Jan Smetana

Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials

BACKGROUND Although fever is part of the normal inflammatory process after immunisation, prophylactic antipyretic drugs are sometimes recommended to allay concerns of high fever and febrile convulsion. We assessed the effect of prophylactic administration of paracetamol at vaccination on infant febrile reaction rates and vaccine responses. METHODS In two consecutive (primary and booster) randomised, controlled, open-label vaccination studies, 459 healthy infants were enrolled from ten centres in the Czech Republic. Infants were randomly assigned with a computer-generated randomisation list to receive three prophylactic paracetamol doses every 6-8 h in the first 24 h (n=226) or no prophylactic paracetamol (n=233) after each vaccination with a ten-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co-administered with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b (DTPa-HBV-IPV/Hib) and oral human rotavirus vaccines. The primary objective in both studies was the reduction in febrile reactions of 38.0 degrees C or greater in the total vaccinated cohort. The second objective was assessment of immunogenicity in the according-to-protocol cohort. These studies are registered with ClinicalTrials.gov, numbers NCT00370318 and NCT00496015. FINDINGS Fever greater than 39.5 degrees C was uncommon in both groups (after primary: one of 226 participants [<1%] in prophylactic paracetamol group vs three of 233 [1%] in no prophylactic paracetamol group; after booster: three of 178 [2%] vs two of 172 [1%]). The percentage of children with temperature of 38 degrees C or greater after at least one dose was significantly lower in the prophylactic paracetamol group (94/226 [42%] after primary vaccination and 64/178 [36%] after booster vaccination) than in the no prophylactic paracetamol group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster vaccination). Antibody geometric mean concentrations (GMCs) were significantly lower in the prophylactic paracetamol group than in the no prophylactic paracetamol group after primary vaccination for all ten pneumococcal vaccine serotypes, protein D, antipolyribosyl-ribitol phosphate, antidiphtheria, antitetanus, and antipertactin. After boosting, lower antibody GMCs persisted in the prophylactic paracetamol group for antitetanus, protein D, and all pneumococcal serotypes apart from 19F. INTERPRETATION Although febrile reactions significantly decreased, prophylactic administration of antipyretic drugs at the time of vaccination should not be routinely recommended since antibody responses to several vaccine antigens were reduced. FUNDING GlaxoSmithKline Biologicals (Belgium).

Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older

BACKGROUND A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). METHODS This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTS In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONS In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229 .).

Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: A phase II, randomized, controlled study

BACKGROUND This study investigated the safety and immunogenicity of different formulations and schedules of a candidate subunit herpes zoster vaccine containing varicella-zoster virus glycoprotein E (gE) with or without the adjuvant system AS01B. METHODS In this phase II, single-blind, randomized, controlled study, adults aged ≥60years (N=714) received one dose of 100μggE/AS01B, two doses, two months apart, of 25, 50, or 100μggE/AS01B, or two doses of unadjuvanted 100μggE/saline. Frequencies of CD4(+) T cells expressing ≥2 activation markers following induction with gE were measured by intracellular cytokine staining and serum anti-gE antibody concentrations by ELISA. RESULTS Frequencies of gE-specific CD4(+) T cells were >3-fold higher after two doses of all gE/AS01B formulations than after one dose of 100μggE/AS01B or two doses of 100μggE/saline. Frequencies were comparable after two doses of 25, 50, or 100μggE/AS01B. Serum anti-gE antibody concentrations were comparable after two doses of 50 or 100μggE/AS01B and higher than in the other groups. Immune responses persisted for at least 36 months. Reactogenicities of all gE/AS01B formulations were similar but greater than with gE/saline. CONCLUSIONS The three formulations of gE/AS01B were immunogenic and well tolerated in adults aged ≥60years. Two vaccinations with gE/AS01B induced higher immune responses than one and the dose of gE impacted humoral but not cellular immune responses (NCT00434577).

Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older

Abstract Background The herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01B Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods Participants (ZOE-50: ≥50; ZOE-70: ≥70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing ≥2 of 4 activation markers assessed (CD42+) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1-fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD42+ T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained ≥5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination. Clinical Trials Registration NCT01165177; NCT01165229.

Decreasing Seroprevalence of Measles Antibodies after Vaccination – Possible Gap in Measles Protection in Adults in the Czech Republic

Aims In recent years, Europe has recorded an increase in the number of measles outbreaks despite the implementation of vaccination into the National Immunization Programs. The Czech Republic introduced vaccination against measles into National Immunization Program in 1969. The aim of this study was to determine seroprevalence of IgG antibodies against measles in adults. Methods Our study was designed as a prospective, multicenter cohort study. Samples of blood were taken from adults aged 18 years and over. Specific IgG antibodies were determined by ELISA method. Results A number of 1911 sera samples were obtained. The total seropositivity reached 83.3%, 14.3% of the results were negative and 2.4% were borderline. When comparing the individual age groups, the highest antibody seropositivity (> 96%) was detected in persons aged 50 years and over who were naturally infected in pre-vaccine era. The lowest seropositivity was recorded in the age groups 30–39 years (61.5%), 40–49 years (77.5%) and 18–29 years (81.1%). Conclusions A long term high rate of seropositivity persists after natural measles infection. By contrast, it decreases over time after vaccination. Similarly, the concentrations of antibodies in persons with measles history persist for a longer time at a higher level than in vaccinated persons. Our results indicate possible gap in measles protection in adults born after implementation of vaccination into the National Immunization Programs. There are two probable reasons, decrease of measles antibody seropositivity in time after vaccination in setting of limited natural booster and one-dose vaccination schedule used in the first years after implementation.

Antibody Persistence and Immune Memory 4 Years Post-Vaccination With Combined Hepatitis A and B Vaccine in Adults Aged Over 40 Years

Persistence of immune response was assessed in adults aged >40 years (N = 596) following primary vaccination with combined hepatitis A/B vaccine or concomitant monovalent hepatitis A and B vaccines. Anti-hepatitis A virus antibody responses persisted for at least 4 years regardless of the vaccine used, with anti-hepatitis B surface antibody responses higher and more sustained in subjects who received the combined hepatitis A/B vaccine. Response rates to an additional dose of the same vaccine(s) used for priming were high.

Prevalence of hepatitis C virus in adult population in the Czech Republic – time for birth cohort screening

Chronic hepatitis C is curable disease. Low detection rate could be one of the reasons of poor treatment uptake. It is important to identify HCV prevalence and anti-hepatitis C virus (HCV) positive patients in population by effective screening strategy such as risk-based or birth cohort screening programs. There are no national population-based estimates of the HCV prevalence in the Czech Republic (CZ). The most recent seroprevalence survey determined a prevalence of positive anti-HCV antibodies of 0.2% (in 2001). The aim of the study was to determine the seroprevalence of HCV, HCV viraemia and HCV genotype in the CZ adult population. We also estimated the number of persons living with chronic hepatitis C in CZ. The examined group included 3000 adults, 18–90 years of age enrolled in 2015. All serum samples were examined to determined anti-HCV antibodies positivity, HCV-RNA positivity and genotypes. Of the 3000 samples, 50 were found to be anti-HCV-positive, for a seroprevalence of 1.67% (2.39% in males, 0.98% in females). The overall prevalence of positive HCV RNA was 0.93%: 1.5% in males, 0.39% in females. HCV genotype (GT) 1a was determined in 25%, GT 1b in 25% and GT 3a in 46%. Since 2001, the HCV seroprevalence has increased 8-fold. The highest HCV seroprevalence occurred in males aged 30–44 years. We can estimate that there are more than 140,000 people with HCV antibodies and more than 80,000 people with chronic hepatitis C living in the CZ. The introduction of birth cohort HCV screening could be beneficial for the country.

