Safety, Tolerability, and Immunogenicity of aH5N1 Vaccine in Adults with and without Underlying Medical Conditions.

Influenza pandemics pose a serious risk to the global population, with the potential for high morbidity and mortality. An adjuvanted H5N1 vaccine (aH5N1) has been approved for prophylaxis against the avian influenza virus H5N1, which is a likely cause of future pandemics. In this phase-III, stratified, randomized, controlled, observer-blind, multicenter study, we evaluated the safety and immunogenicity of aH5N1 in four separate groups of adults: adults 18-60 years of age who were healthy or had high-risk medical conditions and older adults ≥61 years of age who were healthy or had high-risk medical conditions. Subjects were randomly assigned to aH5N1 or the comparator, adjuvanted trivalent seasonal influenza vaccine (aTIV). Antibody responses to aH5N1 were increased in all four subgroups and, within each age stratum, largely consistent between healthy subjects and those with medical conditions. Injection-site pain was reported by 66-73% of younger and 36-42% of older-aH5N1 recipients, and fatigue and myalgia were reported by 22-41% of subjects across age and health subgroups. No serious adverse events or deaths were considered related to the study vaccine. In conclusion, aH5N1 increased antibody responses regardless of age or health status and demonstrated a clinically acceptable safety and tolerability profile.

Accelerated up-dosing of subcutaneous immunotherapy with a registered allergoid grass pollen preparation.

BACKGROUND: Climatic changes causing early pollen flight and new allergens prolonging the pollen season render up-dosing of allergen-specific subcutaneous immunotherapy (SCIT) outside the pollen season considerably more difficult. In addition, for patients with multiple pollen allergies, patients coming near the beginning of pollen season, and patients who wish to up-dose faster, an accelerated induction regimen would be helpful. METHODS: In an open, randomized, parallel group, multicenter safety trial, an accelerated up-dosing regimen (0.1-0.3-0.5 ml in weekly intervals) was compared to conventional up-dosing (0.05-0.1-0.2-0.3-0.4-0.5 ml in weekly intervals) with an allergoid grass pollen SCIT preparation. After up-dosing, the maintenance dose was given in monthly intervals. RESULTS: A total of 146 adult patients with rhinitis or rhinoconjunctivitis with or without mild asthma (FEV1 >70%) due to grass pollen were randomized to either the conventional registered up-dosing or an accelerated regimen. In both groups (accelerated regimen, n = 69; conventional regimen, n = 75), a high proportion of patients (92.75 and 92.0%, respectively) successfully reached the maintenance dose without safety concerns. Furthermore, significant increases in specific IgG and IgG4 after 4 months of treatment were observed in both groups. CONCLUSION: The accelerated SCIT regimen was found to be as safe as the conventional regimen and might be used to up-dose patients within 2 weeks. Moreover, the immunological effects of both up-dosing regimens were comparable.

Antibody responses against heterologous H5N1 strains for an MF59-adjuvanted cell culture-derived H5N1 (aH5n1c) influenza vaccine in adults and older adults.

MF59-adjuvanted H5N1, cell culture-derived inactivated influenza vaccine (aH5N1c, AUDENZ®, Seqirus) is available for persons 6 months of age and older. During a pandemic, lack of preexisting immunity to novel influenza strains increases morbidity and mortality. This study examined the potential for an adjuvanted vaccine to provide cross-protection to novel viruses. Two similarly designed studies involving separate cohorts aged 18-64 and ≥65 y assessed immune responses to five heterologous H5N1 influenza strains elicited by two 7.5 µg doses of aH5N1c given 3 weeks apart. Geometric mean titers (GMT) on Days 1 and 43 and Day 43/Day 1 geometric mean ratios (GMRs) were determined with hemagglutination inhibition (HI) and microneutralization (MN). Rates of seroconversion (SC) and percentages of subjects with HI and MN ≥ 1:40 were determined. Significant increases in GMTs were observed on Day 43 after vaccination for all 5 heterologous strains in all ages tested. SC rates were 28-55% and 17-46% among those aged 18-64 and ≥65 y, respectively. MN ≥ 1:40 was observed in 38-100% of younger and 37-97% of older subjects, and HI ≥ 1:40 was achieved by 28-64% of subjects aged 18-64 y and by 17-57% of subjects aged ≥65 y. A SC rate ≥40% (97.5% CI) was met for two heterologous strains tested in adults aged 18-64 y. In adults aged 18-64 and ≥65 y, two 7.5 µg doses of aH5N1c demonstrated increased immunogenicity from baseline against five heterologous H5N1 strains, illustrating the potential for aH5N1c to provide cross-protection against other H5N1 strains.

