Vaccines for preventing herpes zoster in older adults.

BACKGROUND: Herpes zoster, commonly known as shingles, is a neurocutaneous disease caused by the reactivation of the virus that causes varicella (chickenpox). After resolution of the varicella episode, the virus can remain latent in the sensitive dorsal ganglia of the spine. Years later, with declining immunity, the varicella zoster virus (VZV) can reactivate and cause herpes zoster, an extremely painful condition that can last many weeks or months and significantly compromise the quality of life of the affected person. The natural process of ageing is associated with a reduction in cellular immunity, and this predisposes older adults to herpes zoster. Vaccination with an attenuated form of the VZV activates specific T-cell production avoiding viral reactivation. Two types of herpes zoster vaccines are currently available. One of them is the single-dose live attenuated zoster vaccine (LZV), which contains the same live attenuated virus used in the chickenpox vaccine, but it has over 14-fold more plaque-forming units of the attenuated virus per dose. The other is the recombinant zoster vaccine (RZV) which does not contain the live attenuated virus, but rather a small fraction of the virus that cannot replicate but can boost immunogenicity. The recommended schedule for the RZV is two doses two months apart. This is an update of a Cochrane Review first published in 2010, and updated in 2012, 2016, and 2019. OBJECTIVES: To evaluate the effectiveness and safety of vaccination for preventing herpes zoster in older adults. SEARCH METHODS: For this 2022 update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2022, Issue 10), MEDLINE (1948 to October 2022), Embase (2010 to October 2022), CINAHL (1981 to October 2022), LILACS (1982 to October 2022), and three trial registries. SELECTION CRITERIA: We included studies involving healthy older adults (mean age 60 years or older). We included randomised controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine (any dose and potency) versus any other type of intervention (e.g. varicella vaccine, antiviral medication), placebo, or no intervention (no vaccine). Outcomes were cumulative incidence of herpes zoster, adverse events (death, serious adverse events, systemic reactions, or local reaction occurring at any time after vaccination), and dropouts. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included two new studies involving 1736 participants in this update. The review now includes a total of 26 studies involving 90,259 healthy older adults with a mean age of 63.7 years. Only three studies assessed the cumulative incidence of herpes zoster in groups that received vaccines versus placebo. Most studies were conducted in high-income countries in Europe and North America and included healthy Caucasians (understood to be white participants) aged 60 years or over with no immunosuppressive comorbidities. Two studies were conducted in Japan and one study was conducted in the Republic of Korea. Sixteen studies used LZV. Ten studies tested an RZV. The overall certainty of the evidence was moderate, which indicates that the intervention probably works. Most data for the primary outcome (cumulative incidence of herpes zoster) and secondary outcomes (adverse events and dropouts) came from studies that had a low risk of bias and included a large number of participants. The cumulative incidence of herpes zoster at up to three years of follow-up was lower in participants who received the LZV (one dose subcutaneously) than in those who received placebo (risk ratio (RR) 0.49, 95% confidence interval (CI) 0.43 to 0.56; risk difference (RD) 2%; number needed to treat for an additional beneficial outcome (NNTB) 50; moderate-certainty evidence) in the largest study, which included 38,546 participants. There were no differences between the vaccinated and placebo groups for serious adverse events (RR 1.08, 95% CI 0.95 to 1.21) or deaths (RR 1.01, 95% CI 0.92 to 1.11; moderate-certainty evidence). The vaccinated group had a higher cumulative incidence of one or more adverse events (RR 1.71, 95% CI 1.38 to 2.11; RD 23%; number needed to treat for an additional harmful outcome (NNTH) 4.3) and injection site adverse events (RR 3.73, 95% CI 1.93 to 7.21; RD 28%; NNTH 3.6; moderate-certainty evidence) of mild to moderate intensity. These data came from four studies with 6980 participants aged 60 years or older. Two studies (29,311 participants for safety evaluation and 22,022 participants for efficacy evaluation) compared RZV (two doses intramuscularly, two months apart) versus placebo. Participants who received the new vaccine had a lower cumulative incidence of herpes zoster at 3.2 years follow-up (RR 0.08, 95% CI 0.03 to 0.23; RD 3%; NNTB 33; moderate-certainty evidence), probably indicating a favourable profile of the intervention. There were no differences between the vaccinated and placebo groups in cumulative incidence of serious adverse events (RR 0.97, 95% CI 0.91 to 1.03) or deaths (RR 0.94, 95% CI 0.84 to 1.04; moderate-certainty evidence). The vaccinated group had a higher cumulative incidence of adverse events, any systemic symptom (RR 2.23, 95% CI 2.12 to 2.34; RD 33%; NNTH 3.0), and any local symptom (RR 6.89, 95% CI 6.37 to 7.45; RD 67%; NNTH 1.5). Although most participants reported that their symptoms were of mild to moderate intensity, the risk of dropouts (participants not returning for the second dose, two months after the first dose) was higher in the vaccine group than in the placebo group (RR 1.25, 95% CI 1.13 to 1.39; RD 1%; NNTH 100, moderate-certainty evidence). Only one study reported funding from a non-commercial source (a university research foundation). All other included studies received funding from pharmaceutical companies. We did not conduct subgroup and sensitivity analyses AUTHORS' CONCLUSIONS: LZV (single dose) and RZV (two doses) are probably effective in preventing shingles disease for at least three years. To date, there are no data to recommend revaccination after receiving the basic schedule for each type of vaccine. Both vaccines produce systemic and injection site adverse events of mild to moderate intensity. The conclusions did not change in relation to the previous version of the systematic review.

