Is seasonal vaccination a contributing factor to the selection of influenza epidemic variants?

Influenza A/H3N2 viruses are the most common and virulent subtypes for humans. Antigenic drift, changes in antigenicity through the accumulation of mutations in the hemagglutinin (HA) gene is chiefly responsible for the continuing circulation of A/H3N2 viruses, resulting in frequent updates of vaccine strains based on new variant analyses. In humans, these drift-related mutations are considered to be primarily caused by the immune pressure elicited by natural infection. Whether or not the immune pressure elicited by vaccination (vaccine pressure) can have a certain effect on drift-related mutations is unclear. Recently, our findings suggested the possible effect of vaccine pressure on HA mutations by directly comparing amino acid differences from the corresponding vaccine strains between isolates from vaccinated and unvaccinated patients. It is possible that influenza vaccine pressure selects variants genetically distant from the vaccine strains. Considering the effect of vaccine pressure on HA mutations would contribute to further understanding the mechanism of antigenic drift, which would be helpful for predicting future epidemic viruses.

Continued effectiveness of laninamivir octanate hydrate for influenza treatment in Japan: comparison between the 2011-2012 and 2012-2013 influenza seasons.

The clinical effectiveness of Laninamivir octanoate hydrate (laninamivir) was investigated in the Japanese 2012-2013 influenza season for comparison with that of the Japanese 2011-2012 influenza season. A total of 235 patients were enrolled, of whom 210 were evaluated for the duration of fever and other symptoms. The median durations of fever for A(H3N2) were 32.0 and 38.0 h and the median durations of symptoms for the A(H3N2) were 102.0 and 84.0 h for patients aged under 10 and 10 years or older, respectively. All four influenza B patients were 10 years or older, and their median duration of fever was 43.0 h and the median duration of symptoms was 71.0 h. There was no significant difference in the duration of fever or symptoms between the two seasons. The rates of patients A(H3N2) virus positive at day 5 were 37.2% (16/43) and 12.8% (18/141) for those aged under 10 years and 10 years or older, respectively. The virus positive rate was significantly higher for the patients under 10 years than for the patients aged 10 years or older (p < 0.0001). No significant change in IC50 value was found between days 1 and 5. Adverse drug reactions were reported by 2 of the 231 patients (0.87%), but neither was serious. These results suggest that laninamivir continued to be effective against influenza A(H3N2) with no safety issues and that it is unlikely that the clinical use of laninamivir will lead to virus resistance.

Evaluation of immune response following one dose of an AS03A-adjuvanted H1N1 2009 pandemic influenza vaccine in Japanese adults 65 years of age or older.

OBJECTIVE: This study assessed the immunogenicity, long-term persistence of immune response and safety of a single dose of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (α-tocopherol and squalene based oil-in-water emulsion Adjuvant System) in subjects ≥ 65 y of age (NCT01114620). RESULTS: At Day 21, the HI immune response met all three European guidance criteria [seroconversion rate (SCR): 60.0%; seroprotection rate (SPR): 64.0%; geometric mean fold rise (GMFR): 10.2] and the US guidance criterion for SCR. At month 6, the HI immune response against the A/California/07/2009 H1N1 strain persisted but at levels lower than that observed at Day 21 (SCR: 38.8%; SPR: 42.9%; HI antibody geometric mean titer: 27.6); the European regulatory guidance criteria for SCR and GMFR were still met. Overall, the vaccine was well-tolerated. METHODS: In this open-label, single group study, 50 subjects received one dose of the 3.75 µg hemagglutinin (HA) AS03-adjuvanted H1N1 2009 vaccine. Immunogenicity assessments were made before vaccination, 21 days and six months after vaccination using hemagglutination inhibition (HI) and microneutralization assays. Immunogenicity end points were based on US and European regulatory criteria. CONCLUSION: A single dose of the 3.75 µg HA AS03-adjuvanted H1N1 2009 pandemic vaccine induced immune responses against the vaccine strain that met the European regulatory guidance criteria at day 21 in the elderly Japanese population; the immune response persisted at lower levels at month 6. No safety concerns were identified. These results suggest that two vaccine doses might be useful for the elderly population to improve antibody induction and persistence.

Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults.

