Safety and tolerability of a high-potency zoster vaccine in adults ≥50 years of age

doi:10.1016/j.vaccine.2006.10.027

Vaccine

Volume 25, Issue 10, 26 February 2007, Pages 1877-1883

https://doi.org/10.1016/j.vaccine.2006.10.027 Get rights and content

Abstract

Background

Herpes zoster (HZ) incidence rises with age, especially after 50 years of age, probably due to waning varicella-zoster virus (VZV)-specific immunity. The Shingles Prevention Study [Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults, N Engl J Med 2005;352:2271–84], enrolled people ≥60 years of age and showed that zoster vaccine prevents HZ and postherpetic neuralgia (PHN), presumably through boosting VZV-specific immunity. This study of people ≥50 years of age compared the safety and tolerability of two zoster vaccine potencies.

Methods

Adults ≥50 years old enrolled in a randomized, double-blind, multicenter study to compare the safety and tolerability of one dose of two zoster vaccine potencies, ∼58,000 and ∼207,000 plaque-forming units/dose. Adverse experiences (AEs) were recorded on a standardized Vaccination Report Card for 42 days postvaccination. For assessment of injection-site AEs, clinically acceptable tolerability was predefined based on experience with PNEUMOVAX™ 23, a licensed vaccine recommended for use in older people.

Results

Six hundred and ninety-eight subjects (age 50–90 years, median 64 years) were enrolled. No serious vaccine-related AEs were reported. Similar AE rates were observed in the higher and lower potency groups (overall systemic AEs: 37.5 and 39.3%, vaccine-related systemic AEs: 10.9 and 13.2%, injection-site AEs: 63.0 and 59.8%). Rates for a combined endpoint of moderate or severe injection-site pain/tenderness/soreness and swelling were 17.2% (95% CI 13.9, 21.0) and 9.0% (95% CI 5.6, 13.4), respectively. Most combined endpoint events were reported as moderate in intensity.

Conclusions

Both vaccine potencies were generally well tolerated in this study of people ≥50 years of age. Although rates of some moderate or severe injection-site AEs were greater in the higher potency group, all rates met the prespecified criteria for clinically acceptable tolerability.

Introduction

Herpes zoster (HZ), known also as shingles, is a manifestation of reactivation of varicella-zoster virus (VZV), which, as a primary infection, produces chickenpox (varicella). Following initial infection, the virus remains latent in the dorsal root of spinal nerves or cranial sensory ganglia until it reactivates and replicates, producing HZ [1], [2].

In the United States, Canada, and Europe, the overall annual incidence of HZ is consistently estimated to be 3–4/1000 population [1], [3], [4], [5], [6], [7], [8]. The incidence and severity of HZ increase with age [2], [8], [9], [10], [11], [12] with the annual risk of developing HZ increasing markedly around 50 years of age and rising sharply afterwards, up to 1% per year among those over 75 years of age. The lifetime risk of HZ is estimated to range from 10 to 30% in the general population, with estimates closer to 30% in the more recent studies [13], and is as high as 50% in individuals reaching 85 years of age [2], [9], [14], [15]. Based on current census data, an estimated one million cases of HZ are diagnosed in the United States every year.

Chronic, long-lasting HZ-associated pain, know as postherpetic neuralgia (PHN), constitutes the most common severe complication and cause of morbidity in the HZ patient. PHN is characterized by pain persisting in the area of the HZ rash, beyond the time of cutaneous healing. The frequency and severity of PHN increase with age and may occur in as many as 25–50% of patients over the age of 50 years [2], [15], [16], [17], [18], [19].

If initiated within 72 h of rash onset, treatment with an antiviral agent like acyclovir has been shown to reduce the severity and duration of the acute phase of HZ, as well as the duration of PHN, but has no impact on the risk of developing PHN [20], [21], [22], [23], [24]. Once PHN is established, it is difficult to treat and patients may be left with potentially debilitating pain for several months or years [15], [25], [26], [27].

The U.S. Food and Drug Administration approved ZOSTAVAX™ [zoster vaccine live (Oka/Merck)] for prevention of HZ (shingles) in individuals ≥60 years of age. As demonstrated in the Shingles Prevention Study, ZOSTAVAX™ has been shown to reduce the incidence of HZ and PHN in adults ≥60 years of age, and lessen acute and chronic pain associated with HZ, presumably through boosting VZV-specific immune responses [28].

The present study was designed to compare the safety and tolerability of 2 zoster vaccine potencies administered to adults ≥50 years of age to provide data on an expanded age group. Given the excellent safety experience of zoster vaccine, occurrences of unusual adverse experiences (AEs) were not anticipated. Past experience with PNEUMOVAX™ 23 (pneumococcal vaccine, polyvalent), a licensed vaccine indicated for routine use in older adults, provided an example of clinically acceptable rates of injection-site AEs.

