SUPPLEMENT ARTICLE

Humoral and Cellular Immunity to Varicella-Zoster

Virus: An Overview
Ann M. Arvin
Department of Pediatrics, Stanford University School of Medicine, Stanford, California

INNATE IMMUNITY

MEMORY IMMUNITY
Potential conflicts of interest: A.M.A. has received honoraria from Merck, the
manufacturer of the varicella vaccine.
Financial support: supplement sponsorship is detailed in the Acknowledgments.
Reprints or correspondence: Dr. Ann M. Arvin, G312, Dept. of Pediatrics,
Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305
(aarvin@stanford.edu).
The Journal of Infectious Diseases 2008; 197:S5860
 2008 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2008/19705S2-0006$15.00
DOI: 10.1086/522123

S58 JID 2008:197 (Suppl 2) Arvin

The memory immune response that follows the resolution of naturally acquired primary VZV infection is
characterized by the persistence of VZV IgG antibodies
and, in most cases, VZV IgA antibodies, as well as VZVspecific CD4 and CD8 T cells [1]. VZV-specific IgG
antibodies have been shown to bind many VZV proteins and function to mediate neutralization and antibody-dependent cytotoxicity. The overall frequency of

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Under conditions of naturally acquired primary varicella-zoster virus (VZV) infection, the first response of
the naive host is mediated by the innate immune system
through antiviral cytokines and the activation of NK
cells [1]. These responses are likely to be important for
the initial control of VZV at mucosal sites of inoculation and to trigger the induction and amplification
of adaptive, VZV-specific immunity. NK cells can lyse
VZV-infected targets [2], and activated NK cells are a
major source of interferon (IFN)g production, which
enhances the clonal expansion of antigen-specific T
cells. IFN-a inhibits VZV replication in vitro, and treatment with exogenous type I IFN-a reduced the severity
of varicella in immunocompromised children with varicella [3]. In addition, VZV replication in skin is associated with extensive production of IFN-a by adjacent uninfected epidermal cells in the SCIDhu model
of VZV pathogenesis; blocking this IFN-a response
caused a dramatic increase in VZV spread in skin [4].
Innate mechanisms of immune control have the capacity to maintain the host-virus equilibrium, despite
the VZV immune evasion strategies that inhibit both
class I and class II major histocompatibility complex
(MHC) mechanisms for antigen presentation to T cells
while the virus is being transferred to skin and in early
stages of cutaneous infection [46]. These strategies

appear to be effective for delaying the acquisition of

adaptive immunity; VZV-specific T cells were not detected during the incubation period and emerged gradually after the onset of the varicella rash, appearing in
12%, 31%, and 47% of healthy subjects with varicella
who were tested at 1, 2, and 3 days after onset, respectively [7, 8]. Nevertheless, the acquisition of VZVspecific T cells appears to be necessary to prevent
disseminated infection, as suggested by the risk of lifethreatening varicella in children with malignancies or
congenital T cell immunodeficiencies or who are receiving immunosuppression for organ transplantation,
as well as to achieve resolution of the acute infection.
Children with HIV infection are at risk for chronic
varicella, which is consistent with an important role for
VZV-specific cellular immunity [9]. High frequencies
of T cells that lyse targets expressing VZV gE and immediate early (IE) 62 protein are detected in healthy
subjects, but other viral proteins are also likely to be
recognized by VZV-specific T cells during acute varicella [10]. The adaptive immune response to primary
VZV infection also includes the induction of B cells
that make VZV IgG and IgM antibodies, although the
magnitude of this response does not correlate with the
extent of varicella in healthy or immunodeficient children, and B cell immunodeficiencies do not appear to
predispose to severe varicella [11, 12].

