Varicella-zoster Virus Immunity Research Articles

PA34 A case of disseminated herpes zoster in an immunocompetent child

Abstract Herpes zoster (HZ) caused by the reactivation of varicella-zoster virus (VZV) affects mainly the adult population. The incidence is low in children (0.45 cases per 1000 individuals annually), especially in the immunocompetent. It is said to be disseminated when there are > 20 lesions outside the primary and adjacent affected dermatome. We present this case to highlight a rare complication of cutaneous dissemination in a previously healthy child with HZ, following in utero exposure to varicella at 28 weeks’ gestation. A 15-year-old boy presented with painful blisters in the T2 dermatome of 1 week’s duration, which later spread to trunk, extremities and face. This was associated with fever and neuralgia. There was no previous history of varicella and no recent contact history. He had no significant past medical history and was not on any medications. Antenatal history revealed that his mother had varicella at 28 weeks’ gestation and was treated with aciclovir. He was febrile on admission (39°C). There were coalesced vesiculopustules and crusted lesions with marked perilesional erythema in the T2 dermatome. In addition, disseminated vesicular lesions were seen on the trunk, extremities and face. Remaining systemic examination was unremarkable. C-reactive protein was elevated. Complete blood count and renal function tests were normal. Liver function tests, namely alanine transaminase and γ-­glutamyl transferase were elevated. Blood culture showed no growth. Varicella-zoster IgG was positive. Viral swab (polymerase chain reaction) from the skin lesions was positive for varicella-zoster DNA. Infectious serology for HIV, hepatitis B and hepatitis C was negative. Antinuclear antibody and antineutrophil cytoplasmic antibodies were negative. A clinical diagnosis of HZ with cutaneous dissemination was made, and he was treated with intravenous aciclovir. Intravenous antibiotics were added for suspected secondary bacterial infection. Disseminated zoster is less common in children and mainly occurs in patients with underlying immunodeficiency like HIV, immunosuppressive drug use or malignancy. In immunocompetent children, this can happen when primary infection (varicella) has occurred in utero or the first year of life due to the low response in specific varicella-zoster virus immunity. Complications like cutaneous dissemination due to viraemia are rare in healthy children, but can affect 2–10% of immunocompromised patients. It occurs 3–4 days after the onset of dermatomal lesions. It is important to look for other complications, especially in the immunocompromised, as viraemia can affect the brain, kidneys, lung and liver. Sequelae like postherpetic neuralgia is rare, but it is important to follow-up these children to look for its development.

Cellular Immune Response after Vaccination with an Adjuvanted, Recombinant Zoster Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplant (HSCT) recipients have a high risk of developing primary varicella-zoster virus (VZV) infection and reactivation. VZV vaccination may prevent infection and reactivation. In the current study, recipients of allogeneic HSCT (34 females, 45 males) were vaccinated with adjuvanted, recombinant zoster vaccine Shingrix™, which contains the VZV glycoprotein E. Cellular immunity against various VZV antigens was analyzed by interferon-gamma ELISpot. Peripheral blood mononuclear cells (PBMC) of recipients with versus without prior shingles (n = 36 and n = 43, respectively) showed approximately twofold higher VZV-specific responses prior to and post vaccination. After the first and second vaccination, ELISpot responses towards the glycoprotein E were significantly higher in males versus females (median of spots increment 18 versus 1 and 17 versus 4, respectively, p ≤ 0.02 each). Multivariate analysis showed that shingles and sex both impacts significantly on VZV immunity. Whereas vaccination-induced changes could hardly be detected after stimulation with a whole VZV antigen, there was a significant increase in responses towards glycoprotein E after vaccination (p < 0.005). These data indicate that vaccination with Shingrix™ augmented cellular, VZV-specific immunity in HSCT recipients. Shingles and male sex could both be identified as factors leading to increased immunity.

