The impact of demographic changes, exogenous boosting and new vaccination policies on varicella and herpes zoster in Italy: a modelling and cost-effectiveness study.

BACKGROUND: The present study aims to evaluate the cost-effectiveness of the newly introduced varicella and herpes zoster (HZ) vaccination programmes in Italy. The appropriateness of the introduction of the varicella vaccine is highly debated because of concerns about the consequences on HZ epidemiology and the expected increase in the number of severe cases in case of suboptimal coverage levels. METHODS: We performed a cost-utility analysis based on a stochastic individual-based model that considers realistic demographic processes and two different underlying mechanisms of exogenous boosting (temporary and progressive immunity). Routine varicella vaccination is given with a two-dose schedule (15 months, 5-6 years). The HZ vaccine is offered to the elderly (65 years), either alone or in combination with an initial catch-up campaign (66-75 years). The main outcome measures are averted cases and deaths, costs per quality-adjusted life years gained, incremental cost-effectiveness ratios, and net monetary benefits associated with the different vaccination policies. RESULTS: Demographic processes have contributed to shaping varicella and HZ epidemiology over the years, decreasing varicella circulation and increasing the incidence of HZ. The recent introduction of varicella vaccination in Italy is expected to produce an enduring reduction in varicella incidence and, indirectly, a further increase of HZ incidence in the first decades, followed by a significant reduction in the long term. However, the concurrent introduction of routine HZ vaccination at 65 years of age is expected to mitigate this increase and, in the longer run, to reduce HZ burden to its minimum. From an economic perspective, all the considered policies are cost-effective, with the exception of varicella vaccination alone when considering a time horizon of 50 years. These results are robust to parameter uncertainties, to the two different hypotheses on the mechanism driving exogenous boosting, and to different demographic projection scenarios. CONCLUSIONS: The recent introduction of a combined varicella and HZ vaccination programme in Italy will produce significant reductions in the burden of both diseases and is found to be a cost-effective policy. This programme will counterbalance the increasing trend of zoster incidence purely due to demographic processes.

Combination Measles-Mumps-Rubella-Varicella Vaccine in Healthy Children: A Systematic Review and Meta-analysis of Immunogenicity and Safety.

A combined measles-mumps-rubella-varicella (MMRV) vaccine is expected to facilitate universal immunization against these 4 diseases. This study was undertaken to synthesize current research findings of the immunogenicity and safety of MMRV in healthy children.We searched PubMed, Embase, BIOSIS Previews, Web of Science, Cochrane Library, and other databases through September 9, 2014. Eligible randomized controlled trials (RCTs) were selected and collected independently by 2 reviewers. Meta-analysis was conducted using Stata 12.0 and RevMan 5.3.Twenty-four RCTs were included in qualitative synthesis. Nineteen RCTs compared single MMRV dose with measles-mumps-rubella vaccine with or without varicella vaccine (MMR + V/MMR). Similar seroconversion rates of these 4 viruses were found between comparison groups. There were comparable geometric mean titers (GMTs) against mumps and varicella viruses between MMRV group and MMR + V/MMR group. MMRV group achieved enhanced immune response to measles component, with GMT ratio of 1.66 (95% confidence interval [CI] 1.48, 1.86; P < 0.001) for MMRV versus MMR and 1.62 (95% CI 1.51, 1.70; P < 0.001) for MMRV versus MMR + V. Meanwhile, immune response to rubella component in MMRV group was slightly reduced, GMT ratios were 0.81 (95% CI 0.78, 0.85; P < 0.001) and 0.79 (95% CI 0.76, 0.83; P < 0.001), respectively. Well tolerated safety profiles were demonstrated except higher incidence of fever (relative risks 1.12-1.60) and measles/rubella-like rash (relative risks 1.44-1.45) in MMRV groups.MMRV had comparable immunogenicity and overall safety profiles to MMR + V/MMR in healthy children based on current evidence.

Development of an IFN-γ ELISpot assay to assess varicella-zoster virus-specific cell-mediated immunity following umbilical cord blood transplantation.