The Efficacy of Amenamevir for the Treatment of Disseminated Herpes Zoster Complicated with Probable Varicella-zoster Pneumonia in an Immunocompromised Patient.

We herein report the case of a 78-year-old woman who was diagnosed as having disseminated herpes zoster (DHZ) complicated with probable varicella-zoster pneumonia during maintenance therapy for microscopic polyangiitis. Because the patient had severe renal dysfunction, amenamevir administration was started to avoid any neurotoxicity of acyclovir, which is suggested to be optimal for treatment. It ameliorated her symptoms without any adverse events. This is the first report suggesting the efficacy of amenamevir in the treatment of severe herpes zoster infection with coexisting DHZ and probable varicella-zoster pneumonia. Amenamevir could thus be a treatment option for severe varicella zoster virus infections.

Burden of comorbid conditions in children and young people with juvenile idiopathic arthritis: a collaborative analysis of 3 JIA registries.

OBJECTIVES: Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally-UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild-to quantify the occurrence of selected comorbidities in patients with JIA. METHODS: Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. RESULTS: 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1-1.8%) and uveitis (15-19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). CONCLUSION: This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

Safety of Second-Dose Single-Antigen Varicella Vaccine.

BACKGROUND AND OBJECTIVE: In 2006, routine 2-dose varicella vaccination for children was recommended to improve control of varicella. We assessed the safety of second-dose varicella vaccination. METHODS: We identified second-dose single-antigen varicella vaccine reports in the Vaccine Adverse Event Reporting System during 2006 to 2014 among children aged 4 to 18 years. We analyzed reports by age group (4-6 and 7-18 years), sex, serious or nonserious status, most common adverse events (AEs), and whether other vaccines were administered concomitantly with varicella vaccine. We reviewed serious reports of selected AEs and conducted empirical Bayesian data mining to detect disproportional reporting of AEs. RESULTS: We identified 14 641 Vaccine Adverse Event Reporting System reports after second-dose varicella vaccination, with 494 (3%) classified as serious. Among nonserious reports, injection site reactions were most common (48% of children aged 4-6 years, 38% of children aged 7-18 years). The most common AEs among serious reports were pyrexia (31%) for children aged 4 to 6 years and headache (28%) and vomiting (27%) for children aged 7 to 18 years. Serious reports of selected AEs included anaphylaxis (83), meningitis (5), encephalitis (16), cellulitis (52), varicella (6), herpes zoster (6), and deaths (7). One immunosuppressed adolescent was reported with vaccine-strain herpes zoster. Only previously known AEs were reported more frequently after second-dose varicella vaccination compared with other vaccines. CONCLUSIONS: We identified no new or unexpected safety concerns for second-dose varicella vaccination. Robust safety monitoring remains an important component of the national varicella vaccination program.

α Herpes Virus Infections Among Renal Transplant Recipients.

