There are two VZV vaccines, both of which contain live, attenuated virus. The first to be developed was the varicella (Oka strain) vaccine (Varivax, Merck) which has been used to vaccinate children to prevent varicella (chickenpox) in Japan since 1975 and in the US since 1996. The second vaccine (Zostavax, Merck) is used to prevent zoster in elderly individuals. The only difference between the two vaccines is that Zostavax contains 19,400 pfu per dose, 14-fold more virions than the varicella vaccine. Varivax generates VZV-specific humoral and cell-mediated immune responses, particularly CD8+ T lymphocytes [144
]. The memory cell response that occurs after vaccination protects from infection during re-exposure to VZV.
Zostavax is a live, attenuated virus vaccine indicated for the prevention of herpes zoster in individuals 60 years and older. The most widely used measure of the cell-mediated immune response to VZV in elderly individuals before and after zoster vaccination has been the responder cell frequency [145
]. Indeed, zoster vaccine administered to people over 60 years of age resulted in increased numbers of CD4 and CD8 cells, CD4 and CD8 effector memory T cells, and CD8 early-effector T cells; the half-life of the boost in T cell immunity to VZV is at least 5 years [146
]. Zoster vaccine also boosts VZV-specific immunity in adults with a history of zoster before vaccination or with chronic illness.
The critical trial (Shingles Prevention Study, SPS) of the licensed zoster vaccine was a placebo-controlled, double-blind study of more than 38,000 adults over age 60 years and randomized to receive either zoster vaccine or placebo. All subjects were monitored for zoster. Endpoints included the burden of illness due to zoster and zoster-associated pain as well as the incidence of clinically significant PHN. Subjects received a single dose of Zostavax (n = 19,270) or placebo (n = 19,276). Racial distribution across both vaccination groups was similar: White (95%), Black (2%), Hispanic (1%) and other (1%). The gender distribution was 59% male and 41% female in both groups. The most common side effects reported by participants after zoster vaccination were redness, pain, itching, swelling, warmth or bruising at the injection site and sometimes headache. Varicella-like rashes at the injection site were more common in zoster vaccine than in placebo recipients (0.1% v. 6.4%; p < 0.05).
After a mean follow-up of 3 years, the SPS found that use of the Zostavax vaccine reduced the incidence of zoster by 51%. Subjects in the immunization group who developed zoster reported significantly less pain and discomfort than those in the placebo group, and PHN was less frequent (an overall 61% lower burden of disease). While the vaccine group had a significantly greater risk of a serious adverse event (1.9% v. 1.3%) and experienced more adverse events at the injection site (48.3% v. 16.6%) than the placebo group during the first 42 days after vaccination, no significant differences were seen between zoster vaccine and placebo groups in the incidence of vaccine-related serious adverse events (both <0.1%) at the end of the study.
Baseline immunological measurements from the SPS confirmed that VZV-specific T cell immunity measured by responder cell frequency, as well as by ELISPOT assay, declined continuously with advancing age [147
]. ELISPOT responses peaked at 2 weeks after immunization, with responses at 6 weeks post-immunization approximately 2-fold higher in immunized than in placebo recipients [148
]. All values fell during the first year after immunization, but remained approximately 50% higher than pre-immunization levels for the 3-year study period. Importantly, the boost in VZV-specific T cell-mediated immunity was similar to that developing after naturally occurring zoster [130
]. The magnitude of the boost in cell-medicated immunity to VZV was greatest in younger subjects, consistent with the efficacy of vaccine in preventing zoster which was greater in adults of age 60 to 69 years compared to those more than 70 years of age. The memory responses elicited in older subjects was similar to that seen after vaccination of the elderly with pneumococcal and influenza vaccines. Zoster vaccine was well-tolerated when administered concomitantly or sequentially with an inactivated influenza vaccine or pneumococcal vaccine.
Importantly, in immunized individuals who developed zoster, high VZV-specific cell-mediated immune responses were associated with reduced zoster severity and a lower frequency of PHN than in participants with lower VZV-specific cell-mediated responses, whereas a high humoral response was associated with increased severity of zoster and a higher frequency of PHN than in participants with a lower humoral immune response [130
In the United States, the Center for Disease Control and Prevention Advisory Committee on Immunization Practices recommends zoster vaccine for all persons over the age of 60 years with no prior indications and in persons reporting a previous episode of zoster or who have chronic medical conditions. Although zoster vaccine is not recommended for immunocompromised individuals, it appears that the current zoster vaccine could be safely administered to several groups of moderately immunocompromised adult patients, such as VZV-seropositive HIV patients with CD4 T cell counts greater than 200 cells/ml, or even to patients with rheumatoid arthritis or psoriasis who are receiving moderate doses of methotrexate, steroids or tumour necrosis factor inhibitors [149
]. In addition to the need to test the currently licensed zoster vaccine in moderately immunocompromised patients, higher titre zoster vaccines should be also tested for safety and immunogenicity, especially in light of reports of the safe administration of heat-inactivated VZV vaccine to autologous bone marrow transplant recipients and their accelerated recovery of cell-mediated immunity to VZV and reduced incidence of zoster [134
By 2008, three years after zoster vaccine was licensed and recommended by the Advisory Committee on Immunization Practices for persons age 60 and older, less than 7% of the age group in the US was vaccinated [151
]. This was due to a combination of lack of patient awareness regarding the availability of a vaccine, physicians’ uncertainty about the duration of protection, and different cost-sharing plans for immunization. This is disappointing. Zoster vaccine should be universally administered to all individuals over age 60. Routine immunization is not currently recommended for people age 50-59 because of lack of efficacy data and cost-effectiveness information in this group, but consideration should be given to immunization of this population since 15% of zoster occurs between ages 50 and 59 years.
In the United Kingdom, the live attenuated vaccine against herpes zoster was approved for use in 2006. In England and Wales in people aged 60 or over, there were 88,650 cases and an estimated 18,200 people were still in pain after 3 months. In this age group an estimated 1750 people are hospitalized each year, and herpes zoster is given as the cause of death in 55 cases each year. Zoster generated an overall annual cost to the healthcare system of £17.3m (€20m; $24m), of which £11.5m was related to general practice and the remainder of secondary care. Almost 50% of the total costs related to disease in people aged over 80, because of the higher incidence and likelihood of complications in this group. Vaccination of 65-year-olds at 73.5% coverage was estimated to reduce the lifetime risk of zoster from 15% to 12%, or nearly 11,200 cases. It was also estimated that 1500 fewer cases of postherpetic neuralgia would occur each year, and that vaccination would reduce the annual number of hospitalizations by nearly 150. Vaccination of the 65-year olds was calculated to cost about £23.7m, but would result in savings to the health service of around £1.3m over the lifespan of the cohort, most of which would be saved in primary care. Results from this analysis suggest that immunization is likely to represent a cost-effective intervention for England and Wales, although there is a lost of uncertainty around the duration and range of vaccine-induced protection and the quality adjusted life year loss due to long-term pain. The most cost-effective age to vaccinate is 70 years, or 65 years if the vaccine does not offer additional protection against the severity of disease [152
Several important questions regarding zoster vaccines remain. How many years will the current zoster vaccine maintain immunity to prevent zoster? Is zoster vaccine safe for immunocompromised individuals? Will a killed VZV vaccine produce a significant increase in cell-mediated immunity to VZV? Should multiple vaccinations of the elderly every decade of life after age 60 be considered? Should zoster vaccine be refined to include epitopes that induce cell-mediated immunity to VZV?