Varicella zoster virus (VZV) is a significant cause of morbidity and mortality following umbilical cord blood transplantation (UCBT). For this reason, antiherpetic prophylaxis is administrated systematically to pediatric UCBT recipients to prevent complications associated with VZV infection, but there is no strong, evidence based consensus that defines its optimal duration. Because T cell mediated immunity is responsible for the control of VZV infection, assessing the reconstitution of VZV specific T cell responses following UCBT could provide indications as to whether prophylaxis should be maintained or can be discontinued. To this end, a VZV specific gamma interferon (IFN-γ) enzyme-linked immunospot (ELISpot) assay was developed to characterize IFN-γ production by T lymphocytes in response to in vitro stimulation with irradiated live attenuated VZV vaccine. This assay provides a rapid, reproducible and sensitive measurement of VZV specific cell mediated immunity suitable for monitoring the reconstitution of VZV specific immunity in a clinical setting and assessing immune responsiveness to VZV antigens.  

Interferon-gamma release assay: a simple method for detection of varicella-zoster virus-specific cell-mediated immunity.

Herpes zoster is closely related to decreased varicella-zoster virus (VZV)-specific cell-mediated immunity. We validated a new assay for measuring VZV-specific immunity. We cultured the whole blood of healthy subjects with live attenuated VZV vaccine. Cultured supernatants were harvested at 24-h intervals and assayed for interferon-gamma (IFN-gamma) by an enzyme-linked immunosorbent assay (ELISA). The 48-h culture was suitable for estimating IFN-gamma release. IFN-gamma production was stable after standing for at least 4h at room temperature. IFN-gamma production was observed in whole blood from subjects with recent VZV infection, but not in blood from subjects naïve to the virus. Thus, the IFN-gamma release assay may be useful as a new surrogate assay for measuring VZV-specific immunity.

Varicella-zoster vaccine in the USA: success for control of disease severity, but what next?

In the period from 1990 to 1994, before the introduction of a varicella vaccine to the USA, approximately 100 deaths in otherwise healthy individuals, children and adolescents under 20 years of age, were attributable to varicella complications. The administration of a single-dose vaccine has now been widespread in the USA for nearly 10 years; however, since the effectiveness of a single dose in children under 13 years of age in an outbreak situation is approximately 80%, consideration of a second booster dose is in progress although not yet recommended. Licensure of a measles-mumps-rubella-varicella vaccine may hasten the recommendation.

Varicella susceptibility and vaccine use among young adults enlisting in the United States Navy.

Primary varicella infection, or chicken pox, is a threat to all young adults who join the United States (U.S.) military if they fail to develop immunity prior to enlistment. Historically, outbreaks of chicken pox have caused marked morbidity and impaired military readiness. In December 1996, the U.S. Navy began performing serologic testing for varicella among all new recruits, and vaccinating those found to be sero-negative. We evaluated results of the screening program in its first 4 years, and used multivariable logistic regression modeling to describe factors associated with varicella susceptibility. Cases of chicken pox were tracked among all military services before and after program implementation. More than 190,000 young adults enlisted in the U.S. Navy between 1997 and 2000. Recruits originated from all 50 states and several foreign countries; 84% were male, and their average age was 19 years. Seven percent were found to be susceptible (sero-negative) to varicella. In multivariable modeling, race/ethnicity was associated with susceptibility, but age, gender, and home state were not. The overall incidence of chicken pox in the Navy was reduced by more than 80% after initiation of the screening-vaccination program. A successful varicella screening-vaccination program has been implemented in the U.S. Navy. Results of serologic screening undertaken on this large number of young adults may be useful in tracking the changing epidemiology of varicella in the general population in the post-vaccine era.

Varicella vaccination: impact of vaccine efficacy on the epidemiology of VZV.

