Evaluation of Vaccine Immunogenicity-Correlates to Real-World Protection: Influenza.

Recent events highlighted that, despite decades of studying vaccine immunogenicity and efforts toward finding correlates of protection, evaluating real-world vaccine efficacy as well as establishing meaningful licensing criteria still represents a significant challenge. In this paper, we review all aspects of influenza vaccine immunogenicity, including animal and human challenge studies, humoral and cellular immunity parameters, and their potential correlation with real-life protection from disease.

Extinction of the Influenza B Yamagata Line during the COVID Pandemic-Implications for Vaccine Composition.

Vaccination remains the most effective way to mitigate the enormous burden of influenza on the health care system [...].

Developing Immunity Testing for SARS-CoV-2 and Other Novel Vaccines-Correlates of Immunogenicity Parameters with Protection.

During the assessment and licensing of novel vaccines, as well as post licensure follow up, it is critical to have reliable immunogenicity testing methods that relate well to real life protection [...].

A Reduced Dose Whole Virion Aluminum Adjuvanted Seasonal Influenza Vaccine Is Immunogenic, Safe, and Well Tolerated in Pediatric Patients.

BACKGROUND: Data suggest that pediatric patients might react differently to influenza vaccination, both in terms of immunity and side effects. We have recently shown that using a whole virion vaccine with aluminum phosphate adjuvants, reduced dose vaccines containing 6 µg of viral hemagglutinin (HA) per strain are immunogenic, and well tolerated in adult and elderly patients. Here we show the results of a multicenter clinical trial of pediatric patients, using reduced doses of a new, whole virion, aluminum phosphate adjuvanted vaccine (FluArt, Budapest, Hungary). METHODS: A total of 120 healthy volunteers were included in two age groups (3-11 years, receiving 3 µg of HA per strain, and 12-18 years, receiving 6 µg of HA per strain). We used hemagglutination inhibition testing to assess immunogenicity, based on EMA and FDA licensing criteria, including post/pre-vaccination geometric mean titer ratios, seroconversion and seropositivity rates. Safety and tolerability were assessed using CHMP guidelines. RESULTS: All subjects entered the study and were vaccinated (ITT population). All 120 subjects attended the control visit on Day 21 (PP population). All immunogenicity licensing criteria were met in both age groups for all three vaccine virus strains. No serious adverse events were detected and the vaccine was well tolerated by both age groups. DISCUSSION: Using a whole virion vaccine and aluminum phosphate adjuvants, a reduction in the amount of the viral hemmaglutinin is possible while maintaining immunogenicity, safety and tolerability in pediatric and adolescent patients.

Licensing the first reduced, 6 µg dose whole virion, aluminum adjuvanted seasonal influenza vaccine - A randomized-controlled multicenter trial.

INTRODUCTION: Shortages of vaccine supplies repeatedly occur, limiting our abilities to prevent influenza. Therefore, increasing production volume remains a priority. The presently licensed seasonal influenza vaccines contain 15 µg of viral hemagglutinin per strain in adult, and up to 60 µg in elderly patients. Decreasing the amount of viral parts while maintaining efficacy is one way of increasing production capacity. METHODS: This was multicenter, stratified (18-60 years and >60 years of age), prospective, randomized, double-blind, active-controlled, parallel-arm, non-inferiority clinical trial, conducted in the European Union, involving 1206 patients. We used hemagglutination inhibition assay to assess the immunogenicity of a newly developed, whole virion, seasonal trivalent influenza vaccine, containing 6 µg hemagglutinin per strain (FluArt, Hungary) and to assess whether it is non-inferior to the presently licensed vaccine containing 15 µg hemagglutinin per strain. Safety and tolerability of both vaccines were assessed based on EMEA guidelines. RESULTS: The reduced dose vaccine containing 6 µg of hemagglutinin per strain was safe and non-inferior to the currently licensed 15 µg vaccine, not only in adult, but also in elderly patients, according to the immunogenicity criteria by the FDA and EMEA (seroconversion, seroprotection and post/pre vaccination GMT ratios), and it fulfilled all applicable licensing requirements for both age groups. CONCLUSIONS: Based on the results, the reduced dose vaccine was licensed in the EU member state Hungary and safely administered in over 1.5 million cases so far. The amount of viral hemagglutinin needed can be reduced by using a whole virion vaccine with aluminum phosphate adjuvants. REGISTRATION: This study was registered by the European Clinical Trials Database, EudraCT, number: 2011-003314-16.