Section snippets

Study design

This international, randomized clinical trial (blinded to subject, investigator, and sponsor) was conducted at 18 sites in the United States, Canada, United Kingdom, Germany, and Belgium between October 2003 and June 2004. The protocol was approved by the Ethical Review Committee of each site. Healthy, varicella history-positive (or resident for >30 years in a country with endemic VZV infection), HZ history-negative, men and women ≥50 years of age (females had to be postmenopausal or have a

Study population

Of the 698 subjects enrolled in the study, 459 subjects in the higher potency group and 233 subjects in the lower potency group were vaccinated and completed 42 days of postvaccination follow-up (Fig. 1). With regard to gender, age, and race, the frequencies observed were comparable between vaccine potency groups (Table 1), even though a slightly larger proportion of females was enrolled in the higher potency group (61.2% female) than in the lower potency group (57.3% female).

Vaccine safety and tolerability

Clinical follow-up

Discussion

Overall, one dose of the higher potency zoster vaccine (∼207,000 PFU/0.65-mL dose) was generally well tolerated when compared with the zoster vaccine at a lower potency (∼58,000 PFU/0.65-mL dose) when either was administered to subjects ≥50 years of age.

No vaccine-related serious clinical AEs were reported. The serious clinical AEs that were reported by subjects reflected illnesses typical of this age group and did not predominantly involve a specific disease state or body system. The most

Acknowledgements

The authors would like to thank the subjects for their participation in this study and the other members of the Protocol 009 Study Group.ⁱ