P402 Incidence and outcomes of herpes zoster in the ozanimod phase, 3 ulcerative colitis and relapsing multiple sclerosis clinical program

Abstract Background Patients with ulcerative colitis (UC) and patients with multiple sclerosis (MS) have an elevated risk of developing herpes zoster (HZ), caused by reactivation of latent varicella zoster virus (VZV). Increased incidence of HZ has been reported with sphingosine, 1-phosphatase (S1P) receptor modulators. This analysis examined the number of patients who failed screening due to a lack of demonstrated VZV immunity and the incidence of HZ from completed phase, 3 ozanimod clinical trials. Methods Safety results were included from True North (52-week trial) in patients with UC, and SUNBEAM (12-month trial), and RADIANCE (24-month trial) in patients with MS. All patients were required to have had a positive VZV IgG antibody status or completed VZV vaccination ≥30 days prior to randomization based on known effects of S1P modulators. Patients with a negative VZV antibody titer could choose to receive the VZV vaccination to qualify for the trial. Number of pre-screen failures because of lack of demonstrated immunity, occurrence of HZ, and association between HZ cases and lymphopenia were analyzed. Results Of, 1831 patients with UC screened for VZV immunity, 104 (5.7%) failed screening due to lack of documentation of VZV antibody or VZV vaccination ≥30 days before randomization;, 22% (23/104) subsequently received varicella vaccination and were rescreened and enrolled. Of, 3332 MS patients tested for VZV immunity, 309 (9.3%) tested negative and, 32% (98/309) of these patients were vaccinated prior to randomization. In the UC and MS trials, the incidence of HZ cases was low in ozanimod-treated patients (8 cases [1.0%] and, 5 cases [0.6%], respectively; Table, 1). All cases were distributed across a single dermatome, did not result in a complication of HZ, and were treated with oral antivirals while patients remained on ozanimod. None of the patients discontinued ozanimod because of HZ and none of the HZ cases were associated with grade, 4 lymphopenia (defined as an absolute lymphocyte count &amp;lt;0.2 x, 109/L). Conclusion In the ozanimod phase, 3 UC and MS trials, 5%–10% of patients screened did not have demonstrated VZV immunity;, 22%–32% of these patients received varicella vaccination, were rescreened and enrolled. The overall HZ incidence in clinical trials was low (≤1% of patients), all cases were distributed across a single dermatome, and no serious or complicated cases occurred in ozanimod-treated patients with VZV immunity. Additional studies are warranted to evaluate the incidence of HZ in clinical practice.

Clinical Manifestations of Herpes Zoster Associated with Complications in Children.

Herpes zoster (HZ) is caused by latent varicella-zoster virus (VZV) reactivation when VZV-specific cell-mediated immunity declines. Information on HZ in children is limited. Therefore, we retrospectively investigated HZ’s clinical course and complications in children. We extracted the outpatient and hospitalization medical records of pediatric patients (<19 years) primarily diagnosed with HZ (ICD-10 B02 code) between January 2010 and November 2020. HZ was defined as a typical unilateral dermatomal vesicular rash where HZ was the treating physician’s primary diagnosis. Recognized HZ complications included combined bacterial skin infection, ophthalmic zoster, zoster oticus without facial paralysis, meningitis, and PHN. We identified 602 HZ cases, among which 54 developed HZ complications and were included in our analysis. The median age was 14.7 years, most patients were aged ≥13 years (42, 79%), and none were aged <4 years. Fifty-three were immunocompetent, and only one had systemic lupus erythematosus. The most frequent complication was zoster ophthalmicus (n = 26, 48%). HZ complications were also observed in immunocompetent or vaccinated children exhibiting a head or neck rash before and after VZV immunization. Current VZV vaccination programs may be insufficient in preventing HZ complications. Therefore, close varicella and HZ burden monitoring and the establishment of effective VZV vaccination programs are imperative.

Cross-Sectional Study of Varicella Zoster Virus Immunity in Healthy Korean Children Assessed by Glycoprotein Enzyme-Linked Immunosorbent Assay and Fluorescent Antibody to Membrane Antigen Test.

The prevalence of varicella is especially high among children in the age group of 4–6 years in South Korea, regardless of vaccination. We investigated the immune status of healthy children enrolled in day-care centers and compared pre- and post-vaccination immunity. Antibody titers were measured using a glycoprotein enzyme-linked immunosorbent assay (gpEIA) kit, and the seroconversion rate was assessed using a fluorescent antibody to membrane antigen (FAMA) test. Among 541 vaccinated children, 109 (20.1%) had breakthrough varicella. However, 13 (72.2%) of the 18 unvaccinated children had a history of varicella. The gpEIA geometric mean titers (GMTs) of pre- and 5 weeks post-vaccination in 1-year-old children were 14.7 and 72 mIU/mL, respectively, and the FAMA seroconversion rate was 91.1%. The gpEIA GMTs of 2-, 3-, 4-, 5-, and 6-year-old children were 104.1, 133.8, 223.5, 364.1, and 353.0 mIU/mL, respectively. Even though the gpEIA GMT increased with age, the pattern of gpEIA titer distribution in 4- to 6-year-old vaccinees without varicella history represented both waning immunity and natural boosting immunity. These results suggest that some vaccinees are vulnerable to varicella infection. Therefore, it is necessary to consider a two-dose varicella vaccine regimen in South Korea.