[Safety data of the new, reduced-dose influenza vaccine FluArt after its first season on the market]. / Az új, csökkentett dózisú, hazai gyártású influenzavakcina (FluArt) forgalomba hozatalát követo elso szezonjának biztonságossági vizsgálata.

INTRODUCTION: The currently licensed seasonal influenza vaccines contain split, subunit or whole virions, typically in amounts of 15 µg hemagglutinin per virus strain for adult and up to 60 µg in elderly patients. AIM: The present study reports safety data of the newly licensed, reduced dose vaccine with 6 µg of hemagglutinin per strain produced by Fluart (Hungary) after its first season on the market. The main objective of enhanced safety surveillance was to detect a potential increase in reactogenicity and allergic events that is intrinsic to the product in near real-time in the earliest vaccinated cohorts. METHOD: The study methods were based on the Interim guidance on enhanced safety surveillance for seasonal influenza vaccines in the EU by the European Medicines Agency. STATISTICS: We used the Fisher exact test with 95% confidence intervals. RESULTS: We studied 587 patients and detected a total 24 adverse events, all of which have already been known during the licensing studies of the present vaccine. The frequencies of the adverse events were not different from what had been seen with the previously licensed 15 µg vaccine. CONCLUSIONS: Based on the results, the authors conclude that the new, reduced dose vaccine FluArt is safe and tolerable. Orv Hetil. 2017; 158(49): 1953-1959.

Dose sparing and the lack of a dose-response relationship with an influenza vaccine in adult and elderly patients - a randomized, double-blind clinical trial.

AIMS: The currently licensed seasonal trivalent influenza vaccines contain 15 µg haemagglutinin per strain for adult, and up to 60 µg for elderly patients. However, due to recent shortages, dose sparing to increase production capacity would be highly desirable. In the present study, we attempted to find a dose-response relationship for immunogenicity and, thus, the optimal dose for seasonal influenza vaccines in adult and elderly patients. METHODS: A total of 256 subjects, including adult (aged 18-60 years) and elderly (aged over 60 years) individuals, were enrolled. Subjects were randomly assigned in a 1:1:1:1 ratio to receive a whole-virion, aluminium-adjuvanted trivalent influenza vaccine containing 3.5, 6, 9 or 15 µg haemagglutinin of seasonal A/H1N1, A/H3N2 and B influenza antigens manufactured by Omninvest Ltd., Hungary. Serum antibody titres against the vaccine virus strains were measured by haemagglutination inhibition. RESULT: All vaccines were well tolerated. All four vaccines fulfilled all three immunogenicity licensing criteria, as determined by the European Committee for Proprietary Medicinal Products (CPMP)/Biotechnology Working Party (BWP)/214/96 guideline for all three virus strains and both age groups. The 3.5 µg vaccine showed 28% less seroconversion compared to the 15 µg dose in terms of influenza AH3N2 in the adult group (95% confidence interval -51, -3; P < 0.05). All other doses showed no significant difference in immunogenicity compared with the licensed vaccine containing 15 µg haemagglutinin. CONCLUSIONS: Our data suggested that significant dose sparing is possible with the use of whole-virion vaccines and aluminium adjuvants, without compromising safety. This could have significant economic and public health impacts.

Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the "PEAPETT" study).