In 1995, varicella vaccination was introduced into the infant immunization schedule of the United States. Currently, many other countries are considering mass varicella vaccination. Mass vaccination has two dangers: it could increase the number of varicella cases in adults, where severity is greater, and increase cases of zoster. A deterministic, realistic, age-structured model (RAS) was built to study these concerns. Model parameter estimates were derived from a review of the literature and surveillance data from England and Wales. Different vaccine efficacy scenarios, vaccine coverages, and vaccination strategies were investigated. The model predicts that, although an upward shift in the age at infection occurs, the overall morbidity due to varicella is likely to decrease following mass infant vaccination. On the other hand, cases of zoster may significantly increase in the first 50 years following vaccination. The model predicts that, in a population similar to England and Wales (50 m people), varicella vaccination with 90% coverage would prevent 0.6 m inpatient days due to varicella but would generate an extra 1.1 m inpatient days due to zoster over the first 65 years. Thus, under base-case model assumptions, the gain in reduction of varicella morbidity from infant vaccination is offset in the short-term by the increases in zoster morbidity (using inpatient days as a proxy). Paradoxically, less effective vaccines or vaccine programmes can be more effective in reducing overall morbidity (varicella + zoster) by allowing the virus to circulate more, which produces a smaller shift in the age at infection and a smaller increase in zoster cases.

Varicella in Americans from NHANES III: implications for control through routine immunization.

At the time of varicella vaccine introduction in the United States, an estimated 4 million episodes of varicella occurred annually. This survey of varicella seroprevalence is the first to describe immunity to a vaccine-preventable disease prior to vaccine introduction in the United States population. The objective of this analysis is to describe patterns of naturally-acquired varicella and understand characteristics associated with infection in the varicella vaccine-naive United States population. A nationally representative cross-sectional health examination survey that included venipuncture was conducted among 21,288 U.S. participants aged 6 years and older from 1988 through 1994. Serologic evidence of varicella-zoster virus infection was measured by enzyme immunoassay of varicella-zoster virus-specific IgG antibody. The seroprevalence of IgG antibody to varicella-zoster virus increased from 86.0% in children aged 6 through 11 years to 99.6% in adults aged 40 through 49 years. Immunity to varicella remained at 99% or higher in Americans aged 50 years and older. Among persons aged 6 through 19 years, non-Hispanic black children were 40% less likely to be seropositive compared with white children (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.4-0.8). Among young adults aged 20 through 39 years, women with a history of live birth (OR, 4.3; 95% CI, 2.1-8.7) and married men (OR, 2.7; 95% CI, 1.2-5.7) were more likely to have naturally-acquired immunity to varicella. This study found that, prior to use of varicella vaccine in the United States, age, race, and marital characteristics were independently associated with naturally acquired varicella. Future varicella serosurveys in Americans will provide essential information to interpret the population impact of varicella vaccine.

Varlirix (GlaxoSmithKline).

GlaxoSmithKline (formerly SmithKline Beecham) has developed and launched Varilrix, a preparation of live, attenuated Oka-strain varicella zoster virus, for immunization against varicella zoster infections [455138]. By the end of 1998, Varilrix was available in a few European countries and in India [284490], [455138]. By 2001, the vaccine was also available in Brazil and Hong Kong [396267].

Age-specific seroprevalence to varicella-zoster virus: study in Swiss children and analysis of European data.

Up to date epidemiological data provide the rationale for potential varicella immunization strategies in Europe. The scope of this study was: (1) to generate new seroprevalence data by evaluating sera of 970 individuals aged 0-16 years for the presence of IgG against Varicella-zoster virus (VZV); and (2) to review existing seroprevalence data. Of 256 individuals >12 years of age, 96.1% (95% confidence interval [CI], 93.7-98.5) were seropositive. Swiss citizens > 12 years of age were less likely to be seronegative than foreign citizens (2.3 vs. 15.4%; odds ratio, 0.17; CI, 0.05-0.58). The age-specific seroprevalence curve demonstrated a peak at 7 years of age (84.9%; CI, 75.2-94.5) followed by lower rates at 8 and 9 years. A peak at 7-10 years of age was found in all previously reported seroprevalence curves (chi(2)-test for trend of pooled data, P = 0.09; Poisson analysis, P < 0.001). It is concluded that: (1) > 90% of individuals in Europe acquire immunity against VZV before adolescence; (2) there is no evidence for a recent upward shift of the age at primary varicella; and (3) there may be a north-to-south gradient of seroprevalence. The peak at 7-10 years may represent a transient loss of detectable antibody by some individuals.