Phase 3 Randomized, Multicenter, Placebo-Controlled Study to Evaluate Safety, Immunogenicity, and Lot-to-Lot Consistency of an Adjuvanted Cell Culture-Derived, H5N1 Subunit Influenza Virus Vaccine in Healthy Adult Subjects.

A cell-based process may be better suited for vaccine production during a highly pathogenic avian influenza (HPAI) pandemic. This was a phase 3, randomized, controlled, observer-blind, multicenter study evaluated safety, immunogenicity, and lot-to-lot consistency of two doses of a MF59-adjuvanted, H5N1 influenza pandemic vaccine manufactured on a cell culture platform (aH5N1c) in 3196 healthy adult subjects, stratified into two age groups: 18 to <65 and ≥65 years. Immunogenicity was measured using hemagglutination inhibition (HI) titers. HI antibody responses increased after the first aH5N1c vaccine dose, and 3 weeks after the second vaccination (Day 43), age-appropriate US Center for Biologics Evaluation and Research (CBER) and former European Medicines Authority Committee for Medicinal Products for Human Use (EMA CHMP) immunogenicity criteria were met. Six months after the first vaccination, HI titers were above baseline but no longer met CBER and CHMP criteria. No relevant changes over time were seen in placebo subjects. Solicited AEs were more frequent in the active treatment than the placebo group, primarily due to injection site pain. No serious adverse events (SAEs) related to aH5N1c- were reported. aH5N1c influenza vaccine elicited high levels of antibodies following two vaccinations administered 21 days apart and met both CBER and former CHMP immunogenicity criteria at Day 43 among both younger and older adults with a clinically acceptable safety profile. Consistency of the three consecutive aH5N1c vaccine lots was demonstrated (NCT02839330).

Antibody responses against heterologous A/H5N1 strains for an MF59-adjuvanted cell culture-derived A/H5N1 (aH5N1c) influenza vaccine in healthy pediatric subjects.

BACKGROUND: Vaccines are the main prophylactic measure against pandemic influenza. Adjuvanted, cell culture-derived vaccines, which are not subject to limitations of egg-based vaccine production, have the potential to elicit an antibody response against heterologous strains and may be beneficial in the event of an A/H5N1 pandemic. METHODS: A prespecified exploratory analysis of data from a phase 2, randomized, controlled, observer-blind multicenter trial (NCT01776554) to evaluate the immunogenicity of a MF59-adjuvanted, cell culture-based A/H5N1 influenza vaccine (aH5N1c), containing 7.5 µg hemagglutinin antigen per dose, in subjects 6 months through 17 years of age was conducted. Geometric mean titers (GMT) were determined using hemagglutination inhibition (HI) and microneutralization (MN) assays, and proportions of patients achieving seroconversion, HI and MN titers ≥ 1:40, and a 4-fold increase in MN titers against 5 heterologous strains (influenza A/H5N1 Anhui/2005, Egypt/2010, Hubei/2010, Indonesia/2005, and Vietnam/1203/2004) three weeks after administration of the second dose were assessed. RESULTS: After the second dose, HI GMTs against heterologous strains increased between 8- and 40-fold, and MN GMTs increased 13- to 160-fold on Day 43 vs Day 1. On Day 43, 32-72% of subjects had HI titers ≥ 1:40 and achieved seroconversion against the heterologous strains. Using the MN assay, 84-100% of subjects had MN titers ≥ 1:40 and 83-100% achieved an at least 4-fold increase in MN titers against the heterologous strains. The highest responses were consistently against A/H5N1 Egypt/2010. CONCLUSIONS: When given to children aged 6 months through 17 years, aH5N1c resulted in increased immunogenicity from baseline against all 5 heterologous A/H5N1 strains tested, demonstrating the potential of an MF59-adjuvanted, cell-derived A/H5N1 vaccine to provide cross-protection against other A/H5N1 strains (NCT01776554).

