost-effective-the health effects of the latter vaccination cannot be considered reasonable in relation to its costs. Future observational and surveillance studies are needed to make reasonable predictions on how boosting affects the herpes zoster incidence in the population, and thus the cost-effectiveness of a vaccination programme against varicella. Also, the link between herpes zoster and sequelae need to be studied in more detail to include it suitably in health economic evaluations.

Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines.

Vaccinations are effective in preventing infections; however, it is unknown if patients with chronic lymphocytic leukemia (CLL) who are treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitors (BTKi's) respond to novel adjuvanted vaccines. Understanding the effect of BTKi's on humoral immunity is timely because BTKi's are widely used and vaccination against coronavirus disease 2019 is urgently needed. In 2 open-label, single-arm clinical trials, we measured the effect of BTKi's on de novo immune response against recombinant hepatitis B vaccine (HepB-CpG) and recall response against recombinant zoster vaccine (RZV) in CLL patients who were TN or on BTKi. The primary end point was serologic response to HepB-CpG (anti-hepatitis B surface antibodies ≥10 mIU/mL) and RZV (≥fourfold increase in anti-glycoprotein E). The response rate to HepB-CpG was lower in patients on BTKi (3.8%; 95% confidence interval [CI], 0.7-18.9) than patients who were TN (28.1%; 95% CI, 15.6-45.4; P = .017). In contrast, the response rate to RZV did not differ significantly between the BTKi (41.5%; 95% CI, 27.8-56.6) and TN cohorts (59.1%; 95% CI, 38.7-76.7; P = .2). BTKi's were associated with a decreased de novo immune response following HepB-CpG, whereas recall immune response following RZV was not significantly affected by BTKi therapy. These trials were registered at www.clinicaltrials.gov as #NCT03685708 (Hep-CpG) and #NCT03702231 (RZV).

Updated insights into the mechanism of action and clinical profile of the immunoadjuvant QS-21: A review.

BACKGROUND: Vaccine adjuvants are compounds that significantly enhance/prolong the immune response to a co-administered antigen. The limitations of the use of aluminium salts that are unable to elicite cell responses against intracellular pathogens such as those causing malaria, tuberculosis, or AIDS, have driven the development of new alternative adjuvants such as QS-21, a triterpene saponin purified from Quillaja saponaria. PURPOSE: The aim of this review is to attempt to clarify the mechanism of action of QS-21 through either receptors or signaling pathways in vitro and in vivo with special emphasis on the co-administration with other immunostimulants in new adjuvant formulations, called adjuvant systems (AS). Furthermore, the most relevant clinical applications will be presented. METHODS: A literature search covering the period 2014-2018 was performed using electronic databases from Sci finder, Science direct, Medline/Pubmed, Scopus, Google scholar. RESULTS: Insights into the mechanism of action of QS-21 can be summarized as follows: 1) in vivo stimulation of Th2 humoral and Th1 cell-mediated immune responses through action on antigen presenting cells (APCs) and T cells, leading to release of Th1 cytokines participating in the elimination of intracellular pathogens. 2) activation of the NLRP3 inflammasome in mouse APCs with subsequent release of caspase-1 dependent cytokines, Il-1ß and Il-18, important for Th1 responses. 3) synthesis of nearly 50 QS-21 analogs, allowing structure/activity relationships and mechanistic studies. 4) unique synergy mechanism between monophosphoryl lipid A (MPL A) and QS-21, formulated in a liposome (AS01) in the early IFN-γ response, promoting vaccine immunogenicity. The second part of the review is related to phase I-III clinical trials of QS-21, mostly formulated in ASs, to evaluate efficacy, immunogenicity and safety of adjuvanted prophylactic vaccines against infectious diseases, e.g. malaria, herpes zoster, tuberculosis, AIDS and therapeutic vaccines against cancer and Alzheimer's disease. CONCLUSION: The most advanced phase III clinical applications led to the development of two vaccines containing QS-21 as part of the AS, the Herpes Zoster vaccine (HZ/su) (Shingrix™) which received a license in 2017 from the FDA and a marketing authorization in the EU in 2018 and the RTS,S/AS01 vaccine (Mosquirix™) against malaria, which was approved by the EMA in 2015 for further implementation in Sub-Saharan countries for routine use.