Experience with live attenuated varicella vaccine (Oka strain) in healthy Japanese subjects; 10-year survey at pediatric clinic.

Live attenuated varicella vaccine (Oka strain, Biken Institute, Osaka, Japan) was administered to 973 healthy individuals over a 10-year period (1987-1997) at the pediatric clinic of Showa Hospital in Japan. We evaluated the relevant serological and clinical data, which were collected by questionnaire. Seroconversion by the immune adherence hemagglutination method was documented in 94% (805/860) of the initially seronegative subjects. Of the initially seropositive subjects, 56% (63/113) showed enhancement of antibody after vaccination. Reactions to the vaccine were generally insignificant, except for a rash at the injection site, seen in the first 3 days post-administration in 17% (41/241) of the recently vaccinated subjects. In March 1998, we conducted a survey of 559 of the initially seronegative subjects who had received the vaccine 0.6-10. 8 (mean 5.4) years earlier. Of these subjects, 21% (119/559) contracted breakthrough varicella. However, their symptoms were milder than those caused by natural varicella seen in unvaccinated children. Seroconversion was demonstrated in 92% (109/119) of these cases. The incidence of breakthrough disease decreased with a rise in postvaccination antibody titer to >==32. Four of the subjects (0.7% of 559) developed herpes zoster following vaccination, two of whom had earlier exhibited breakthrough varicella. Lesions in one case of zoster, without breakthrough varicella, appeared on the cervical dermatome at the injection site. The vaccine was safe and effective. However, there was a relatively high incidence of rash at the injection site with certain lot numbers used in recent years which warrants investigation.

The value of varicella vaccination in healthy children: cost-benefit analysis of the situation in France.

The purpose of the cost-benefit analysis described in this article is to determine the economic value of vaccination of healthy children against varicella in France. It is based on the results of two specific investigations--an epidemiological model and a prospective observational study (1832 cases studied) of the socio-economic consequences of varicella. This cost-benefit analysis was conducted from the viewpoint of the society and that of the patient, for vaccination coverage rates ranging from 10 to 90%. This analysis demonstrates the value of varicella vaccination when associated with measles-mumps-rubella (MMR) vaccination: if varicella and MMR vaccines are co-administered, the vaccination of 80% of the children against varicella leads to a reduction in medical costs associated with varicella including that of vaccination, ranging from 10 to 77% according to the values adopted for vaccination costs, varicella treatment costs, discount rate and vaccine efficacy. The results of this study also underline the benefits of a vaccination policy that aims to achieve a high rate of coverage, thereby reaping the highest benefit from vaccination, and also avoiding potential negative consequences.

Immune response to varicella-zoster virus glycoproteins in guinea pigs infected with Oka varicella vaccine.

A varicella skin test antigen has been developed based on the induction of delayed-type hypersensitivity to varicella-zoster virus (VZV), and has been used to evaluate the immune status to VZV. The authors have purified gB, gE:gI and gH:gL and examined their cutaneous reactivity in guinea pigs infected with Oka varicella vaccine. The cutaneous reaction to each glycoprotein was observed and the maturation process of cutaneous reaction was examined in infected guinea pigs. Cutaneous reaction to gH:gL, a major target of virus-neutralizing antibody, appeared first on day 3 among three glycoprotein complexes and the reaction to gE:gI, the most abundant glycoprotein, became strongest three weeks after infection. The earliest recognition of gH:gL may contribute to minimizing the spread of viral infection. Thus, the skin test may be a suitable marker to assess the cell-mediated immunity in varicella, including vaccine recipients and zoster, in relation to the immune status of glycoproteins.