Elsevier

Vaccine

Volume 18, Issue 16, 25 February 2000, Pages 1700-1706
Vaccine

Vaccination of immunocompetent elderly subjects with a live attenuated Oka strain of varicella zoster virus: a randomized, controlled, dose-response trial

https://doi.org/10.1016/S0264-410X(99)00510-1Get rights and content

Abstract

After primary infection in childhood, varicella zoster virus (VZV) remains latent in the dorsal route ganglia. Its reactivation later in life can lead to a zoster episode. VZV-specific, T-cell-mediated immunity (VZV-CMI) is likely to be important in preventing symptomatic reactivation. As CMI declines with age, a vaccine enhancing VZV-CMI might be effective in decreasing the incidence or severity of zoster in elderly subjects. A randomized, double blind controlled trial assessing CMI responses of elderly subjects immunized with a live attenuated, VZV-Oka vaccine was conducted. Two hundred healthy volunteers (55–75 years of age) received either a single injection of the VZV vaccine (PMC), containing 3200 (Oka 3200), 8500 (Oka 8500), or 41,650 (Oka 41650) PFU of live VZV, or a pneumococcus vaccine control group (Pneumo 23(®). The immune response to VZV was assessed by measuring the T-cell response to VZV antigens, i.e. proliferation (stimulation index, SI), precursor cell frequency (PCF), cytokine secretion, and antibody titers. Six weeks post-vaccination, VZV-specific SI (adjusted mean values) was significantly greater (P<0.0001) in the 3 vaccine groups (with SI=5.6 for Oka 3200; SI=5.0 for Oka 8500, and SI=7.2 for Oka 41,650) than in the control group (SI=2.9). The increase in PCF was striking, with 72.4, 91.2 and 85.1 precursors per million cells respectively in these 3 vaccine groups, vs 26.3 in the control group. No significant IL-4 secretion was observed in any subject, whereas the presence of IFN-γ secretion was found to correlate with good responder status. The increase of these CMI parameters did not depend upon the titer of virus injected. Geometric mean titers of VZV antibodies increased in all vaccine groups and remained unchanged in the control group. Nevertheless, no correlation between the antibody response and the cell-mediated response was found. Live attenuated VZV vaccine caused a significant increase in VZV-CMI in a healthy, elderly population. No relationship between vaccine dose and the intensity of the specific response was found.

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.

References (20)

  • A Gershon et al.

    Live attenuated varicella vaccine for prevention of herpes zoster

    Biologicals

    (1997)
  • A Arvin

    The T-lymphocyte response to varicella zoster virus and its relevance to vaccine development

    Review in Medical Virology

    (1994)
  • M.W Ragozzino et al.

    Population-based study of herpes zoster and its sequelae

    Medicine (Baltimore)

    (1982)
  • R Berger et al.

    Decrease of the lymphoproliferative response to varicella-zoster virus antigen in the aged

    Infect. Immun.

    (1981)
  • D.E Jenkins et al.

    Interleukin (IL)-10, IL-12, and interferon-gamma production in primary and memory immune responses to varicella-zoster virus

    J. Infect. Dis.

    (1998)
  • Y Zhang et al.

    Cytokine production in varicella-zoster virus-stimulated lymphocyte cultures

    Neurology

    (1995)
  • A.M Arvin et al.

    Equivalent recognition of a varicella-zoster virus immediate early protein (IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype

    J. Immunol.

    (1991)
  • P.S Diaz et al.

    T lymphocyte cytotoxicity with natural varicella-zoster virus infection and after immunization with live attenuated varicella vaccine

    J. Immunol.

    (1989)
  • C Sadzot-Delvaux et al.

    Varicella-zoster virus IE63, a virion component expressed during latency and acute infection, elicits humoral and cellular immunity

    J. Infect. Dis.

    (1998)
  • M Sharp et al.

    Kinetics and viral protein specificity of the cytotoxic T lymphocyte response in healthy adults immunized with live attenuated varicella vaccine

    J. Infect. Dis.

    (1992)
There are more references available in the full text version of this article.

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