Humoral Immunity to Varicella Zoster Virus in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis Compared to Healthy Controls.

Background: The prevalence of herpes zoster (HZ) is high in patients with rheumatic diseases. Systemic lupus erythematosus (SLE) doubles the risk for developing HZ. However, little is known about natural humoral immunity against varicella zoster virus (VZV) in patients with SLE. Hence, we compared VZV IgG antibody concentrations in a group of SLE patients with healthy controls and patients with rheumatoid arthritis (RA). Methods: n = 56 patients with SLE, n = 54 patients with RA, and n = 56 healthy controls were included in this study. The VZV IgG antibody concentration was measured using an enzyme-linked immunosorbent assay (ELISA). The antibody concentrations were compared between the groups. Results: Overall IgG antibody titers for VZV in SLE patients were comparable to healthy controls but higher when compared to patients with rheumatoid arthritis (p = 0.0012). In consequence, antibody levels in controls were higher than in RA patients (p = 0.0097). Stratification by age revealed highest titers among SLE patients in the fourth life decade (p = 0.03 for controls, p = 0.0008 for RA patients) whereas RA patients in their sixth decade had the lowest antibody concentration (p = 0.03 for controls, p = 0.04 for SLE patients). Regarding the individual HZ history, antibody levels of SLE patients with a positive history exceeded all other groups. Conclusions: Although humoral VZV immunity in SLE patients is comparable to healthy controls it seems to be pronounced in young SLE patients between 30 and 39. The lowest VZV IgG levels were found in RA patients. HZ seems to induce antibody production, particularly in patients with SLE. Immunological processes might contribute to VZV antibody levels in SLE patients, but further investigations are needed to substantiate this hypothesis. Even though the increased HZ prevalence seems to be independent of humoral immunity in SLE patients, reduced humoral immunity might contribute to HZ in RA patients. The available HZ subunit vaccination might be an appropriate way to reduce the HZ risk in patients with rheumatic diseases.

Use of specific pesticides is associated with increased risk of developing shingles in the Agricultural Health Study

BACKGROUND: Some pesticides are immunotoxic and may increase risk of immune-mediated diseases. Risk of shingles, the clinical reactivation of varicella zoster virus (VZV), increases with aging and immunosuppression; little is known about associations with pesticides. OBJECTIVE: We evaluated pesticide use in relation to incident shingles among licensed pesticide applicators in the Agricultural Health Study, a prospective cohort in Iowa and North Carolina. METHODS: We identified 590 incident shingles cases among 12,820 applicators (97% male farmers) enrolled in 1993-7 and followed for a median of 12 years (IQR 11,13). We evaluated associations with ever-use of 48 pesticides reported at enrollment and examined exposure-response trends for cumulative intensity-weighted lifetime days of use. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models, adjusting for state and correlated pesticides, and allowing estimates to vary by median age of cases (60 years). RESULTS: Shingles risk was associated with ever-use of 14 pesticides (5 insecticides, 2 fumigants, 2 fungicides, and 5 herbicides (HRs 1.22 to 1.94). Increasing exposure-response trends (p&lt;0.01) were seen for four insecticides (coumaphos, carbaryl, diazinon, permethrin on crops), two fumigants (methyl bromide, carbon tetrachloride), and two herbicides (trifluralin, and 2,4-D). In older participants, shingles was associated with self-reported history of a high pesticide exposure event (HR 1.89; 95%CI 1.45, 2.45). Findings were similar after excluding those with a history of leukemia/lymphoma or autoimmune diseases. CONCLUSIONS: Specific pesticides were related to shingles risk in farmers, with several demonstrating exposure-response trends. These novel findings support further investigation of pesticides in relation to shingles risk and VZV immunity. Some pesticides may compromise cell-mediated immune responses to VZV, as seen with aging and immunosuppressant medications, which may have broader implications for vaccine efficacy and susceptibility to other infections.

