Vaccination of immunocompetent elderly subjects with a live attenuated Oka strain of varicella zoster virus: a randomized, controlled, dose-response trial
Introduction
In humans, varicella zoster virus (VZV) is responsible for chickenpox during primary infection and shingles during reactivation episodes later in life. After primary infection, VZV remains latent in the dorsal route ganglia of the nervous system [1]. Its reactivation, later in life, gives rise to shingles that can be characterized by unilateral neuralgia followed by vesiculobullus eruption. It is estimated that over a lifetime approx. 15% of VZV infected individuals will eventually develop zoster [2]. The incidence of herpes zoster is higher in adults above 55 years old, in subjects that were infected before 1 year of age and in immunocompromized people. Several articles [2], [3], [4] demonstrated that the risk of VZV reactivation is inversely correlated to the level of host’s VZV-specific T cell mediated immunity, suggesting that T cells play an important role against herpes zoster whereas no correlation was ever observed with VZV specific humoral response. Jenkins et al. as well as Zhang et al. [5], [6] have shown that VZV specific T cells secrete IFN-γ and have an exclusive Th1 phenotype both in naturally infected and vaccinated normal healthy adults. Several studies [7], [8], [9], [10] also demonstrated the existence of a high frequency of VZV-specific CTL to a variety of antigens (gpI, IE62, IE63) in naturally infected young adults. They found this frequency lower in elderly subjects, also suggesting a role of these cells in protection against herpes zoster.
Altogether, these data strongly suggest that it would be possible to protect elderly from zoster reactivation by boosting their VZV-specific cellular immune response. Berger et al. [11] were the first to demonstrate that it is possible to enhance VZV-specific cell mediated immunity by immunization with a live attenuated strain of VZV. These results were then confirmed by Levin et al. [12] who vaccinated a cohort of 202 healthy elderly subjects with one or two doses of different concentrations of a live, attenuated VZV-Oka vaccine and demonstrated that both humoral and cellular VZV-specific immune responses can be enhanced. Moreover, the six-year follow up suggests that the vaccination with VZV-Oka may decrease the severity of zoster episodes. Recent publications reporting vaccination of immunocompromized subjects also demonstrated a decrease in zoster severity among vaccinated subjects [13], [14].
Vaccination with live, attenuated VZV vaccine thus represents a potential strategy for preventing herpes zoster in the elderly population or at least decreasing symptoms associated to this reactivation such as post-neuralgia pain. A randomized, double blind controlled trial in 200 healthy elderly subjects was conducted by Pasteur Mérieux Connaught to evaluate the cell-mediated and humoral immune responses of three doses of a live, attenuated VZV-Oka strain vaccine, manufactured by Pasteur Mérieux Connaught, compared to a control vaccine. Specificity and phenotype of these cells were also investigated.
Section snippets
Study population and design
This study was described in detail in a precedent paper from Berger et al. [15]. Briefly, healthy elderly subjects, age over 55 years, with positive serology for VZV and a competent immune system (no sign of immunodeficiency) were randomly assigned to one of the four vaccine groups. Three groups received a subcutaneous injection of live VZV-Oka [concentrations 3200, 8500 or 41,650 PFU (plaque forming unit) per dose] under double-blind conditions, whereas the fourth one received a licensed
Response to whole VZV-Ag fraction
In vitro lymphoproliferation assays were performed with three consecutive dilutions of VZV-Ags, 1/600, 1/3000 and 1/15,000 referred to as VZV-600, VZV-3000 and VZV-15000 and their respective control MRC5 600, 3000 and 15,000. Pre-tests with naturally immune young adult PBMCs had given the best results with these three doses (data not shown). Only the VZV-3000 concentration will be presented below.
Table 1 shows the mean T cell stimulation index (SI) in response to VZV-3000 concentration before,
Discussion
Three different formulations of a VZV-Oka strain vaccine were standardized for a content of 3200, 8500 and 41,650 live virus particles per vaccine dose and tested in elderly healthy subjects. All parameters for a cell-mediated immune response (lymphocyte proliferation, precursor cell frequency and IFN-γ production) and the geometric mean titer of VZV antibody [15] were significantly higher at day 42 in the three groups who had received the VZV-Oka vaccine, compared to the control group
Acknowledgements
We would like to thank Pierre Meulien who made this work possible, Catherine Caillet for her helpful review of the manuscript and Catherine Rossignol for her assistance.
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Risk of recurrent herpes zoster in a population-based cohort study of older adults
2021, Journal of the American Academy of DermatologyCitation Excerpt :This could be a real decrease or it may be an artifact from using the 180-day time interval to define the first zoster episode, because when we used 90 days, the decreased incidence in the first year disappeared (see Supplementary Fig 1; available via Mendeley at https://doi.org/10.17632/vkxmd63vkc.2). It has been suggested that a first episode of zoster protects individuals against a recurrence by boosting cell-mediated immunity,7 and this hypothesis is supported by immunological studies26 and the proven effectiveness of live-attenuated zoster vaccines against zoster incidence.27-29 However, we observed a lower incidence of zoster only in those with a prior episode in the first year after the first zoster.
Zoster Vaccines
2017, Plotkin's VaccinesThe vaccine against shingles: Your questions and their answers
2015, NPG Neurologie - Psychiatrie - GeriatrieComparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged ≥50 years: A randomised non-inferiority clinical trial
2015, VaccineCitation Excerpt :Zostavax® (commercialised in Europe by Sanofi Pasteur MSD, manufactured by Merck Sharpe and Dohme) is a live, attenuated VZV vaccine developed specifically for the prevention of HZ and PHN in individuals aged ≥50 years [33]. The vaccine boosts VZV-specific cell-mediated immunity (CMI); this boosted CMI controls reactivation of the latent VZV and/or replication and, therefore, prevents herpes zoster or attenuates its severity [17,34–39]. In the large-scale Shingles Prevention Study (SPS) involving more than 38,000 subjects aged ≥60 years, vaccine efficacy for the prevention of HZ was 63.9% (95% confidence interval (CI): 55.5–70.9) in individuals aged 60–69 years, and 37.6% (95% CI: 25.0–48.1) in those aged ≥70 years [40,41].