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We estimated the relative efficacy and safety of vaccines for prevention of herpes zoster (HZ) using network meta-analysis (NMA) based on evidence from randomized controlled trials.
A systematic literature review evaluated two different HZ vaccines: adjuvanted recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL), with different formulations assessed. Detailed feasibility assessment indicated that a NMA was feasible for efficacy (incidence of HZ and postherpetic neuralgia [PHN]) and safety (serious adverse events [SAE] and reactogenicity [injection-site reactions, systemic reaction]) outcomes. Primary analyses included frequentist NMAs with fixed effects for efficacy outcomes, due to limited data availability, and both fixed and random effects for safety and reactogenicity outcomes. As age is a known effect modifier of vaccine efficacy (VE), VE analyses were stratified by age.
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RZV is significantly more effective in reducing HZ and PHN incidence in adults ≥60 YOA, compared with ZVL. As anticipated with an adjuvanted vaccine, RZV results in more reactogenicity following immunization. No differences in SAEs were found between RZV and ZVL.
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Zoster vaccine is a single dose live, attenuated vaccine (ZVL) indicated for individuals ≥50 years-old for the prevention of herpes zoster (HZ). Safety data from clinical trials and post-licensure studies provided reassurance that ZVL is generally safe and well tolerated. The objective of this review was to provide worldwide post-marketing safety information following 10 years of use and >34 million doses distributed.
All post-marketing adverse experience (AE) reports received worldwide between 02-May-2006 and 01-May-2016 from healthcare professionals following vaccination with ZVL and submitted to the MSD AE global safety database, were analyzed.
A total of 23,556 AE reports, 93% non-serious, were reported. Local injection site reactions (ISRs), with a median time-to-onset of 2 days, were the most frequently reported AEs followed by HZ. The majority of HZ reports were reported within 2 weeks of vaccination and considered, based on time-to-onset, pathogenesis of HZ, and data from clinical trials, to be caused by wild-type varicella-zoster virus (VZV). HZ confirmed by PCR analysis to be VZV Oka/Merck vaccine-strain was identified in an immunocompetent individual 8 months postvaccination and in 4 immunocompromised individuals. Disseminated HZ was reported very rarely (<1%) with 38% occurring in immunocompromised individuals. All reports of disseminated HZ confirmed by PCR as VZV Oka/Merck vaccine-strain were in individuals with immunosuppressive conditions and/or therapy at the time of vaccination.
The safety profile of ZVL, following 10 years of post-marketing use, was favorable and consistent with that observed in clinical trials and post-licensure studies.
STING Is Involved in Antiviral Immune Response against VZV Infection via the Induction of Type I and III IFN Pathways
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The skin is a major site where the signature varicella and zoster lesions appear as cutaneous vesicles; thus, skin-mediated innate immunity against VZV is essential for early control of VZV infection (Zerboni et al., 2014). Although vaccines for varicella and zoster prevention are currently available, the effectiveness of zoster vaccines has been reported to wane over time, particularly in the elderly (Quan et al., 2007; Tyring et al., 2007). Despite the availability of VZV vaccines, the immune response to VZV, which leads to activation of VZV sensing and the antiviral immune response, has not been well characterized.
Varicella zoster virus (VZV) is a human-restricted α-herpesvirus that exhibits tropism for the skin. The VZV host receptors and downstream signaling pathways responsible for the antiviral innate immune response in the skin are not completely understood. Here, we show that STING mediates an important host defense against VZV infection in dermal cells including human dermal fibroblasts and HaCaT keratinocytes. Inhibition of STING using small interfering-RNA or short hairpin RNA-mediated gene disruption resulted in enhanced viral replication but diminished IRF3 phosphorylation and induction of IFNs and proinflammatory cytokines. Pretreatment with STING agonists resulted in reduced VZV glycoprotein E expression and viral replication. Additionally, using RNA sequencing to analyze dual host and VZV transcriptomes, we identified several host immune genes significantly induced by VZV infection. Furthermore, significant up-regulation of IFN-λ secretion was observed after VZV infection, partly through a STING-dependent pathway; IFN-λ was shown to be crucial for antiviral defense against VZV in human dermal cells. In conclusion, our data provide an important insight into STING-mediated induction of type I and III IFNs and subsequent antiviral signaling pathways that regulate VZV replication in human dermal cells.
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Une vaccination contre le zona et ses complications est disponible en France depuis le mois de juin 2015. Son bénéfice pour la santé publique est encore sujet à controverse et son niveau d’efficacité n’assure pas une protection individuelle optimale. Ces raisons semblent suggérer une faible acceptation de la part des médecins vaccinateurs.
Évaluation étendue de l’efficacité, la sécurité, et le rapport coût/bénéfice de la vaccination contre le zona chez les personnes ≥50 ans.
Revue systématique dans Medline et PubMed avec une recherche par mots clés : « herpes zoster vaccine », « zoster vaccine » et « post herpetic neuralgia vaccine ».
Les études randomisées et observationnelles publiées en anglais et en français ont été sélectionnées par deux relecteurs.
Sur 1886 articles répertoriés, 62 études ont été inclues dans la revue systématique dont 21 essais randomisés, 21 études observationnelles et 17 études médicoéconomiques concernaient le vaccin sans adjuvant. L’ensemble des études considérées montraient une efficacité sur le zona de 50 et 60 % sur l’incidence des douleurs postzostérienne du vaccin sans adjuvant. Cinq essais randomisés ont analysé l’efficacité et la sureté du vaccin avec adjuvant. L’efficacité globale du vaccin était > 90 % quel que soit l’âge des sujets y compris après 70 et 80 ans. Les études médicoéconomiques réalisées dans plusieurs pays montraient un bénéfice de la politique de vaccination chez les personnes âgées de 60 ans ou plus.
Les principales informations d’efficacité et de tolérance ne sont apportées que par 2 études contrôlées (SPS et ZEST) pour le vaccin sans adjuvant et une seule pour le vaccin avec adjuvant.
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A vaccination against herpes zoster and its complication is available in France since June 2015. Its exact benefit for public health is still controversial and its level of protection is not optimal. All those reasons seem to suggest a low acceptation rate from general practitioners.
To evaluate the effectiveness, the safety, and the cost/benefit ratio of the vaccination against herpes zoster in people aged 50 year or over.
Systematic review in Medline and PubMed with research by key words: “herpes zoster vaccine”, “zoster vaccine” and “post herpetic neuralgia vaccine”.
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On 1886 articles identified, 62 studies were included in this systematic review of which 21 randomized trials, 21 observational studies, and 17 medico-economic studies concerned the unadjuvanted vaccine. Considered studies showed an effectiveness of 50% against herpes zoster and 60% on post-herpetic neuralgia incidence of the unadjuvanted vaccine. Five randomized controlled studies were identified for the adjuvanted vaccine. The overall effectiveness of this vaccine was > 90% whatever the age of subjects including those over age 70 and 80. The medico-economic studies conducted in many countries have shown that vaccine policies were beneficial in individuals aged 60 years or over.
Most of data of effectiveness, and tolerance result from 2 large controlled studies only (SPS and ZEST) for the unadjuvanted vaccine and only one for the adjuvanted vaccine.
Despite controversy and few uncertainties, the vaccine significantly reduces herpes zoster and its complication incidence. In terms of public health objectives, it reduces the burden of the disease and has a positive medico-economic impact. Preliminary data concerning the adjuvanted vaccine, whilst very promising, are still too limited. Up to now, no group of people with particularly high risk of herpes zoster-related complication who will beneficiate the most of the vaccination has been identified yet and only an age criteria has been considered for the recommendation.

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Safety and tolerability of a high-potency zoster vaccine in adults ≥50 years of age

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study design

Study population

Vaccine safety and tolerability

Discussion

Acknowledgements

J Infect

Pain

Eur J Pain

J Pain Symptom Manage

Postherpetic neuralgia

J R Coll Gen Pract

Herpes zoster

N Engl J Med

Epidemiology of Varicella-Zoster Virus in England and Wales

J Med Virol

Herpes zoster and postherpetic neuralgia: incidence and risk indicators using a general practice research database

Fam Pract

The incidence of herpes zoster

Arch Intern Med