Roman Chlibek

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

BACKGROUND In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response. METHODS We conducted a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults. RESULTS A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups. CONCLUSIONS The HZ/su vaccine significantly reduced the risk of herpes zoster in adults who were 50 years of age or older. Vaccine efficacy in adults who were 70 years of age or older was similar to that in the other two age groups. (Funded by GlaxoSmithKline Biologicals; ZOE-50 ClinicalTrials.gov number, NCT01165177.).

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 an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults≥50 years of age

BACKGROUND An adjuvanted varicella-zoster virus glycoprotein E (gE) subunit vaccine candidate for herpes zoster is in development. In this trial we compared the safety, reactogenicity, and immunogenicity of the vaccine antigen combined with different adjuvant doses. METHODS This was a phase II, observer-blind, randomized, multinational study. Adults ≥50 years old were randomized 4:4:2:1 to be vaccinated at months 0 and 2 with gE combined with a higher (AS01B) or lower (AS01E) dose adjuvant, unadjuvanted gE, or saline. Following each dose, solicited events were recorded for 7 days and unsolicited adverse events for 30 days. Serious adverse events were collected for 1 year. Cell-mediated and humoral immune responses were assessed at baseline and following each dose. RESULTS No vaccine-related severe adverse events were reported. Solicited adverse events were generally mild to moderate and transient. For all gE-based vaccines, pain was the most common local symptom and fatigue the most common general symptom. Immune responses were significantly enhanced by AS01B and AS01E compared to unadjuvanted gE and were significantly stronger for gE/AS01B than for gE/AS01E. CONCLUSIONS AS01 improved the immunogenicity of gE while retaining acceptable safety and reactogenicity profiles. The enhancement of gE-specific cellular and humoral responses was adjuvant dose dependent. CLINICAL TRIALS REGISTRATION NCT00802464.

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).

Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults.

BACKGROUND An investigational subunit vaccine containing the varicella-zoster virus (VZV) glycoprotein E (gE) and the AS01B adjuvant system is being evaluated for the prevention of herpes zoster (HZ) in older adults. A phase II trial evaluating different formulations of this vaccine (containing 25μg, 50μg, or 100μg gE) was conducted in adults ≥60 years of age and showed that all formulations elicited robust cellular and humoral immune responses for up to 3 years after vaccination. In this follow-up study in subjects who received two doses of the 50μg gE/AS01B formulation (HZ/su), we assessed the persistence of the immune responses for up to 6 years after vaccination. METHODS This phase II, open-label, multicenter, single-group trial conducted in the Czech Republic, Germany, Sweden, and the Netherlands followed 129 subjects who had received two doses (2 months apart) of HZ/su during the initial trial. Vaccine-induced immune responses (frequencies of gE-specific CD4(+) T cells expressing ≥2 activation markers and serum anti-gE antibody concentrations) were evaluated at 48, 60, and 72 months after the first HZ/su dose. RESULTS Six years after vaccination with HZ/su, gE-specific cell-mediated immune responses and anti-gE antibody concentrations had decreased by 20-25% from month 36, but remained higher than the prevaccination values. At month 72, the gE-specific cell-mediated immune response was 3.8 times higher than the prevaccination value (477.3 vs. 119.4 activated gE-specific CD4(+) T cells per 10(6) cells), and the anti-gE antibody concentration was 7.3 times higher than the prevaccination value (8159.0 vs. 1121.3mIU/mL). No vaccine-related serious adverse events were reported between months 36 and 72. CONCLUSIONS gE-specific cellular and humoral immune responses persisted for 6 years after two-dose vaccination with HZ/su in healthy older adults. No safety concerns were identified.

Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for influenza vaccination in children

BackgroundInfluenza vaccination in infants and children with existing health complications is current practice in many countries, but healthy children are also susceptible to influenza, sometimes with complications. The under-recognised burden of disease in young children is greater than in elderly populations and the number of paediatric influenza cases reported does not reflect the actual frequency of influenza.DiscussionVaccination of healthy children is not widespread in Europe despite clear demonstration of the benefits of vaccination in reducing the large health and economic burden of influenza. Universal vaccination of infants and children also provides indirect protection in other high-risk groups in the community. This paper contains the Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for the vaccination of infants and children against influenza. The aim of CEVAG is to encourage the efficient and safe use of vaccines to prevent and control infectious diseases.SummaryCEVAG recommends the introduction of universal influenza vaccination for all children from the age of 6 months. Special attention is needed for children up to 60 months of age as they are at greatest risk. Individual countries should decide on how best to implement this recommendation based on their circumstances.

Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group (CEVAG).

Tick-borne encephalitis (TBE) is a viral neurological zoonotic disease transmitted to humans by ticks or by consumption of unpasteurized dairy products from infected cows, goats, or sheep. TBE is highly endemic in areas of Central and Eastern Europe and Russia where it is a major public health concern. However, it is difficult to diagnose TBE as clinical manifestations tend to be relatively nonspecific and a standardized case definition does not exist across the region. TBE is becoming more important in Europe due to the appearance of new endemic areas. Few Central European Vaccination Awareness Group (CEVAG) member countries have implemented universal vaccination programmes against TBE and vaccination coverage is not considered sufficient to control the disease. When implemented, immunization strategies only apply to risk groups under certain conditions, with no harmonized recommendations available to date across the region. Effective vaccination programmes are essential in preventing the burden of TBE. This review examines the current situation of TBE in CEVAG countries and contains recommendations for the vaccination of children and high-risk groups. For countries at very high risk of TBE infections, CEVAG strongly recommends the introduction of universal TBE vaccination in children > 1 y of age onwards. For countries with a very low risk of TBE, recommendations should only apply to those traveling to endemic areas. Overall, it is generally accepted that each country should be free to make its own decision based on regional epidemiological data and the vaccination calendar, although recommendations should be made, especially for those living in endemic areas.

Safety of the 11-valent pneumococcal vaccine conjugated to non-typeable Haemophilus influenzae-derived protein D in the first 2 years of life and immunogenicity of the co-administered hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio virus, Haemophilus influenzae type b and control hepatitis A vaccines

This randomized (1:1), double-blind, multicenter study, included 4,968 healthy infants to receive either the 11-valent pneumococcal protein D (PD)-conjugate study vaccine or the hepatitis A vaccine (HAV) (control) at 3, 4, 5, and 12-15 months of age. The three-dose primary course of both vaccines was co-administered with combined hexavalent DTPa-HBV-IPV/Hib vaccine. The pneumococcal PD-conjugate study vaccine did not impact the immune response of co-administered hexavalent vaccine and the control HAV vaccine induced seropositivity (antibodies >or=15 mIU/mL) in all infants. The incidence of solicited symptoms was higher with the 11-valent pneumococcal PD-conjugate study vaccine, yet similar to that induced by concomitant DTPa-HBV-IPV/Hib vaccine. Overall, the reactogenicity and safety profile of the 11-valent pneumococcal PD-conjugate vaccine when co-administered with the hexavalent DTPa-HBV-IPV/Hib vaccine, as well as the immunogenicity of the co-administered hexavalent vaccine, were consistent with previous reports for the licensed DTPa-HBV-IPV/Hib and pneumococcal conjugate vaccines.

Fulminant hepatitis and death associated with disseminated varicella in an immunocompromised adult from the Czech Republic caused by a wild-type clade 4 varicella-zoster virus strain

Varicella zoster virus typically causes a benign disease in childhood called varicella (chickenpox) and can reactivate in adults as a dermatomally distributed, painful rash illness known as herpes zoster (HZ). Infection with VZV can however lead to severe complications in immunocompromised patients that can result in hospitalization and, occasionally, death. Here we describe a patient, who acquired primary VZV infection during a 3-week-long treatment regimen with corticosteroids. The disease took a fulminant course, leading to a liver failure and severe coagulopathy. The patient died 9 days following hospital admission, despite intensive antiviral and supportive treatment. Wild-type VZV DNA was detected from multiple samples from esophagus, liver and skin. Genotypic analysis based on single nucleotide polymorphism profiles in open reading frames (ORFs) 21, 22 and 50 identified this strain as a clade 4 isolate, which is typically found in tropical countries. This is the first description of a clade 4 strain from a patient in the Czech Republic.