A critical appraisal of 'Shingrix', a novel herpes zoster subunit vaccine (HZ/Su or GSK1437173A) for varicella zoster virus.

HZ/Su, branded as 'Shingrix', is one of the newest vaccines to be submitted for multi-national regulatory approval. It is targeted to prevent shingles, a global concern with aging populations. A live attenuated vaccine for shingles has been available for over a decade, however it is contraindicated in specific subgroups of people, and there are added concerns regarding long-term immunogenicity. HZ/Su is the first subunit vaccine developed to protect against shingles. This paper provides a critical appraisal of current evidence regarding HZ/Su.

The alpha-herpesviridae in dermatology : Varicella zoster virus.

The second part of this publication deals with varicella zoster virus (VZV) and presents an overview of new, rare, and atypical clinical manifestations, including photolocalized varicella, hemorrhagic bullae during varicella, the implication of VZV in immunoglobulin A vasculitis, VZV-related alopecia, ulcerative varicella skin lesions, childhood herpes zoster (HZ), prolonged prodromal pains, recurrent HZ, VZV implication in burning mouth syndrome, verruciform VZV lesions, the significance of satellite lesions during HZ, and late HZ complications, either neurological or internal. Furthermore, certain associations between the occurrence of HZ and subsequent internal pathologies, as well as risk factors for HZ and new developments in vaccination against HZ will be addressed.

Non-clinical safety assessment of single and repeated administration of gE/AS01 zoster vaccine in rabbits.

HZ/su is an investigational recombinant subunit vaccine for the prevention of shingles, a disease resulting from the reactivation of varicella zoster virus. The vaccine is composed of recombinant varicella zoster virus glycoprotein E (gE), and liposome-based Adjuvant System AS01. To evaluate the potential local and systemic effects of this vaccine, three studies were performed in rabbits. In the first two studies, rabbits received a single intramuscular (IM; study 1) or subcutaneous (SC; study 2) dose of gE/AS01, AS01 alone (in study 2 only) or saline, and the local tolerance was evaluated up to 3 days after administration. Under these conditions, only local inflammatory reactions at the injection sites were detected by microscopic evaluation. In the third study, gE/AS01, AS01 alone or saline, were injected SC or IM on four occasions at 2 week intervals. General health status, local tolerance, ophthalmology, haematology and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed after termination of the study. The only treatment-related changes included a transient increase in neutrophils, C-reactive protein and fibrinogen levels and microscopic signs of inflammation at the injection sites, which are expected observations related to the elicited inflammatory reaction. The SC and IM routes of administration produced similar systemic effects. However, microscopic findings at the injection sites differed. One month after the last injection, recovery was complete in all groups. In conclusion, the single and repeated SC and IM administration of the gE/AS01 vaccine were locally and systemically well-tolerated in rabbits and support the clinical development of the vaccine. Copyright © 2016 John Wiley & Sons, Ltd.

Preventative Care in the Patient with Inflammatory Bowel Disease: What Is New?

Patients with inflammatory bowel disease (IBD) do not receive routine preventative care at the same rate as general medical patients. This patient population is at increased risk of vaccine preventable illness such as influenza and pneumococcal pneumonia. This review will discuss health maintenance needs and preventative care issues in patients with IBD.

Comparative preclinical evaluation of AS01 versus other Adjuvant Systems in a candidate herpes zoster glycoprotein E subunit vaccine.