Analyses of Safety Profile and Homologous Antibody Responses to a Mammalian Cell-Based, MF59-Adjuvanted, A/H5N1, Pandemic Influenza Vaccine across Four Phase II/III Clinical Trials in Healthy Children, Adults, and Older Adults.

Modern cell culture-based technology eliminates vaccine manufactures reliance on embryonated chicken eggs, which may become compromised during an avian influenza pandemic. Four studies (total N = 6230) assessed the immunogenicity and safety of mammalian cell-based, MF59®-adjuvanted, A/H5N1 vaccine (aH5N1c; AUDENZ™) as two doses administered on Days 1 and 22 in children (NCT01776554), adults (NCT01776541; NCT02839330), and older adults (NCT01766921; NCT02839330). Immunogenicity of formulations at 7.5 µg and 3.75 µg antigen per dose were assessed by hemagglutination inhibition and microneutralization assays on Days 1, 22, 43, and 183 or 387. Solicited local and systemic adverse events (AEs) were recorded for 7 days after each vaccination. Unsolicited AEs were collected for 21 days after each vaccination, and serious and other selected AEs were recorded for one year. Antibody responses after two 7.5 µg doses met CBER licensure criteria in all age groups. Overall, an age-related response was evident, with the highest responses observed in children <3 years old. In children, antibody titers met seroconversion criteria 12 months after vaccination. MF59 allowed for antigen dose sparing. Solicited AEs were mild to moderate in nature, of short duration, and less frequent after the second dose than the first, demonstrating a favorable risk-benefit profile.

A prospective study comparing the efficacy and safety of two sublingual birch allergen preparations.

BACKGROUND: SUBLIVAC FIX Birch (SUB-B) is a liquid oral preparation of Betula verrucosa pollen extract for the treatment of allergic rhinitis/rhinoconjuctivitis induced by birch pollen. The major allergen content of SUB-B and Staloral Birch (Stal-B) have been shown to be comparable. In order to compare the clinical efficacy and safety of both products, the present study was designed to investigate efficacy of treatment with SUB-B compared to Stal-B by means of reduction in allergy symptoms assessed by a titrated nasal provocation test (TNPT) in subjects suffering from IgE mediated allergy complaints triggered by birch pollen. METHODS: A prospective, randomized, open, blinded endpoint (PROBE), controlled, single-centre study in 74 birch allergic adults was performed. Treatment consisted of either SUB-B (10,000 AUN/ml) or Stal-B (initial phase 10 I.R./ml and maintenance phase 300 I.R./ml) for 16-20 weeks at maintenance dose. The primary efficacy outcome was defined by the difference in change of the TNPT-threshold dose between the two treatment groups at baseline and after completion of treatment. Secondary outcomes included determination of birch pollen specific IgE and IgG levels, safety lab and ECG. During the first 30 days of treatment, subjects were requested to fill out a diary concerning compliance with study medication, occurrence of AEs and the use of concomitant medication. RESULTS: Analysis of the primary efficacy parameter showed that the percentage of subjects showing a beneficial treatment effect was similar in both treatment groups, 33.3% for SUB-B vs. 31.4% for Stal-B in the intention to treat population. Evaluation of the immunologic response, showed that treatment with SUB-B and Stal-B induced similar increases (approximately 2 times) in IgE, IgG and IgG4 specific for Bet v 1. In total, 143 related adverse events (AEs) were reported. The majority of the AEs was of mild intensity. The same pattern of AEs was observed for both products. No clinically relevant changes in other safety parameters, such as safety laboratory parameters, vital signs, physical examination and ECGs were observed. CONCLUSION: Taken together, treatment with both products was effective by means of reduction in allergic symptoms during a TNPT. In addition, safety analysis revealed a good tolerability of both SLIT extracts.