Immune response to varicella-zoster virus before and after renal transplantation

BackgroundHerpes zoster (HZ) risk is high in renal transplant recipients. Vaccination prior to transplantation may provide a useful strategy for the prevention of HZ in the posttranplantation period. However, it is not known whether immunity to varicella-zoster virus (VZV) is affected due to treatment surrounding transplantation. MethodsBoth humoral and cellular immunity to VZV were determined prior to and 2–3 years after renal transplantation in 60 adult patients, and 62 matched healthy controls. VZV-specific cellular immunity was measured by an interferon gamma (IFNγ) enzyme-linked immunospot (ELISpot) assay and by analyzing T-cell functionality using flowcytometry. VZV-IgG levels were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (gpELISA). ResultsUsing paired analysis, it was determined that numbers of IFNγ-producing cells did not change after transplantation, but were significantly lower in transplant recipients after transplantation than in controls (p = 0.028). Patients in whom the post-transplant period was complicated by rejection or any acute infection (excluding HZ) had a lower number of IFNγ-producing cells than patients who did not. VZV IgG levels did not differ from controls, but a significant decrease was observed after transplantation (p < 0.0001). ConclusionsVZV-specific cellular immunity, which is essential in the prevention of HZ, did not markedly change in patients following renal transplantation. This suggests that preventive vaccination before transplantation may be beneficial. Our results extend knowledge on VZV immunity after transplantation, vital when considering strategies for the prevention of HZ in these patients.

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

BackgroundIn phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZVIN) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZVIN immunogenicity from these studies.MethodsPatients were randomized to ZVIN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling.ResultsEstimated geometric mean fold rise ratios (ZVIN/placebo) by gpELISA and IFN-y ELISPOT ~28 days post–dose 4 were 2.02 (95% confidence interval [CI], 1.53–2.67) and 5.41 (95% CI, 3.60–8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79–1.98) and 2.10 (95% CI, 1.69–2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81–3.05) in patients with HM.ConclusionsZVIN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZVIN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations.Clinical trial registrationNCT01229267, NCT01254630.

Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Adult Hematopoietic Cell Transplant Recipients: A Single Center Study

<h3>Background</h3> Hematopoietic cell transplant (HCT) recipients are at high risk for Varicella zoster virus (VZV) reactivation. Shingrix, the adjuvanted recombinant zoster vaccine, is a new alternative to the live-attenuated VZV vaccine for immunocompromised individuals. Post-marketing data on its immunogenicity and safety in HCT is limited. <h3>Objectives</h3> To assess the safety and immunogenicity of Shingrix vaccine in HCT recipients. <h3>Methods</h3> Single center retrospective study of 134 consecutive adult allogenic and autologous HCT recipients who received the full series (two doses) of Shingrix vaccine. Primary study end points were safety and immunogenicity defined as either seroconversion in previously seronegative individuals or 4-fold increase from baseline VZV IgG titers in previously exposed patients. <h3>Results</h3> Among the 134 patients who completed vaccine series, 39 patients including 25 allogeneic and 14 autologous HCT recipients (Figure), had serological data available at baseline and after completion of vaccine series. The median age of patients at the time of HCT was 61 years (IQR, 53-67). The median time from HCT to first dose of Shingrix vaccine was 9 months (IQR, 7-14) for the entire cohort, but it was significantly shorter in autologous versus allogeneic HCT recipients: 7 (IQR, 6-8) vs. 12 (IQR, 9-16) months (P=0.003 by Mann Whitney test), respectively. Vaccine administration was very well tolerated, out of 134 patients only two (1.4%) had documented adverse events following Shingrix (and other vaccines co-administered), including injection site reaction after second dose and flu-like syndrome with fatigue and non-productive cough after the first dose (n=1 each). Both reactions occurred in autologous HCT recipients. The median time from the second Shingrix dose to post-vaccination VZV IgG titer assessment was 3.5 (IQR, 2-6) months. A total of 16 (41%) patients had documented humoral vaccine responses as measured by post vaccination VZV IgG levels including 8/14 (57%) autologous HCT recipients compared to 8/25 (32%) allogeneic HCT recipients (P=0.18 by Fisher's exact test). Among the 16 responders, the VZV IgG antibody concentration index increased from 179 (2.1-559) to 3,868 (2,232-4,000) (P<0.0001 by Wilcoxon matched-pairs signed rank test). Of interest, 100% of the patients who were seronegative prior to vaccination (n=8) seroconverted in response to Shingrix. <h3>Conclusions</h3> A 2-dose course of adjuvanted recombinant zoster vaccine was well tolerated among adult HCT recipients. Vaccine humoral responses occurred in less than half of the patients although vaccine seems to be more immunogenic following autologous HCT and among seronegative patients. Although Shingrix vaccine is currently only licensed for VZV seropositive patients, our data indicate that this recombinant vaccine may also be useful for primary VZV immunization. Larger studies are needed.