The candidate vaccine HZ/su is being developed to prevent herpes-zoster disease (HZ). HZ occurrence is attributed to declines in varicella-zoster virus (VZV) specific T-cell immunity. HZ/su contains VZV antigen, gE, and Adjuvant System AS01B (liposome-based formulation of MPL and QS-21). In clinical trials, AS01B enhances CD4+ T-cell responses to gE. In clinical trials of other vaccines, Adjuvant Systems AS03 and AS04 also enhance antigen-specific CD4+ T-cell responses. Hence the purpose of this study was to evaluate gE formulated with AS01B, AS01E (50% less MPL and QS-21 than AS01B), AS03 or AS04 in C57BL6 mice primed with live-attenuated VZV. Four-weeks post-vaccination, the gE-specific CD4+ T-cell response to gE/AS01B was 5.4, 2.8 and 2.2-fold greater than those to gE/AS03, gE/AS04 and gE/AS03, respectively (p<0.001). Therefore in the VZV-primed mouse model, CD4+ T-cell responses to gE appeared most enhanced by AS01B, and adds further support for the use of AS01B in the HZ/su formulation.

Systemic Therapy for Psoriasis and the Risk of Herpes Zoster: A 500,000 Person-year Study.

IMPORTANCE: The risk for herpes zoster (HZ) in patients with psoriasis treated with biologic medications or other systemic treatments has been given little attention to date. OBJECTIVE: To describe the risk for HZ in patients with psoriasis and its relation to treatment. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was performed using the administrative database of Clalit Health Services, the largest public health care provider organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. We extracted information for all patients who received a psoriasis diagnosis from January 2002 to June 2013. Follow-up was conducted until the end of July 2013. The study included 95,941 patients with psoriasis in the analysis, with 522,616 person-years of follow-up. Incidence of HZ events was calculated for each systemic antipsoriatic medication provided, during a follow-up period of 11 years and 7 months. We used a generalized estimating equation Poisson regression model to examine the effect of each systemic treatment for psoriasis on HZ incidence, adjusting for age, sex, psoriasis severity, Charlson comorbidity index, steroid treatment, and socioeconomic status. MAIN OUTCOMES AND MEASURES: Incidence of HZ associated with systemic therapies. RESULTS: In a multivariate analysis, it was observed that treatment with phototherapy (rate ratio [RR], 1.09 [95% CI, 0.62-1.93]; P = .99), methotrexate (RR, 0.98 [95% CI, 0.78-1.23]; P = .83), cyclosporine (RR, 1.16 [95% CI, 0.48-2.80]; P = .49), and biologic medications as a single agent (RR, 2.67 [95% CI, 0.69-10.3]; P = .14) was not associated with HZ. The use of combination treatment with biologic medications and methotrexate was significantly associated with an increased incidence of HZ (RR, 1.66 [95% CI, 1.08-2.57]; P = .02). The use of acitritin was associated with decreased incidence of HZ (RR, 0.69 [95% CI, 0.49-0.97]; P = .004). CONCLUSIONS AND RELEVANCE: Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ.

The burden of Herpes Zoster and its complications in Poland in according to the age.

BACKGROUND: Incidence of shingles in different regions of the world ranged from 300 to 500/100,000 persons, and in the population older than 80 years of age reaches more than 1000/100,000. In the age group 50+ the incidence is enough high to be a serious medical and economic burden. Lack of details about the incidence and frequency of complications in Polish population let us too made an attempt to assess the scale of the problem, among others to the purpose of the evaluation of the legitimacy of implementing vaccination in the 50+ population. METHODS: First, based on coming data from the Swietokrzyskie Province Division of the National Health Fund we judged the incidence of shingles in this province in 2013 in individual ancient groups and depending on detailed diagnoses and with the division into the basic health, clinic and hospital care. Second, based on gathered data through NIZP-PZH, we judged hospital morbidity connected with shingles in Poland in 2008-2012 years, in individual ancient groups. RESULTS: Extrapolating the data from the Swietokrzyskie province we assess the incidence of shingles on average 338.8/100,000. She is tallest in the age group 50+ (614.3/100,000) and in this group also the most complications are being observed. Hospital morbidity in entire Poland showed in 2008-2012 years the frequency on average 4.93-5.42/100,000, in the group of 0-19 years; 0.10-1.50/100,000, in the group of 20-49 years; 4.9-5.42/100,000 and in the 50+ group--9.99-13.37/100,000. CONCLUSIONS: (1) Shingles, especially in the 50+ age group, constitutes a serious health problem in Poland, being a cause of numerous advices in basic health care and at clinics in Poland, as well of numerous hospitalizations and dangerous complications. (2) It seems, that active immunization against shingles, especially of 50+ persons, would be a favourable solution from the individual, as well as public perspective.