GENOTYPING OF VARICELLA-ZOSTER VIRUS (VZV) WILD-TYPE STRAINS ISOLATED IN THE CZECH REPUBLIC

OBJECTIVES Monitoring of the varicella-zoster virus is becoming an important tool for analysis of the circulation of individual strains of VZV which differ not only at the genomic level, but show a variability in their clinical and epidemiological characteristics. Such data are not available on a large scale from the Czech population and could help understanding the epidemiological and evolutionary characteristics of the virus, as well as its potential for reinfection and increased pathogenesis in the population groups at higher risk for complications. The main aim of this study was detection and monitoring of wild-type or vaccine VZV strain isolates in the region of Eastern Bohemia and genotypic characterization of these isolates. MATERIAL A total of 273 clinical samples were obtained from patients exhibiting symptoms of varicella zoster virus (VZV) infection manifested as chickenpox or herpes zoster (HZ) treated in the Faculty Hospital of Charles University, Medical School in Hradec Kralove, Czech Republic. METHODS Characterization of individual short VZV DNA sequences was performed utilizing restriction fragment length polymorphisms (RFLPs), PCR and sequencing. Single nucleotide polymorphisms (SNP) in open reading frames (ORF) 21, 22 and 50 were used to identify individual VZV strains. RESULTS All clinical isolates (97 from varicella, 176 from herpes zoster) were VZV positive wild-type strains. Sequencing analysis showed that 89 isolates were of the European E1 genotype, 180 were of the European E2 genotype and 2 were identified as the Mosaic M1 strain. In addition, for the first time in this region two unusual genotypes were identified, both representing a combination of E1 and M2 strain specific SNPs. CONCLUSION Our prospective VZV genotyping study which is the first to monitor the VZV epidemiological situation in the Czech Republic using such a large set of clinical specimens, has provided valuable epidemiological data and identified two unique VZV recombinants.

Influenza vaccination in the elderly.

ABSTRACT Seasonal influenza is a prevalent and serious annual illness resulting in widespread morbidity and economic disruption throughout the population; the elderly and immunocompromised are particularly vulnerable to serious sequelae and mortality. The changing demographics worldwide to an aging society have important implications for public health policy and pharmaceutical innovations. For instance, primary prevention via immunization is effective in reducing the burden of influenza illness among the elderly. However, the elderly may be insufficiently protected by vaccination due to the immunosenescence which accompanies aging. In addition, vaccine hesitancy among the younger populations increases the likelihood of circulating infectious diseases, and thus concomitant exposure. While it is clear that the development of more immunogenic vaccines is an imperative and worthy endeavor, clinical trials continue to demonstrate that the current influenza vaccine formulation remains highly effective in reducing morbidity and mortality when well matched to circulating strains.

Serological survey of mumps antibodies in adults in the Czech Republic and the need for changes to the vaccination strategy

ABSTRACT Mumps outbreaks, especially in adolescents and young adults, have been reported in the Czech Republic. The aim of the presented study was to determine the seroprevalence of specific IgG antibodies against mumps in the adult population of the Czech Republic. The study was designed as a multicenter serological survey of adults aged 18 years and over. Specific IgG antibodies against mumps were detected in blood samples using an enzyme-linked immunosorbent assay (ELISA). A total of 1,911 serum samples were examined. The overall seropositivity reached 55.3%. In individual age groups, the highest seropositivity 63% (63.5–65.2%) was recorded in adults aged 40 years and over; the lowest seropositivity was found in adults aged 18–29 years (27.4%). The difference in seropositivity rate between the 18–29 years age group and the 40 years and over age groups was statistically significant (p < 0.001). Only the 18–29 years age group included both vaccinated and unvaccinated (born in the pre-vaccine era) individuals. In vaccinated individuals, seropositivity was reported in only 19.1% of persons; in unvaccinated individuals, seropositivity reached 48.2%. Our results demonstrate the long-term persistence of antibodies following natural infection and the decrease in seropositivity that occurs after vaccination over time. This immunity waning may account for the higher susceptibility of adolescents and young adults to mumps. Therefore, the current vaccination program in the Czech Republic could be considered as less effective. It will be modified with the shifting of the second dose of vaccine from two years of age to the preschool age.