OBJECTIVE: Pulseless electrical activity (PEA) during cardiac arrest portends a poor prognosis. There is a paucity of data in the use of thrombolytic therapy in PEA and cardiopulmonary arrest due to confirmed pulmonary embolism (PE). We evaluated the outcome of low-dose systemic thrombolysis with tissue plasminogen activator (tPA) in patients presenting with PEA due to PE. METHODS: During a 34-month period, we treated 23 patients with PEA and cardiopulmonary arrest due to confirmed massive PE. All patients received 50 mg of tPA as intravenous push in 1 minute while cardiopulmonary resuscitation was ongoing. The time from initiation of cardiopulmonary resuscitation to administration of tPA was 6.5 ± 2.1 minutes. RESULTS: Return of spontaneous circulation occurred in 2 to 15 minutes after tPA administration in all but 1 patient. There was no minor or major bleeding despite chest compression. Of the 23 patients, 2 died in the hospital, and at 22 ± 3 months of follow-up, 20 patients (87%) were still alive. The right ventricular/left ventricular ratio and pulmonary artery systolic pressure dropped from 1.79 ± 0.27 and 58.10 ± 7.99 mm Hg on admission to 1.16 ± 0.13 and 40.25 ± 4.33 mm Hg within 48 hours, respectively (P< .001 for both comparisons). There was no recurrent venous thromboembolism or bleeding during hospitalization or at follow-up. CONCLUSION: Rapid administration of 50 mg of tPA is safe and effective in restoration of spontaneous circulation in PEA due to massive PE leading to enhanced survival and significant reduction in pulmonary artery pressures.

Transforming and simplifying the treatment of pulmonary embolism: "safe dose" thrombolysis plus new oral anticoagulants.

BACKGROUND: Administration of systemic thrombolysis in pulmonary embolism (PE) has been limited to severe forms due to the risk of intracerebral hemorrhage (ICH). There is growing evidence from small studies that low-dose systemic thrombolysis has equal efficacy to standard dose, while eliminating the risk of ICH. Little data exists on the combined use of low-dose systemic thrombolysis and new oral anticoagulants (NOAC). We evaluated the clinical and echocardiographic outcome of patients treated with low or "safe dose" thrombolysis (SDT) and NOAC at intermediate term. METHODS: We retrospectively identified 159 patients with massive and submassive PE who were treated with SDT and NOAC over a 2-year period by our group. They were followed prospectively for PE-related mortality, recurrent PE, bleeding, change in right/left ventricle (RV/LV) size, pulmonary artery systolic pressure (PASP), and clinical improvement at a mean follow-up of 18 ± 3 months. RESULTS: At 6 months, the RV/LV size was reduced from 1.29 ± 0.28 to 0.89 ± 0.03 (p < 0.001). The PASP dropped from 53.12 ± 3.85 mmHg to 30.39 ± 3.93 mmHg (p < 0.001). There was no ICH or in-hospital major or minor bleeding. At 18 months, three patients died of cancer. Recurrent PE developed in one patient who had been later switched to warfarin. The duration of hospitalization was 1.8 ± 0.3 days. CONCLUSION: With combination of SDT and NOAC, treatment of massive and submassive PE becomes identical and is transformed from an "anticoagulation first" to a "thrombolysis first" approach, thereby making treatment streamlined, simple, safe and effective, accessible and inexpensive.

New oral anticoagulants in the treatment of heparin-induced thrombocytopenia.

BACKGROUND: Heparin induced thrombocytopenia (HIT) is a potentially catastrophic syndrome with a high incidence of vascular thrombosis. There are little data on the efficacy of new oral anticoagulants (NOAC) in this setting. This study reports on the outcome of patients with HIT, treated with NOAC. MATERIALS AND METHODS: We retrospectively identified 22 patients with HIT who were treated by our group with a combination of NOAC and a short course of argatroban. These patients were evaluated in a prospective fashion for development of outcomes at a mean follow up of 19±3 months. RESULTS: There were a total of 5 deep and 2 superficial vein thromboses diagnosed at index hospitalization. No patient developed arterial thrombosis. All patients tolerated NOAC and their platelet count normalized before discharge. At 19 months of follow-up, 6 patients had died of non-thrombotic causes. There was no bleeding, limb loss or recurrent venous thromboembolism in any patient. CONCLUSIONS: In patients with HIT, a short course of parenteral treatment with argatroban followed by administration of a NOAC is highly safe and effective in prevention of thrombosis and normalization of platelet count. Development of HIT however, portends a poor prognosis independent of vascular thrombosis.

Protection of Chinese painted quails (Coturnix chinensis) against a highly pathogenic H5N1 avian influenza virus strain after vaccination.