New approaches to controlling an outbreak of chickenpox in a large immigration detention setting in England: the role of serological testing and mathematical modelling.

Chickenpox is caused by varicella-zoster-virus (VZV) and is highly contagious. Immigration detention settings are a high-risk environment for primary VZV transmission, with large, rapidly-changing populations in close quarters, and higher susceptibility among non-UK-born individuals. During outbreaks, operational challenges occur in detention settings because of high-turnover and the potential need to implement population movement restriction for prolonged periods. Between December 2017 and February 2018, four cases of chickenpox were notified amongst 799 detainees in an immigration removal centre (IRC). Microbiological investigations included case confirmation by vesicular fluid polymerase chain reaction, and VZV serology for susceptibility testing. Control measures involved movement restrictions, isolation of cases, quarantining and cohorting of non-immune contacts and extending VZV immunity testing to the wider detainee population to support outbreak management. Immunity was tested for 301/532 (57%) detainees, of whom 24 (8%) were non-immune. The level of non-immunity was lower than expected based on the existing literature on VZV seroprevalence in detained populations in England. Serology results identified non-immune contacts who could be cohorted and, due to the lack of isolation capacity, allowed the placement of cases with immune detainees. The widespread immunity testing of all detainees was proving challenging to sustain because it required significant resources and was having a severe impact on operational capacity and the ability to maintain core business activities at the IRC. Therefore, mathematical modelling was used to assess the impact of scaling back mass immunity testing. Modelling demonstrated that interrupting testing posed a risk of one additional case compared to continuing with testing. As such, the decision was made to stop testing, and the outbreak was successfully controlled without excessive strain on resources. Operational challenges generated learning for future outbreaks, with implications for a local and national policy on IRC staff occupational health requirements, and proposed reception screening of detainees for VZV immunity.

The impact of childhood varicella vaccination on the incidence of herpes zoster in the general population: modelling the effect of exogenous and endogenous varicella-zoster virus immunity boosting

BackgroundA controversy exists about the potential effect of childhood varicella vaccination on Herpes Zoster (HZ) incidence. Mathematical models projected temporary HZ incidence increase after vaccine introduction that was not confirmed by real-world evidence. These models assume that absence of contacts with infected children would prevent exogenous boosting of Varicella-Zoster-Virus (VZV) immunity and they do not include an endogenous VZV immunity-boosting mechanism following asymptomatic VZV reactivation. This study aims to explore the effect of various assumptions on exogenous and endogenous VZV immunity-boosting on HZ incidence in the general population after introduction of routine childhood varicella vaccination.MethodsAn age-structured dynamic transmission model was adapted and fitted to the seroprevalence of varicella in France in absence of vaccination using the empirical contact matrix. A two-dose childhood varicella vaccination schedule was introduced at 12 and 18 months. Vaccine efficacy was assumed at 65%/95% (dose 1/dose 2), and coverage at 90%/80% (dose 1/dose 2). Exogenous boosting intensity was based on assumptions regarding HZ-immunity duration, age-dependent boosting effect, and HZ reactivation rates fitted to observed HZ incidence. Endogenous boosting was the same as pre-vaccination exogenous boosting but constant over time, whilst exogenous boosting depended on the force of infection. Five scenarios were tested with different weightings of exogenous (Exo) - endogenous (Endo) boosting: 100%Exo–0%Endo, 75%Exo–25%Endo, 50%Exo–50%Endo, 25%Exo–75%Endo, 0%Exo–100%Endo.ResultsHZ incidence before varicella vaccination, all ages combined, was estimated at 3.96 per 1000 person-years; it decreased by 64% by year 80 post vaccine introduction, for all boosting assumptions. The 100%Exo-0%Endo boosting scenario, predicted an increase in HZ incidence for the first 21 years post vaccine introduction with a maximum increase of 3.7% (4.1/1000) at year 9. However, with 0%Exo-100%Endo boosting scenario an immediate HZ decline was projected. The maximum HZ incidence increases at 10, 3, and 2 years post vaccination were 1.8% (75%Exo-25%Endo), 0.8% (50%Exo-50%Endo) and 0.2% (25%Exo-75%Endo), respectively.ConclusionsAssuming modest levels of endogenous boosting, the increase in HZ incidence following childhood varicella vaccination was smaller and lasted for a shorter period compared with 100%Exo-0%Endo boosting assumption. Endogenous boosting mechanism could partly explain the divergence between previous HZ-incidence projections and real-world evidence.