Background Long-term persistence of immune response and safety of two doses of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) administered 21 d apart was evaluated in Japanese adults [NCT00989612]. Methods One-hundred healthy subjects aged 20-64 y (stratified [1:1] into two age strata 20-40 y and 41-64 y) received 21 d apart, two doses of AS03-adjuvanted 3.75µg haemagglutinin (HA) H1N1 2009 vaccine. Immunogenicity data by haemagglutination inhibition (HI) assay six months after the first vaccine dose (Day 182) and microneutralization assay following each of the two vaccine doses (Days 21 and 42) and at Day 182 are reported here. Results Persistence of strong HI immune response was observed at Day 182 that met the US and European regulatory thresholds for pandemic influenza vaccines (seroprotection rate: 95%; seroconversion rate: 93%; geometric mean fold-rise: 20). The neutralizing antibody response against the A/Netherlands/602/2009 strain (antigenically similar to vaccine-strain) persisted for at least up to Day 182 (vaccine response rate: 76%; geometric mean titer: 114.4) and paralleled the HI immune response at all time points. No marked difference was observed in HI antibody persistence and neutralising antibody response between the two age strata. The vaccine had a clinically-acceptable safety profile. Conclusion Two priming doses of H1N1 2009 pandemic influenza vaccine induced an immune response persisting for at least six months after the first vaccine dose. This could be beneficial in evaluating the importance and effect of vaccination with this AS03-adjuvanted pandemic influenza vaccine.

A randomized, controlled trial comparing traditional herbal medicine and neuraminidase inhibitors in the treatment of seasonal influenza.

The herbal medicine, maoto, has been traditionally prescribed to patients with influenza in Japan. To better understand the efficacy of maoto for the treatment of influenza, a randomized trial was conducted for comparison with oseltamivir or zanamivir. Adult patients with influenza symptoms, including fever, positive for quick diagnostic kit for influenza within 48 h of fever onset were assessed for enrollment. The data of 28 patients randomly assigned to maoto (n = 10), oseltamivir (n = 8), or zanamivir (n = 10) were analyzed for the duration of fever (>37.5°C) and total symptom score from symptom cards recorded by the patient. Viral isolation and serum cytokine measurements were also done on days 1, 3, and 5. Maoto granules, a commercial medical dosage form, are made from four plants: Ephedra Herb, Apricot Kernel, Cinnamon Bark, and Glycyrrhiza Root. Median durations of fever of patients assigned maoto, oseltamivir, or zanamivir were 29, 46, or 27 h, respectively, significantly different for maoto and oseltamivir. No significant between-group differences were found in total symptom score among three groups. Viral persistent rates and serum cytokine levels (IFN-α, IL-6, IL-8, IL-10, and TNF-α) during the study period showed no differences among three groups. The administration of oral maoto granules to healthy adults with seasonal influenza was well tolerated and associated with equivalent clinical and virological efficacy to neuraminidase inhibitors.

A phase II, open-label, multicentre study to evaluate the immunogenicity and safety of an adjuvanted prepandemic (H5N1) influenza vaccine in healthy Japanese adults.

BACKGROUND: Promising clinical data and significant antigen-sparing have been demonstrated for a pandemic H5N1 influenza split-virion vaccine adjuvanted with AS03A, an α-tocopherol-containing oil-in-water emulsion-based Adjuvant System. Although studies using this formulation have been reported, there have been no data for Japanese populations. This study therefore aimed to assess the immunogenicity and tolerability of a prepandemic (H5N1) influenza vaccine adjuvanted with AS03A in Japanese adults. METHODS: This open-label, single-group study was conducted at two centres in Japan in healthy Japanese males and females aged 20-64 years (n = 100). Subjects received two doses of vaccine, containing 3.75 µg haemagglutinin of the A/Indonesia/5/2005-like IBCDC-RG2 Clade 2.1 (H5N1) strain adjuvanted with AS03A, 21 days apart. The primary endpoint evaluated the humoral immune response in terms of H5N1 haemagglutination inhibition (HI) antibody titres against the vaccine strain (Clade 2.1) 21 days after the second dose. Ninety five percent confidence intervals for geometric mean titres, seroprotection, seroconversion and seropositivity rates were calculated. Secondary and exploratory endpoints included the assessment of the humoral response in terms of neutralising antibody titres, the response against additional H5N1 strains (Clade 1 and Clade 2.2), as well as the evaluation of safety and reactogenicity. RESULTS: Robust immune responses were elicited after two doses of the prepandemic influenza vaccine adjuvanted with AS03A. Overall, vaccine HI seroconversion rates and seroprotection rates were 91% 21 days after the second vaccination. This fulfilled all regulatory acceptance criteria for the vaccine-homologous HI antibody level. A substantial cross-reactive humoral immune response was also observed against the virus strains A/turkey/Turkey/1/2005 (Clade 2.2) and A/Vietnam/1194/2004 (Clade 1) after the second vaccine administration. A marked post-vaccination response in terms of neutralising antibody titres was demonstrated and persistence of the immune response was observed 6 months after the first dose. The vaccine was generally well tolerated and there were no serious adverse events reported. CONCLUSIONS: The H5N1 candidate vaccine adjuvanted with AS03A elicited a strong and persistent immune response against the vaccine strain A/Indonesia/5/2005 in Japanese adults. Vaccination with this formulation demonstrated a clinically acceptable reactogenicity profile and did not raise any safety concerns in this population. TRIAL REGISTRATION: Clinicaltrials.gov NCT00742885.