Chinese painted quails immunized with a single dose (6 µg HA) of inactivated H5N1 (clade 1) influenza vaccine NIBRG-14 and challenged with 100 LD50 of the heterologous A/Swan/Nagybaracska/01/06(H5N1) (clade 2.2) strain were protected, whereas unvaccinated quails died after challenge. No viral antigens or RNA were detected in cloacal swabs from immunized animals. Sera obtained post-immunization gave low titres in serological assays against the vaccine and the challenge viruses. Our results demonstrate the protective efficacy of the NIBRG-14 strain against the challenge virus and the usefulness of these small birds in protection studies of influenza vaccines.

A reduced-dose seasonal trivalent influenza vaccine is safe and immunogenic in adult and elderly patients in a randomized controlled trial.

With the recent pandemic of influenza A (H1N1) and vaccine shortages, there has been considerable interest in developing influenza vaccines with reduced doses, allowing for increased production capacity. Here we report a prospective, randomized, double-blind, single-center clinical trial of a reduced-dose whole-virion inactivated, adjuvanted influenza vaccine in adult and elderly volunteers. A total of 234 subjects, including 120 adults (18 to 60 years of age) and 114 elderly subjects (>60 years of age) were enrolled to receive either 6 µg or the conventional 15-µg dose of seasonal trivalent influenza vaccines. The subjects were followed for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition testing. The subjects developed antibody responses against the seasonal influenza A virus H1N1 and H3N2 strains, as well as the seasonal influenza B virus included in the vaccines. Single doses of 6 µg fulfilled licensing criteria for seasonal influenza vaccines. No significant differences in rates of seroconversion or seroprotection or in geometric mean titers were found between the two dosage levels. All adverse events were rare, mild, and transient. We found that the present reduced-dose vaccine is safe and immunogenic in healthy adult and elderly subjects and triggers immune responses that comply with licensing criteria.

The seasonal influenza vaccine Agriflu(®).

Seasonal influenza continues to have a large impact annually. Combined with pneumonia, influenza is the sixth leading cause of death in the USA, and vaccination has been the most important tool to prevent it. Agriflu(®) is an egg-derived, subunit, nonadjuvanted trivalent inactivated vaccine indicated for immunization to prevent disease caused by influenza virus subtypes A and B contained in the vaccine. Agriflu was approved in the USA by the US FDA on 27 November 2009, for those aged 18 years and older, to prevent disease caused by influenza virus subtypes A and B. Based on clinical trial evidence, Agriflu has been shown to be safe, with <1% serious adverse event rates, and immunogenic. It has been proven to be highly effective to prevent culture-confirmed influenza and, thus, is an alternative to previously licensed seasonal influenza vaccines. Besides Fluvirin(®), Agriflu is the only subunit vaccine available in the USA. Owing to the economic burden, morbidity and mortality caused by seasonal influenza, addition of new, safe and effective vaccines to the available tools, to reduce the impact of influenza, is of importance and benefit, especially in the face of the recent shortages of influenza vaccines.

Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009-10 influenza season: a multicentre, randomised controlled trial.

BACKGROUND: With the ongoing 2009 pandemic of influenza A H1N1, development of pandemic influenza vaccines has generated much interest. We investigated the safety and immunogenicity of a whole-virion, inactivated, adjuvanted pandemic H1N1 vaccine in adult and elderly volunteers, given without or simultaneously with the 2009-10 seasonal trivalent influenza vaccine. METHODS: This prospective, randomised study was undertaken in two centres in Hungary. 355 participants, including 203 adults (18-60 years) and 152 elderly people (>60 years), were assigned by stratified randomisation to either 0.5 mL of the pandemic vaccine (Fluval P, a monovalent vaccine with 6 microg haemagglutinin per 0.5 mL content and aluminium phosphate gel adjuvant; n=178) or 0.5 mL of the pandemic vaccine and 0.5 mL of the seasonal trivalent vaccine (Fluval AB, a trivalent inactivated whole-virion influenza vaccine; n=177). All vaccinations were done by specific study personnel, who did not take part in the assessment of safety or immunogenicity. Co-primary objectives were safety and immunogenicity by haemagglutinin inhibition testing. All analyses were done according to a pre-established analysis plan. This study is registered with ClinicalTrials.gov, number NCT01010893. FINDINGS: Two participants receiving the pandemic vaccine only (group 1) and one receiving pandemic and seasonal vaccines (group 2) were lost to follow-up. Participants in both groups developed antibody responses against the pandemic influenza A H1N1 virus (group 1: seroconversion for adults 74.3%, 95% CI 64-6-82.4 and for elderly people 61.3%, 49.1-72.4; group 2: 76.8%, 67.2-84.7 and 81.8%, 71.4-89.7, respectively). Single doses of 6 microg fulfilled European Union and US licensing criteria for interpandemic and pandemic influenza vaccines. Simultaneously, participants in group 2 developed the immune responses needed for licensing for all three seasonal strains in the seasonal vaccine for the 2009-10 season. All adverse events were rare, mild, and transient; the most frequent were pain at injection site (eight cases in group 1 vs 18 in group 2) and fatigue for 1-2 days after vaccination (three vs five cases). INTERPRETATION: The present pandemic vaccine is safe and immunogenic in healthy adult and elderly patients, and needs low doses and only one injection to trigger immune responses to comply with licensing criteria. It can be safely co-administered with the 2009-10 seasonal influenza vaccine. FUNDING: Omninvest, Hungary.