Serological and T Cell Responses After Varicella Zoster Virus Vaccination in HIV-Positive Patients Undergoing Renal Dialysis.

Limited data on varicella zoster virus (VZV) vaccine responses are available in HIV-positive adults, especially among those with end-stage renal disease on dialysis or undergoing kidney transplantation (KT). Serological and T cell responses were analyzed using anti-VZV IgG titers, enzyme-linked immunosorbent assay and flow cytometric intracellular cytokine staining (ICS) in two HIV-positive kidney transplant candidates undergoing dialysis and receiving VZV immunization. The results were compared with two HIV-positive and two HIV-negative VZV-seropositive patients (two kidney transplant candidates and two kidney transplant recipients), and with one HIV-negative vaccinee. HIV-positive VZV-susceptible patients received two doses of VZV vaccine 12 weeks apart. No adverse events were reported. Serological data were indicative of immunological response in one patient and corresponded to T cell responses. The second patient showed only a transient increase in anti-VZV IgG titers, but reported positive CD4+ T cell responses that were maintained after KT. Positive T cell and serological responses were detected in both HIV-positive and HIV-negative controls. VZV vaccination appeared safe and effective in HIV-positive KT candidates. VZV-specific T cell immunity was detected among transplant candidates and after KT. The assessment of VZV-specific T cell immunity using flow cytometric ICS may be more reliable compared to serology in assessing responses to VZV vaccine in this group.

Seroprevalence of varicella-zoster virus among pregnant women in Fayoum Governorate, Egypt

BackgroundChickenpox infection acquired during pregnancy is a serious condition. There may be congenital malformations and neonatal varicella syndrome with significant morbidity and mortality. Egypt has no routine varicella-zoster vaccination program.ObjectiveTo assess the immune status against varicella-zoster virus (VZV) antibodies among a group of pregnant women and to study the relationship between VZV seroprevalence and some sociodemographic characteristics.Subjects and methodsA descriptive cross-sectional study was conducted on a group of pregnant women (n = 333) attending antenatal care (ANC) clinic at Fayoum University Hospital. Serologic testing for VZV was performed using ELISA through the years 2016–2017.ResultsVZV seroprevalence was detected in 294 (88.3%) of the 333 recruited pregnant women. Older age > 25 years old was significantly associated with low percent of VZV-negative antibodies (6.7% in versus 17.4% in younger age, OR (95%CI) 0.34 (0.17–0.70)), also having more than one child was significantly associated with a low percent of VZV-negative antibodies (8.2% versus 16.1% among participants with no children or having one child, OR 0.34 (0.17–0.70)).ConclusionsDespite the absence of a routine VZV vaccination program in Egypt, VZV immunity was high among pregnant women, but less than that reported in many developed countries. We recommend targeted vaccination for women in the reproductive age especially young and primipara.Trial registrationEthical Committee Registration number R67 session 42: date 12/11/2017(retrospectively registered).

Seroepidemiology of varicella zoster virus infection in Vojvodina, Serbia.

The present cross-sectional serosurvey constitutes the first effort to describe the varicella zoster virus (VZV) seroepidemiology in Serbia. An age-stratified serum bank of 3570 residual samples collected between 2015 and 2016 in each of the seven districts of the Vojvodina Province was tested for IgG anti-VZV antibodies with an enzyme immunoassay. Results were standardised into common units according to the European Sero-Epidemiology Network (ESEN2) methodology. Univariable and multivariable analyses were used to examine the relationships between standardised anti-VZV positivity or logarithmically transformed antibody titres and demographic features of study subjects. Seropositivity (85% overall) increased with age, in parallel with geometric mean titres. By the time of school entry, 68% of children were immune. The slower subsequent acquisition of immunity leaves epidemiologically relevant proportions of adolescents (7%), young adults (6%) and especially females of reproductive age (6%) prone to more severe forms of varicella. In the ongoing pre-vaccine era, natural infection provides a high level of collective immunity, with the highest VZV transmission in children of preschool age. The detected gaps in VZV immunity of the Serbian population support the adoption of the official recommendations for varicella immunisation of non-immune adolescents and young adults, including non-pregnant women of childbearing age.

Varicella zoster virus transmission dynamics in Vojvodina, Serbia.