[Postherpetic neuralgia]. / Postzosterneuralgie.

Postherpetic neuralgia is considered to be a neuropathic pain syndrome. Typically, patients experience pain in the dermatomes of skin lesions persisting for more than 3 months after skin restitution. About 10% of patients with herpes zoster develop postherpetic neuralgia. Its prevalence increases with age. Common clinical symptoms include continuous burning pain, sharp pain attacks, and allodynia. Additionally, sensory hyperactivation or loss in the affected skin area is present. Pathophysiology includes mechanisms of peripheral and central sensitization, based on damaged nerve fibers as the main mechanisms for pain generation and its maintenance. Clinical studies did show pain relief in postherpetic neuralgia after administration of antidepressants, antiepileptic drugs, opioids, and topical capsaicin and lidocaine. Nevertheless, about one third of patients do not respond to conventional treatment. Given the fact that postherpetic neuralgia is considered to be a chronic pain disease, a multidisciplinary treatment approach is necessary.

Nutritional factors in herpes zoster, postherpetic neuralgia, and zoster vaccination.

Herpes zoster (HZ) results from a reactivation of latent varicella-zoster virus (VZV). HZ and its most common complication, termed postherpetic neuralgia (PHN), often cause long-term psychological distress and physical disabilities leading to profoundly negative impacts on the quality of patients' lives. The incidence and severity of HZ and PHN increase with advanced age as a consequence of declining cell-mediated immunity. Aging has been linked to progressive senescence of the immune system and also is associated with a greater susceptibility to nutritional deficiencies. Suppressing VZV reactivation depends on intact cell-mediated immunity, which requires adequate nutrients to maintain its efficient function. Contrarily, nutritional deficiencies may lead to dysfunction of the host immune responses. Recently, micronutrient deficiencies have been shown to increase the risk of HZ and PHN and to affect the immune response to vaccinations, whereas nutritional supplements effectively reduce herpetic pain and pain in patients with PHN. As the elderly population grows, the incidence and severity of HZ and PHN are expected to increase and cause a substantial financial burden on the health care system. Thus, enhancing knowledge of the risk factors of HZ and PHN and developing better interventions to treat and prevent HZ and PHN are important to public health. This article provides an overview of the present understanding of the association among nutritional deficiencies, diminished cell-mediated immunity, and the risk of HZ and PHN, and then illustrates the potential of nutritional intervention in the prevention, vaccination, and management of HZ and PHN.

Evidence-based case report: the prevention and management of postherpetic neuralgia with emphasis on interventional procedures.

OBJECTIVE: A patient with postherpetic neuralgia (PHN) did not respond to medications, either singly or in combination, or to intrathecal methylprednisolone but responded to intrathecal alcohol. This evidenced-based case management article evaluates and grades the evidence for the prevention and treatment of PHN. METHODS: A search of published English-language studies on the prevention and treatment of PHN was made. RESULTS: Randomized clinical studies showed the efficacy of antiviral agents in the prevention of PHN and the use of anticonvulsants, antidepressants, opioids, and Lidoderm patch in the treatment of PHN (level A evidence). The role of epidural local anesthetic and steroid injections in preventing PHN has not been completely established (level B evidence). Intrathecal steroid injections and topical capsaicin may be effective in PHN (level B evidence). No randomized controlled study supports the usefulness of spinal cord stimulation and intrathecal alcohol. CONCLUSIONS: Postherpetic neuralgia should be managed pharmacologically. If not effective, intrathecal steroid injections or nerve blocks may be tried. Spinal cord stimulation or intrathecal alcohol should be used only as a last resort.