A single-dose influenza A (H5N1) vaccine safe and immunogenic in adult and elderly patients: an approach to pandemic vaccine development.

With the ongoing pandemic of influenza A (H1N1) virus infection and the threat of high fatality rates for recent human cases of infection with highly pathogenic H5N1 strains, there has been considerable interest in developing pandemic vaccines. Here we report a randomized multicenter dose-finding clinical trial of a whole-virion, inactivated, adjuvanted H5N1 vaccine in adult and elderly volunteers. Four hundred eighty patients were randomly assigned to receive one or two doses of 3.5 microg of the vaccine or one dose of 6 or 12 microg. The subjects were monitored for safety analysis, and serum samples were obtained to assess immunogenicity by hemagglutination inhibition and microneutralization tests. The subjects developed antibody responses against the influenza A (H5N1) virus. Single doses of > or = 6 microg fulfilled EU and U.S. licensing criteria for interpandemic and pandemic influenza vaccines. Except for occasional injection site pain, malaise, and fever, no adverse events were observed. We found that the present vaccine is safe and immunogenic in healthy adult and elderly subjects and requires low doses and, unlike any other H5N1 vaccines, only one injection to trigger immune responses which comply with licensing criteria. A vaccine using the same methods as those described in this report, but based on a wild-type swine-origin 2009 (H1N1) influenza A virus isolate from the United States (supplied by the CDC), has been developed and is currently being tested by our group.

Cardiovascular risk status and primary prevention in postmenopausal women: the MENOCARD study.

OBJECTIVE: Our aim was to evaluate the usefulness of screening for cardiovascular risk factors and the effect of applying professional guidelines for risk reduction in postmenopausal women, as judged by the Framingham and the high-risk systematic coronary risk evaluation (SCORE) methods. METHODS: 18 menopause clinics in Hungary participated in the study, enrolling a total of 2789 patients. Physicians were asked to follow professional guidelines for the primary prevention of cardiovascular disease. Patients were requested to attend follow-up every four months for 12 months. RESULTS: The mean age of the patients was 56.7+/-6.9 years, and the time elapsed since the last menstrual period was 9.2+/-7.2 years. Overall, 29.4% of patients attended at least one follow-up visit. At the initial visit, high total cholesterol level (>5 mmol/l) was detected in 78% of patients, high triglyceride level (>1.7 mmol/l) in 29%, high systolic and/or diastolic blood pressure (>140/90 mmHg) in 32%, fasting plasma glucose level>6.1 mmol/l in 15%. Increased waist circumference (>88 cm) was found in 85.8% of the patients; 18.3% of the patients smoked, which did not change. After 12 months, all laboratory parameters and the blood pressure had improved significantly. Both the Framingham and SCORE systems showed a significant improvement in the cardiovascular risk status, and the rate of metabolic syndrome had decreased significantly by the end of the study. CONCLUSIONS: Screening postmenopausal women for cardiovascular risk and the application of professional guidelines for primary prevention may significantly reduce the risk of coronary artery disease in this group. Patient compliance with follow-up visits needs improvement.

Influenza A (H5N1) pandemic prototype vaccine Fluval.