This study aimed at establishing baseline key epidemiological parameters for varicella zoster virus (VZV) infection in Vojvodina, Serbia, with the ultimate goal to quantify the VZV transmission potential in the population. Seroprevalence data generated during the first large cross-sectional VZV serosurvey were modelled, using a two-tiered modelling approach to calculate age-specific forces of infection (FOI), the basic reproduction number (R0) and herd immunity threshold (H). Seroprevalence and modelling data were compared with corresponding pre-vaccination epidemiological parameters from 11 countries participating in the European Sero-Epidemiology Network 2 (ESEN2) project. Serbia fits into the general dynamic VZV transmission patterns in Europe in the pre-vaccine era, with estimated R0 = 4.12, (95% CI: 2.69–7.07) and H = 0.76 (95% CI: 0.63–0.86). The highest VZV transmission occurs among preschool children, as evidenced by the estimation of the highest FOI (0.22, 95% CI: 0.11–0.34) in the 0.5–4 age group, with a peak FOI of 0.25 at 2.23 years. Seroprevalence was consistently lower in 5–14 year-olds, resulting in considerable shares of VZV-susceptible adolescents (7.3%), and young adults (6%), resembling the situation in a minority of European countries. The obtained key epidemiological parameters showed most intense VZV transmission in preschool children aged <4 years, justifying the consideration of universal childhood immunization in the future. National immunization strategy should consider programs for VZV serologic screening and immunization of susceptible groups, including adolescents and women of reproductive age. This work is an important milestone towards the evaluation of varicella immunization policy options in Serbia.

Varicella-zoster-virus vaccination in immunosuppressed children with rheumatic diseases using a pre-vaccination check list

BackgroundThe goal of this study was to apply the varicella zoster virus (VZV) vaccine to patients with pediatric rheumatic diseases (PRD) at risk for severe chickenpox, without interrupting their current immunosuppression, including biological agents, using an immunological-based pre-vaccination checklist to assure safety. A pre-vaccination checklist was implemented to ensure adequate immune competence prior to immunization.MethodsThis prospective study included seronegative patients (VZV-IgG ≤200 mIU/ml) and patients who had previously received only a single dose of VZV vaccine. All vaccinees demonstrated clinically inactive PRD. Patients were categorized according to their actual treatment in low-intensity IS (LIIS) and high-intensity IS (HIIS) including biological therapy. The pre-vaccination checklist defined thresholds for the following basic laboratory tests: white blood cell count ≥3000/mm3, lymphocytes ≥1200/mm3, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml. In case of HIIS additional specifications included a CD4+ lymphocyte count ≥200/mm3 and a positive T-cell function (via analyzable positive control of a standard tuberculosis interferon-gamma-release-assay (TB-IGRA) indicating mitogen-induced T cell proliferation). Patients who met the criteria of the pre-vaccination checklist received the first and/or second VZV vaccination. Immunologic response and side effects were monitored.ResultsTwenty-three patients were recruited of whom nine had already received one VZV immunization before initiating IS. All patients met the pre-vaccination checklist criteria despite ongoing IS. There was no overall difference in VZV-IgG levels when comparing the LIIS (n=9) and HIIS (n=14) groups. In total, 21 patients (91%) showed a positive vaccination response, after the first immunization the median VZV-IgG across all patients was 224 (59-1219) mIU/ml (median (range)), after booster immunization it increased to 882 (30-4685) mIU/ml. Two patients in the HIIS group failed to raise positive VZV-IgG, despite booster immunization. All nine patients receiving only the second immunization on IS reached high titers of VZV-IgG >500 mIU/ml (1117 (513-4685) mIU/ml). There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare.ConclusionsVZV vaccination is safe and largely immunogenic in children with ongoing IS fulfilling an immunological based pre-vaccination checklist. This new approach is based on immunologic function rather than on type of medications.Trial registration numberISRCRTN trial registration number 21654693, date of registration February 12, 2018, retrospectively registered.