The α herpes viruses HSV-1, HSV-2, and VZV often reactivate in the setting of immune suppression after solid organ transplantation. Oral or genital mucocutaneous disease is the most common clinical manifestation of HSV disease while VZV manifests as varicella (or chickenpox) or reactivation herpes zoster, characterized by a diffuse rash, or a painful unilateral vesicular eruption in a dermatomal distribution, respectively. The diagnosis of HSV and VZV is primarily based on history and clinical presentation, although diagnostic tests may be necessary for atypical presentations of disease. Treatment usually involves oral or intravenous antiviral therapy, depending on severity of illness.

Modelling Hospitalisation Ratios for Febrile Convulsions and Severe Varicella Under Combined Measles, Mumps, Rubella, and Varicella (MMRV-Priorix-Tetra™) Compared to Separate MMR + V Vaccination.

INTRODUCTION: Measles, mumps, rubella, and varicella combination vaccines (MMRV) facilitate varicella vaccination uptake compared with separate administration of measles, mumps, and rubella vaccine (MMR) with varicella vaccine (V). However, the risk of developing febrile convulsions (FC) is higher in children vaccinated with MMRV. OBJECTIVES: The aim was to demonstrate how to put the increased FC risk associated with MMRV into perspective by comparing it with the lower V-coverage risk associated with MMR + V. METHODS: FC and varicella burdens were measured by total numbers or duration of hospitalisations. A model, based on several assumptions and integrating parameters from heterogeneous data sources relevant to Germany, was developed to evaluate hospitalisation ratios (HRs; ratios between yearly numbers of varicella-related hospitalisation days prevented by MMRV and yearly numbers of FC-related hospitalisation days attributed to MMRV, both compared with MMR + V). A sensitivity analysis estimated HR under different scenarios beyond the German experience. RESULTS: For parameter values compatible with the German experience, where MMRV (Priorix-Tetra™, GSK, Belgium) was introduced in 2006, the model predicted that transitioning from MMR + V to MMRV would induce 225 vaccine-related FC hospitalisation days whilst preventing 1976 varicella-related hospitalisation days per year. The HR estimated by Monte Carlo simulations was 8.5 (95 % confidence interval: 1.99-25.22). A sensitivity analysis on two key parameters suggested that transitioning from MMR + V to MMRV would be favourable in situations where MMRV use would significantly impact varicella vaccination uptake. CONCLUSIONS: MMRV use instead of MMR + V can substantially reduce the number of hospitalisation days, despite increased FC risk when MMRV is used as a first dose of measles-containing vaccine.

Fatal varicella due to the vaccine-strain varicella-zoster virus.

We describe a death in a 15-mo-old girl who developed a varicella-like rash 20 d after varicella vaccination that lasted for 2 mo despite acyclovir treatment. The rash was confirmed to be due to vaccine-strain varicella-zoster virus (VZV). This is the first case of fatal varicella due to vaccine-strain VZV reported from the United States. The patient developed severe respiratory complications that worsened with each new crop of varicella lesions; vaccine-strain VZV was detected in the bronchial lavage specimen. Sepsis and multi-organ failure led to death. The patient did not have a previously diagnosed primary immune deficiency, but her failure to thrive and repeated hospitalizations early in life (starting at 5 mo) for presumed infections and respiratory compromise treated with corticosteroids were suggestive of a primary or acquired immune deficiency. Providers should monitor for adverse reactions after varicella vaccination. If severe adverse events develop, acyclovir should be administered as soon as possible. The possibility of acyclovir resistance and use of foscarnet should be considered if lesions do not improve after 10 d of treatment (or if they become atypical [e.g., verrucous]). Experience with use of varicella vaccine indicates that the vaccine has an excellent safety profile and that serious adverse events are very rare and mostly described in immunocompromised patients. The benefit of vaccination in preventing severe disease and mortality outweigh the low risk of severe events occurring after vaccination.

Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review.

