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Estimating Age-Specific Immunity and Force of Infection of Varicella Zoster Virus in Norway Using Mixture Models.

ABSTRACT: This study applies mixture modelling to examine age-specific immunity to varicella zoster virus (VZV) infection in Norway based on the first large-scale serological study in the general population. We estimated the seropositive proportions at different ages and calculated the underlying force of infection by using a sample of 2103 residual sera obtained from patients seeking primary and hospital care. A rapid increase in the VZV-associated immunity is observed in the first years of life with 63% of children being immune by age 5. The increase in the immunity levels slows down thereafter, with a large proportion of adults still susceptible by age 20 (around 14.5%), thus at risk of serious sequelae of varicella infection. The corresponding force of infection peaks during the preschool period, subsequently declines to a minimum between ages 10 and 20 years, and afterwards moderately increases to reach a plateau lasting throughout the childbearing period. In comparison with the traditional cut-off approach, mixture modelling used the whole data without producing any inconclusive cases, led to an unbiased classification of individuals between susceptible and immune, and provided a smoother immune profile by age. These findings represent an important step towards any decision about the introduction of varicella vaccination in Norway, as they are a primary input for mathematical transmission models aimed at evaluating potential vaccination scenarios.

SUBMITTER: Del Fava E

PROVIDER: S-EPMC5045180 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Estimating Age-Specific Immunity and Force of Infection of Varicella Zoster Virus in Norway Using Mixture Models.

Del Fava Emanuele E Rimseliene Grazina G Flem Elmira E Freiesleben de Blasio Birgitte B Scalia Tomba Gianpaolo G Manfredi Piero P

PloS one 20160930 9

This study applies mixture modelling to examine age-specific immunity to varicella zoster virus (VZV) infection in Norway based on the first large-scale serological study in the general population. We estimated the seropositive proportions at different ages and calculated the underlying force of infection by using a sample of 2103 residual sera obtained from patients seeking primary and hospital care. A rapid increase in the VZV-associated immunity is observed in the first years of life with 63% ...[more]

PMID: 27689800

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Project description:Background:Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Methods:Blood samples were taken pre-, 14?days, 28?days, and 1?year after a primary VZV vaccination (Zostavax) at middle age (N?=?53, 50-65?years of age). VZV-specific IFN?-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Results:Robust short-term enhancement of the VZV-specific IFN?-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFN?-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFN?-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFN?-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFN?-producing cells. Conclusion:These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFN?-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.

Project description:IntroductionHerpes zoster, which can have a major impact on quality of life, results from reactivation of a latent varicella zoster virus (VZV) infection. We hypothesized that giant cell arteritis (GCA) patients are at increased risk of herpes zoster because of treatment with high-dose glucocorticoids and advanced age. Aim of the study, therefore, was to determine cell-mediated and humoral immunity to VZV in patients with GCA, patients with closely related disease polymyalgia rheumatica (PMR; treated with lower doses of glucocorticoids) and healthy controls (HCs).MethodsCell-mediated immunity to VZV was determined by performing interferon-γ (IFNγ) enzyme-linked immunospot and intracellular cytokine flow cytometry measurements in 11 GCA and 15 PMR patients and in 26 age/sex-matched HCs. Immunoglobulin G antibodies to VZV glycoprotein (VZV-IgG) were measured in serum samples of 35 GCA and 26 PMR patients at different times of follow-up and in 58 age and sex-matched HCs by an enzyme-linked immunosorbent assay.ResultsThe number of VZV-specific IFNγ spot-forming cells was significantly lower in GCA patients on treatment, than in age-matched HCs (p = 0.029), but was not different in PMR patients on treatment. Similar levels of VZV-IgG were found in GCA and PMR patients at baseline, compared to HCs.ConclusionThe finding of a decreased cell-mediated immunity to VZV, known to be of great importance in defense to the virus, indicates an increased herpes zoster risk in GCA patients compared to an already at-risk elderly population. Herpes zoster vaccination is, therefore, of special importance in GCA patients, and would ideally be administered at time of diagnosis. Interestingly, as VZV was suggested to be the trigger in GCA pathogenesis, similar levels of VZV-IgG were found in GCA patients at time of diagnosis and age-matched HCs, indicating that GCA patients did not experience herpes zoster substantially more often in the months preceding diagnosis than controls.

Project description:Older age is associated with increased infectious morbidity and decreased immune responses to vaccines, but the mechanisms that mediate this effect are incompletely understood. The efficacy and immunogenicity of the live attenuated zoster vaccine (ZVL) have a very-well-described negative association with the age of the vaccinee. In a study of 600 ZVL recipients 50 to >80 years of age, we investigated immunological factors that might explain the effect of age on the immunogenicity of ZVL. Using FluoroSpot assays and flow cytometry, we determined that varicella-zoster virus (VZV)-specific peak T helper 1 (VZV-Th1) responses to ZVL were independently predicted by prevaccination VZV-Th1 responses, regulatory T cells (Treg), and PD1-expressing immune checkpoint T cells (Tcheck) but not by the age of the vaccinee. Persistence of VZV-Th1 1 year after vaccination was independently predicted by the factors mentioned above, by peak VZV-Th1 responses to ZVL, and by the age of the vaccinee. We further demonstrated by ex vivo blocking experiments the mechanistic role of PD1 and CTLA4 as modulators of decreased VZV-Th1 responses in the study participants. VZV-specific cytotoxic T cell (VZV-CTL) and T follicular helper responses to ZVL did not correlate with age, but similar to other Th1 responses, VZV-CTL peak and baseline responses were independently correlated. These data expand our understanding of the factors affecting the magnitude and kinetics of T cell responses to ZVL in older adults and show the importance of prevaccination Treg and Tcheck in modulating the immunogenicity of ZVL. This presents new potential interventions to increase vaccine responses in older adults.IMPORTANCE Vaccination is the most effective method to protect older adults against viral infections. However, the immunogenicity of viral vaccines in older adults is notoriously poor. The live attenuated zoster vaccine (ZVL) provides the best example of a gradual decrease of vaccine immunogenicity with every 10-year age increase above 50 years. Here we show that the abundance of regulatory T cells before vaccine administration to older adults has a significant inhibitory effect on immune responses to ZVL and, together with baseline immunity to varicella-zoster virus, explains the effect of age on the immunogenicity of ZVL. Moreover, in vitro blockade of regulatory T cell mechanisms of action with biologic modulators restores immune responses to varicella-zoster virus in vaccinees. Collectively, these observations suggest that immune modulators that block regulatory T cell activity may increase responses to viral attenuated vaccines in older adults.

Dataset Information

Estimating Age-Specific Immunity and Force of Infection of Varicella Zoster Virus in Norway Using Mixture Models.

Publications

Estimating Age-Specific Immunity and Force of Infection of Varicella Zoster Virus in Norway Using Mixture Models.

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