The timely development of safe and effective vaccines is likely to be the single most important public-health tool for decreasing the morbidity, mortality and economic effects of the influenza pandemic. The objective of this article is to provide a detailed description of the chemistry and immunogenicity of one of the better studied inactivated whole-virion aluminum phosphate-adjuvanted vaccines, Fluval (Omninvest, Hungary), while we discuss safety data of all clinical trials published on H5N1 vaccines to date. Fluval was chosen for detailed discussion owing to its immunogenicity after only one dose, the fact that it was one of the very first H5N1 vaccines that demonstrated the potential for dose sparing and, unlike all mainstream oil-in-water adjuvanted reverse genetics-derived H5N1 vaccines, it is whole virion based.

Cross-reactive immunity to clade 2 strains of influenza virus A subtype H5N1 induced in adults and elderly patients by Fluval, a prototype pandemic influenza virus vaccine derived by reverse genetics, formulated with a phosphate adjuvant, and directed to clade 1 strains.

High fatality rates and multiple cases of transmission of avian H5N1 influenza viruses to humans illustrate the urgent need for an efficacious, cross-protective vaccine against H5N1 strains. Extensive genetic characterization of H5N1 strains has elucidated the natural evolutionary relationship of these strains, linking groups known as clades to a common ancestor. Although the clades and subclades probably differ sufficiently in their antigenic structure to warrant the preparation of different vaccines, there is some evidence that cross-reactive immunity can be afforded. We aimed to assess the immunogenicity of a clade 1 H5N1 (NIBRG-14) whole-virus vaccine with an aluminum phosphate adjuvant and to determine whether it can induce cross-reactive immunity against antigenically drifted clade 2 H5N1 strains, both those derived by reverse genetics and wild-type isolates. A total of 88 (44 adult and 44 elderly) subjects, who received one dose (6 microg) of the vaccine, were studied. As judged by U.S. and European licensing criteria based on hemagglutination inhibition, the subjects developed cross-reactive immunity against all studied H5N1 strains belonging to a clade different from that of the strain utilized to produce the vaccine. Our findings highlight the importance of stockpiling, since cross-immune reactions induced by prepandemic vaccines will likely reduce morbidity and mortality in case of a pandemic.

Safety and immunogenicity of a prepandemic influenza A (H5N1) vaccine in children.

BACKGROUND: The avian influenza A (H5N1) virus is considered to be a potential cause of the next influenza pandemic. Children may be particularly vulnerable to the pandemic virus, and they may react differently than adults to vaccines. We report the results of the first clinical trial of an H5N1 vaccine in children. METHODS: Twelve healthy children (mean age +/- SD: 12.73 +/- 2.77 years) received a single dose of 6 microg of the inactivated whole virus vaccine Fluval. Twenty-one days after vaccination, immunogenicity was assessed by hemagglutination inhibition and microneutralization assays. Safety information was collected for 180 days. RESULTS: No side-effects were observed, and the vaccine fulfilled all applicable U.S. and European immunogenicity criteria for licensure. The post/prevaccination geometric mean titer ratio was 16.95, the rate of seroconversion was 75% and the rate of seroprotection was also 75% 21 days after vaccination. CONCLUSIONS: We confirmed our earlier findings of the present vaccine in adults showing encouraging safety and immunogenicity properties in children. Studies with the present vaccine in elderly subjects are underway.

[Our experience with the preparation of fixed segmented bridges with nonrigid extracoronally placed connectors. Case series]. / Extrakoronális csúztatóval kombinált osztott hidak készitésével szerzett tapasztalataink. Esetismertetés.

AIMS: For the replacement of dental deficiencies when the difference in axis between the future abutment teeth is considerable and preparation of a fixed bridge-prosthesis is planned without the sacrifice of too much extra dental tissue, one possibility is to prepare fixed separated dentures with nonrigid connectors. METHODS: From 1999 to 2007, we prepared such dentures, initially using intracoronal retainers in accordance with the literature, after that we positioned the retainers extracoronally whenever this was possible. RESULTS: In 35 cases we prepared multi-unit fixed prostheses with a total of 43 retainers. These segmented prostheses could be fixed rigidly after cementation. All of them remain in place without any complaint. CONCLUSION: Fixed dentures prepared with extracoronal retainers proved safe and esthetic and extra dental tissue is not sacrificed.