Μg Hemagglutinin Antigen Research Articles

Immunological priming induced by a two-dose series of H5N1 influenza antigen, administered alone or in combination with two different formulations of AS03 adjuvant in adults: Results of a randomised single heterologous booster dose study at 15 months

One influenza pandemic preparedness strategy involves priming a population with a pre-pandemic subtype-specific vaccine and boosting the immunological response at the time of the pandemic with a strain-matched vaccine. In the current study, adults (n=469) randomised 15 months previously to receive an A/Indonesia/5/2005 (H5N1) influenza vaccine (3.75μg haemagglutinin antigen [HA]) administered alone or in combination with an oil-in-water emulsion based Adjuvant System containing 11.86mg (AS03A) or 5.93mg (AS03B) tocopherol per dose, received one booster dose of A/turkey/Turkey/1/2005 (H5N1) vaccine (3.75μg HA) with or without AS03A. An anamnestic antibody response that met US regulatory acceptance criteria was observed 15 months after priming. Although superior immunogenicity of AS03-adjuvanted compared to unadjuvanted priming was not demonstrated, higher antibody titres which persisted longer were seen when both priming and boosting regimens were adjuvanted. This may affect duration of response or heterologous immunity. The booster vaccines had a clinically acceptable safety/reactogenicity profile after adjuvanted or unadjuvanted priming. This study has been registered at www.clinicaltrials.govNCT00771615.

Immunogenicity and safety of AS03-adjuvanted H1N1 pandemic vaccines in children and adolescents

Vaccines with acceptable efficacy profile against the H1N1 A/California/7/2009 virus are needed for use in children. The two studies presented here evaluated the immunogenicity and the reactogenicity/safety of A/H1N1/2009 vaccines containing either 3.75μg haemagglutinin antigen (HA) and AS03A-adjuvant (3.75μg HA/AS03A study) (N=210 [53, 57 and 100 in the 3–5, 6–9 and 10–17 years age strata, respectively]) or 1.9μg HA and AS03B-adjuvant (1.9μg HA/AS03B study) (N=244 [61, 65 and 118 in the 3–5, 6–9 and 10–17 years age strata, respectively]), given as two-dose series. Although the haemagglutination inhibition antibody titres were higher in the 3.75μg HA/AS03A study, both vaccine dosages were highly immunogenic and exceeded regulatory acceptance criteria after the first and the second doses. Seroprotection rates reached 100% and seroconversion rates ranged from 98.2% to 99.1% after each dose of both vaccine dosages. Geometric mean titres increased from 456.5 to 1538.5 and from 297.9 to 1106.7 between the first and the second doses in the 3.75μg HA/AS03A study and the 1.9μg HA/AS03B study, respectively. Despite an observed slight increase of the reactogenicity following the second dose in the 3.75μg HA/AS03A study, the vaccines safety profiles were considered clinically acceptable. In conclusion, both dosages of the AS03-adjuvanted A/H1N1/2009 pandemic influenza vaccines were highly immunogenic and well-tolerated in children and adolescents.

Immune response of single dose vaccination against 2009 pandemic influenza A (H1N1) in the Taiwanese elderly

We conducted a multi-center, randomized and laboratory-blinded clinical trial with subgroup analyses, involving adults aged greater than 60 years old (range 61–86 years old), to investigate the immunogenicity and the potential factors affecting the immune response of a monovalent, unadjuvanted, inactivated, split-virus vaccine. A total of 107 subjects were randomized to receive 15 and 30 μg of hemagglutinin antigen in a 1:1 ratio. The immunogenicity was detected through hemagglutination inhibition (HAI) test of serum obtained before and 3 weeks after vaccination. By 3 weeks after vaccination, HAI titer ≧1:40 was observed in 75.5% and 81.1% of participants receiving 15 and 30 μg of hemagglutinin antigen, respectively. Positive seroconversion was observed in 71.7% and 81.1% of recipients of the 15 and the 30 μg, respectively. The GMTs increased by a factor of 10.7 and 17.4 in the groups of 15 and 30 μg, respectively. This study indicated that one dose of 15 μg hemagglutinin antigen without adjuvant induced protective immune response in the majority of elderly. Multivariate logistic regression analyses showed that gender, age and diabetes were statistically significant factors affecting the seroprotection rate ( p = 0.04, 0.01 and 0.01, respectively) and seroconversion rate ( p = 0.01, 0.01 and 0.01, respectively).

Immunogenicity of a monovalent pandemic influenza A H1N1 vaccine in health‐care workers of a university hospital in Japan

A phase III observational study evaluating a single-dose of an inactivated, split-virus, unadjuvanted AH1pdm vaccine in HCW was conducted. A safe and effective vaccine was needed after the emergence of AH1pdm in April 2009. We analyzed the immunogenicity and safety of the vaccine. A total of 409 subjects were enrolled and given 15 μg hemagglutinin antigen by s.c. injection. Antibody titers were measured using hemagglutination-inhibition antibody assays before vaccination and 28 days after. The co-primary immunogenicity end-points were the proportion of subjects with antibody titers of 1:40 or more, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer. We collected 389 pair samples. Antibody titers of 1:40 or more were observed in 148 of 389 subjects (38.0%, 95% CI: 33.2-42.9). The immunogenicity was also confirmed in other end-points, but was not sufficient and was lower than in previous reports. A total of 96 of adverse events was reported: 51 local events and 57 systemic events. There were 12 subjects with both local and systemic events. Nearly all events were mild to moderate except in four subjects. A single 15-μg dose of AH1pdm vaccine did not induce sufficient immunogenicity in HCW, with mild-to-moderate vaccine-associated adverse events. We need to consider further improvement of the AH1pdm vaccine program in HCW for the prevention of nosocomial infection, as well as for the benefit of HCW.