Clinical safety of licorice flavonoid oil (LFO) and pharmacokinetics of glabridin in healthy humans.

OBJECTIVE: Licorice flavonoids have various physiological activities such as abdominal fat-lowering, hypoglycemic and antioxidant effects. Licorice flavonoid oil (LFO: Kaneka Glavonoid Rich Oil) is a new dietary ingredient containing licorice flavonoids dissolved in medium-chain triglycerides (MCT). Glabridin is one of the bioactive flavonoids included specifically in licorice Glycyrrhiza glabra L. and is the most abundant flavonoid in LFO. In this study, we assessed the safety of LFO in healthy humans and determined the plasma concentration profile of glabridin as a marker compound. METHODS: A single-dose and two multiple-dose studies at low (300 mg), moderate (600 mg) and high (1200 mg) daily doses of LFO were carried out using a placebo-controlled single-blind design. In each study the safety of LFO and the pharmacokinetics of glabridin were assessed. RESULTS: Pharmacokinetic analysis in the single-dose study with healthy male subjects (n = 5) showed that glabridin was absorbed and reached the maximum concentration (Cmax) after approximately 4 h (Tmax), and then eliminated relatively slowly in a single phase with a T1/2 of approximately 10 h at all doses. The Cmax and AUC(0-24 h) increased almost linearly with dose. The multiple-dose studies with healthy male and female subjects for 1 week and 4 weeks suggested that plasma glabridin reached steady state levels within 2 weeks with a single daily administration of 300 to 1200 mg/day LFO. In these human studies at three dose levels, there were no clinically noteworthy changes in hematological or related biochemical parameters. All clinical events observed were mild and considered to be unrelated to LFO administration even after repeated administration for 4 weeks. CONCLUSION: These studies demonstrated that LFO is safe when administered once daily up to 1200 mg/day. This is the first report on the safety of licorice flavonoids in an oil preparation and the first report on the pharmacokinetics of glabridin in human subjects.

Safety assessment of coenzyme Q10 (Kaneka Q10) in healthy subjects: a double-blind, randomized, placebo-controlled trial.

The safety profile of Coenzyme Q10 (Kaneka Q10) at high doses for healthy subjects was assessed in a double-blind, randomized, placebo-controlled study. Kaneka Q10 in capsule form was taken for 4 weeks at doses of 300, 600, and 900 mg/day by a total of eighty-eight adult volunteers. No serious adverse events were observed in any group. Adverse events were reported in 16 volunteers with placebo, in 12 volunteers with the 300 mg dose, in 20 volunteers with the 600 mg, dose and in 16 volunteers with the 900 mg dose. The most commonly reported events included common cold symptoms and gastrointestinal effects such as abdominal pain and soft feces. These events exhibited no dose-dependency and were judged to have no relationship to Kaneka Q10. Changes observed in hematology, blood biochemistry, and urinalysis were not dose-related and were judged not to be clinically significant. The plasma CoQ10 concentration after 8-month withdrawal was almost the same as that before administration. These findings showed that Kaneka Q10 was well-tolerated and safe for healthy adults at intake of up to 900 mg/day.