OBJECTIVES: Methotrexate (MTX) has become the foundation disease-modifying anti-rheumatic drug (DMARD) for RA. However, concern exists regarding its possible association with infectious complications including varicella zoster virus (VZV) and herpes zoster (HZ). Furthermore, no consensus exists regarding pre-MTX VZV screening or the use of VZV vaccine. METHODS: We undertook systematic literature review (SLR) investigating the relationship between the use of MTX in patients with RA and VZV and HZ infection. Additionally, the European Centre for Disease Prevention and Control, HPA, the CDC, Rheumatology societies and WHO web sites and publications were consulted. RESULTS: Thirty-five studies fulfilled the inclusion criteria comprising 29 observational studies and 6 case reports. The case reports and 13 observation studies considered the association between MTX and HZ. Three of the observational studies reported a positive association although in 5 cases, patients were concurrently treated with prednisolone. Five studies concluded that there was no association between HZ and MTX. Three studies comparing the infection rates of MTX with other RA therapies found that MTX did not result in higher HZ infection rates. Three studies examining the association between HZ and MTX treatment duration failed to show a link. CONCLUSIONS: No evidence exists to support an association between MTX and VZV infection in RA patients and the data regarding the role of MTX in HZ development is conflicting. The role of pre-MTX VZV screening is controversial and, as it may delay initiation of RA treatment, we suggest against VZV screening in this context.

Latent simian varicella virus reactivates in monkeys treated with tacrolimus with or without exposure to irradiation.

Simian varicella virus (SVV) infection of primates resembles human varicella-zoster virus (VZV) infection. After primary infection, SVV becomes latent in ganglia and reactivates after immunosuppression or social and environmental stress. Herein, natural SVV infection was established in 5 cynomolgus macaques (cynos) and 10 African green (AG) monkeys. Four cynos were treated with the immunosuppressant tacrolimus (80 to 300 μg/kg/day) for 4 months and 1 was untreated (group 1). Four AG monkeys were exposed to a single dose (200 cGy) of x-irradiation (group 2), and 4 other AG monkeys were irradiated and treated with tacrolimus for 4 months (group 3); the remaining 2 AG monkeys were untreated. Zoster rash developed 1 to 2 weeks after tacrolimus treatment in 3 of 4 monkeys in group 1, 6 weeks after irradiation in 1 of 4 monkeys in group 2, and 1 to 2 weeks after irradiation in all 4 monkeys in group 3. All monkeys were euthanized 1 to 4 months after immunosuppression. SVV antigens were detected immunohistochemically in skin biopsies as well as in lungs of most monkeys. Low copy number SVV DNA was detected in ganglia from all three groups of monkeys, including controls. RNA specific for SVV ORFs 61, 63, and 9 was detected in ganglia from one immunosuppressed monkey in group 1. SVV antigens were detected in multiple ganglia from all immunosuppressed monkeys in every group, but not in controls. These results indicate that tacrolimus treatment produced reactivation in more monkeys than irradiation and tacrolimus and irradiation increased the frequency of SVV reactivation as compared to either treatment alone.

Rituximab-related viral infections in lymphoma patients.

Recently, a human/mouse chimeric monoclonal antibody, rituximab, has been successfully used to treat cases of B-cell non-Hodgkin's lymphoma and some autoimmune diseases. However, several viral infections related to rituximab have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 64 previously reported cases of serious viral infection after rituximab treatment. The median age of the cases was 61 years (range: 21 - 79). The median time period from the start of rituximab treatment to viral infection diagnosis was 5.0 months (range: 1 - 20). The most frequently experienced viral infections were hepatitis B virus (HBV) (39.1%, n = 25), cytomegalovirus infection (CMV) (23.4%, n = 15), varicella-zoster virus (VZV) (9.4%, n = 6), and others (28.1%, n = 18). Of the patients with HBV infections, 13 (52.0%) died due to hepatic failure. Among the 39 cases that had viral infections other than HBV, 13 died due to these specific infections. In this study, about 50% of the rituximab-related HBV infections resulted in death, whereas this was the case in only 33% of the cases with other infections. Close monitoring for viral infection, particularly HBV and CMV, in patients treated with rituximab should be recommended.

[Severe varicella infection during treatment with infliximab for Crohn's disease]. / Une varicelle grave lors d'un traitement par infliximab pour maladie de Crohn.

Immunosupressive agents have improved the treatment of severe Crohn's disease. Infliximab is increasingly used in the treatment of Crohn's disease refractory to the usual treatment or with fistulas. However, there is a risk of infection and benign viral infections can became severe. We report the case of a patient treated by azathioprine and infliximab who developed serious chickenpox with multi visceral localisations and transfer to intensive care. There are a few cases of severe varicella infection in the literature with hepatitis and pneumonia in patients treated with infliximab. We review the clinical aspects, therapeutic strategy and prevention of chickenpox in immunodepressed patients.