P486 Immunization status of children and adolescents with inflammatory bowel disease or autoimmune hepatitis in Germany

Background: Long-term immunosuppressed patients with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH) are at risk of severe infections with vaccination preventable diseases. Several recent studies demonstrated insufficient immunization coverage in children and adolescents with IBD. Therefore, we evaluated the vaccination rate of children and adolescents with IBD and AIH in Germany. Methods: As part of the German multicentre clinical trial called “VARICED”, the immunization rate of patients with IBD and AIH below 18 years of age was assessed from the certificate of vaccination, medical history of chicken pox and by analysing varicella zoster virus (VZV) IgG and measles virus IgG antibody titres by ELISA. Results: To date 229 patients (51% female, mean age at diagnosis 9.9 years) are registered: 137 have Crohn's disease (CD), 53 ulcerative colitis (UC), 19 IBD-unclassified (IBD-U) and 20 AIH. The majority of the patients (n=190, 83%) are on immunosuppressive therapy (AIH 100%, CD 89%, UC 68%). A complete basic immunisation consisting of 4 doses of a hexavalent vaccine were given to 89% of the total cohort. A combined inoculation for measles, mumps, and rubella (MMR) was documented in 225 (98%) patients, 208 (92%) received two doses. VZV vaccination was introduced in 2004 to the vaccination schedule from the German Standing Committee on Vaccination (STIKO). A good implementation with 90% was found in the birth cohorts from 2005 onwards. In children born before 2005 (n=190) only 22% received VZV vaccination catch up. VZV vaccination was documented in only 77 (34%) patients, but 17 patients (22%) did not display sufficient VZV IgG titres. Already 144 (63%) patients had a medical history of chicken pox. However, three of them did not have verifiable VZV IgG antibodies. In addition, 37 patients had neither a history of a chicken pox infection nor VZV inoculation, but 11 out of them were found to have sufficient VZV IgG titres. Conclusions: There is a good implementation of the vaccination schedule from the German Standing Committee on Vaccination (STIKO) in the group of children and adolescents with IBD and AIH. Our data suggests a gap in VZV immunity in birth cohorts before 2005 in Germany. Moreover, neither the certificate of vaccination nor the medical history of chicken pox infection is reliable for assessing VZV immunity. Serologic investigations demonstrated that some non-immunized patients may undergo occult immunization, and immunized patients did not present sufficient VZV-IgG titres. Thus, we recommend VZV IgG serology within the check-up in newly diagnosed IBD or AIH and VZV vaccination before initiating immunosuppressive therapy, if applicable.

Immunogenicity of Varicella Vaccine and Immunologic Predictors of Response in a Cohort of Elderly Nursing Home Residents.

Little is known about the immunogenicity of live-attenuated Oka/Merck varicella zoster virus (VZV)-containing vaccine (hereafter, "varicella vaccine") in frail nursing homes residents nor about immune phenotypes associated with a response. A cohort of 190 frail nursing home residents aged 80-102 years and a cohort of 50 community-dwelling seniors aged 60-75 years (a comparison group) received varicella vaccine. Interferon γ (IFN-γ) enzyme-linked immunospot assays were performed before and 6 weeks after vaccination. Cellular markers of immunosenescence were measured in the nursing home elderly. The average number of IFN-γ spot-forming cells at baseline was significantly lower in the elderly nursing home residents than in the community-dwelling seniors. However, following vaccination, the VZV immune response increased in both cohorts, and no difference was noted in the fold difference of the response between the 2 cohorts. Upon further examination of the elderly nursing home residents, we found that higher frequencies of regulatory T cells and cytomegalovirus-specific CD4+ T cells correlated negatively with the magnitude of VZV-specific responses. The Oka/Merck varicella vaccine induces VZV immunity in elderly nursing home residents that is similar to that produced in community-dwelling seniors. NCT01328548.

Application of Oral Fluid Assays in Support of Mumps, Rubella and Varicella Control Programs.

Detection of specific viral antibody or nucleic acid produced by infection or immunization, using oral fluid samples, offers increased potential for wider population uptake compared to blood sampling. This methodology is well established for the control of HIV and measles infections, but can also be applied to the control of other vaccine preventable infections, and this review describes the application of oral fluid assays in support of mumps, rubella and varicella national immunization programs. In England and Wales individuals with suspected mumps or rubella, based on clinical presentation, can have an oral fluid swab sample taken for case confirmation. Universal varicella immunization of children has led to a drastic reduction of chickenpox in those countries where it is used; however, in England and Wales such a policy has not been instigated. Consequently, in England and Wales most children have had chickenpox by age 10 years; however, small, but significant, numbers of adults remain susceptible. Targeted varicella zoster virus (VZV) immunization of susceptible adolescents offers the potential to reduce the pool of susceptible adults and oral fluid determination of VZV immunity in adolescents is a potential means of identifying susceptible individuals in need of VZV vaccination. The main application of oral fluid testing is in those circumstances where blood sampling is deemed not necessary, or is undesirable, and when the documented sensitivity and specificity of the oral fluid assay methodology to be used is considered sufficient for the purpose intended.