Immunogenicity and Safety of H5N1 A/Vietnam/1194/2004 (Clade 1) AS03-Adjuvanted Prepandemic Candidate Influenza Vaccines in Children Aged 3 to 9 Years

The development of vaccines against pandemic influenza viruses for use in children is a public health priority. In this phase II, randomized, open study, the immunogenicity and reactogenicity of H5N1 A/Vietnam/1194/2004 (NIBRG-14) (clade 1) prepandemic influenza vaccine were assessed in children aged 3 to 5 and 6 to 9 years. Children were randomized to receive 2 doses, given 21 days apart, of A/Vietnam/1194/2004 vaccine containing 1.9 microg or 3.75 microg hemagglutinin antigen (HA), adjuvanted with a tocopherol-based oil-in-water emulsion (AS03) containing 11.86 mg (AS03(A)) or 5.93 mg (AS03(B)) tocopherol. Control groups received 2 doses of trivalent influenza vaccine (TIV). Humoral immune responses, reactogenicity, and safety were the primary outcome measures; cross-reactivity and cell-mediated responses were also assessed (NCT00502593). Between 49 and 51 children in each age stratum (aged 3-5 and 6-9 years) received H5N1 vaccine, and between 17 and 18 children in each age stratum received TIV. After the second dose, recipients of H5N1 vaccine (1.9 microg HA/AS03(B), 3.75 microg HA/AS03(B), and 3.75 microg HA/AS03(A)) achieved humoral antibody titers against the vaccine-homologous strain, which fulfilled the United States influenza vaccines licensure criteria for immunogenicity. With the exception of 1 child, there were no H5N1 immune responses in children who received TIV. The most frequent injection-site event was pain in all groups, and the H5N1 vaccine had a clinically acceptable reactogenicity and safety profile. Exploratory analyses in children aged 3 to 5 years indicated that the induction of CD4 T-cell responses polarized in favor of a T-helper 1 profile. The results showed that 2 doses of AS03-adjuvanted H5N1 influenza vaccine at antigen-sparing doses of 1.9 microg or 3.75 microg HA elicited broad and persistent immune responses with acceptable reactogenicity, and without safety concerns, in children aged 3 to 9 years.

Improved antibody responses in infants less than 1 year old using intradermal influenza vaccination

Antibody response to influenza vaccine is limited in early. Infants have poorer hemagglutination-inhibiting antibody responses than 12-month-old. Intradermal administration reportedly elicited immune responses similar to or better than a standard intramuscular dose. We hypothesized that intradermal injection could achieve a better response in infants than subcutaneous injection. We randomized 34 healthy infants 6-12 months old to either intradermal immunization (0.1 ml of trivalent influenza vaccine containing at least 3 microg of hemagglutinin antigen per strain) or subcutaneous immunization (also 0.1 ml). Changes in hemagglutination inhibition titer were compared using Mann-Whitney U-test, changes in positivity rate, seroconversion, and seroprotection. Local and systemic adverse events were assessed. All 32 infants received both injections. Antibody titers on days at 42 after intradermal injection were significantly greater than subcutaneous injection (P=0.032 in A/New Caledonia (H1N1), 0.019 in A New York (H3N2) and 0.044 in B/Shanghai. Positive titers for A New York (H3N2) were attained significantly more often after intradermal (73.3%) than subcutaneous injection (23.5%) on day 28, and significantly more often 42 days after intradermal injection (93.3% for A/New Caledonia (H1N1) and 73.3% for B/Shanghai) than after subcutaneous injection. Positive rates for other stains were similar between groups on days 28 and 42. Seroconversion rates were similar between groups. Seroprotection on day 42 for A New York (H3N2) was significantly greater in the intradermal (86.7%) than in the subcutaneous group (35.3%). Seroprotection rates for other stains were similar. Intradermal administration to infants of two doses of influenza vaccine was more immunogenic than subcutaneous injection. Seroconversion and seroprotection rates remained insufficient. Further study of route, quantity, and frequency are needed to improve of responses in infants.

A Phase I, Randomized, Controlled Trial to Study the Reactogenicity and Immunogenicity of a Nasal, Inactivated Trivalent Influenza Virus Vaccine in Healthy Adults

We performed a randomized, placebo-controlled, dose-escalating clinical trial to evaluate thesafety and immunogenicity of an inactivated, split virion, trivalent, nasal influenza vaccine usinglipid/polysaccharide molecules as carriers. A total of 64 adults (mean age 29; range 19-69 years)were randomly allocated to receive a mixture of lipid/polysaccharide carrier molecules and 7.5,15, or 30 µg hemagglutinin antigen of each of the three influenza strains (A/Johannesburg/82/96[H1N1], A/Nanchang/933/95 [H3N2], B/Harbin/07/94) or placebo via nasal spray on twooccasions separated by 28 days. Adverse events were assessed immediately after immunizationand for 14 days after each dose. Nasal and serum antibodies were measured before and twoweeks after each dose. All but three participants completed the study; no withdrawals werebecause of adverse events. Adverse events were similar immediately after immunization exceptfor anterior nasal dripping after the first dose which was more common in the combined vaccinegroups (64.4%) than in the placebo group (31.3%; p