VACCINE IMMUNITY
According to current models, memory antiviral immunity is
thought to be a consequence of the magnitude of the expansion
of effector cell populations elicited by primary exposure to the
pathogen [22] (figure 1). Memory immune responses are lower
when the initial immunologic burst is limited, because virusspecific effector cell populations are normally regulated to decrease during the weeks to months after primary sensitization
and expansion. The antigenic signal appears to be the most
important factor in driving the expansion and, therefore, is
expected to have direct consequences for the immunologic set
point of the memory immune response. VZV immune responses peak within a few weeks after naturally acquired infection and decline to a persistent memory response with the
characteristics described earlier. The capacity of the live attenuated varicella vaccine to elicit VZV IgG and T cell immunity

Figure 1. Importance of the initial burst of the adaptive host response for establishing long-term antiviral immunity. VZV, varicella-zoster
virus.

in the naive healthy host was established in the prelicensure

clinical evaluations of the vaccine [23]. As expected, the magnitude of these VZV-specific immune responses was related to
the infectious virus content and to the antigen content of the
vaccine preparation [24, 25]. Host factors also play a role, in
that achieving responses in naive adolescents and adults that
were equivalent to those of younger children required the administration of 2 doses of varicella vaccine. However, providing
2 doses to younger children resulted in higher VZV IgG antibody titers and T cell proliferation responses, and some evidence, as reviewed by Watson [26] in this supplement, suggests
that memory responses were sustained more effectively. This
information has led to the recent recommendation to implement a 2-dose regimen of varicella vaccine in all age groups
[27]. Because varicella epidemics have occurred annually in
temperate climates and primary VZV infection appears to result
invariably in the establishment of latent infection, with the
potential for causing subclinical reactivation, it has not been
possible to determine the relative importance of the primary
host response and subsequent boosting for preserving protective immunity against VZV. By comparison with other live
attenuated vaccines, such as measles vaccine, repeated exogenous or endogenous contact with wild-type VZV will probably
not be required to maintain persistent immunity. However, the
continuation of active and passive surveillance programs to
monitor VZV infections in all age groups, as described in this
supplement, will make it possible to determine whether additional booster doses of varicella vaccine should be given.

Acknowledgments
Supplement sponsorship. This article was published as part of a supplement entitled Varicella Vaccine in the United States: A Decade of Prevention and the Way Forward, sponsored by the Research Foundation for
Microbial Diseases of Osaka University, GlaxoSmithKline Biologicals, the
Sabin Vaccine Institute, the Centers for Disease Control and Prevention,
and the March of Dimes.

Humoral and Cellular Immunity to VZV JID 2008:197 (Suppl 2) S59

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VZV-specific memory T cells with proliferative capacity has

been estimated to be 1:40,000 peripheral blood mononuclear
cells [13]. These cells recognize VZV glycoproteins gE, gB, gC,
and gH and the IE62 protein [7, 14, 15], and most produce
IFN-g and tumor necrosis factora [16]. Among these populations are MHC class I or class IIrestricted cytotoxic T cells
that recognize VZV proteins, including include gC, gE, gI, and
IE62 and IE63 proteins [10, 13, 17, 18]. In VZV-immune
subjects tested 120 years after varicella, the mean  SD frequency of memory cytotoxic T cells specific for IE62 was 1:
105,000  85,000, and that for gE was 1: 121,000  86,000.
The function of VZV IgG antibodies in protecting the host
is presumed to be primarily the neutralization of infectious
VZV at sites of inoculation on reexposure to the virus by contact with individuals who have varicella or herpes zoster (HZ).
Should the virus evade this first line of defense as well as the
local innate responses, it is likely that VZV-specific T cells are
important for preventing symptomatic disease after exogenous
reexposure. In addition, because VZV establishes latency in
sensory ganglia, the adaptive T cell response is needed to prevent symptomatic reactivations of endogenous VZV. The common age-related decrease in VZV-specific T cells or a decrease
resulting from immunosuppressive diseases or therapies is associated with an increased risk of HZ [19]. One hypothesis is
that these exogenous and endogenous exposures to infectious
VZV may promote the maintenance of robust VZV memory
immunity, because household exposure to varicella often results
in boosts in VZV humoral and cellular immune responses, and
HZ stimulates a dramatic increase in VZV IgG antibodies and
VZV-specific T cell frequencies [20, 21]. Alternatively, the persistence of memory immunity may result from the initial clonal
expansion of VZV-specific T cells with helper and effector functions, without any requirement for subsequent restimulation
in the immune host.

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