Assessment of squalene adjuvanted and non-adjuvanted vaccines against pandemic H1N1 influenza in children 6 months to 17 years of age.

Vaccines were urgently needed in 2009 against A/H1N1 pandemic influenza. Based on the H5N1 experience, it was originally thought that 2 doses of an adjuvanted vaccine were needed for adequate immunogenicity. We tested H1N1 vaccines with or without AF03, a squalene-based adjuvant, in children.   Two randomized, open-label, trials were conducted. Participants 3-17 y received two injections of 3.8 µg or 7.5 µg hemagglutinin (HA) with adjuvant or 15 µg HA without adjuvant. Participants aged 6-35 mo received two injections of 1.9 µg or 3.8 µg HA with full or half dose adjuvant or 7.5 µg HA without adjuvant. All subjects 3 to 17 y reached seroprotection (hemagglutination inhibition (HI) titer ≥ 40) after the first dose of the adjuvanted vaccine, and 94% and 98% in the 3-8 and 9-17 y groups respectively with the non-adjuvanted vaccine. In children aged 6-35 mo responses were modest after one dose, but after two doses virtually all children were seroprotected regardless of HA or adjuvant dose. In this age group, antibody titers were 5 to 7 times higher after adjuvanted than non-adjuvanted vaccine. The higher responses with the adjuvanted vaccine were also reflected as better antibody persistence. There was no clustering of adverse events that would be suggestive of a safety signal. While a single injection was sufficient in subjects from 3 y, in children aged 6-35 mo two injections of this A/H1N1 pandemic influenza vaccine were required. Formulation of this vaccine with adjuvant provided a significant advantage for immunogenicity in the latter age group.

Safety and immunogenicity of three different formulations of a liquid hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine at 2, 4, 6 and 12-14 months of age.

The current recommended infant vaccination schedules require many injections at multiple sites, which increase stress for infants and parents and may create challenges to vaccination compliance. Therefore, combination vaccines, which reduce the number of injections at each medical visit, can be an essential method to improve compliance. The objective of this study was to assess the safety and immunogenicity of an investigational, liquid, hexavalent, pediatric vaccine at 2, 4, 6, and 12-14 months of age. In this multicenter, open-label controlled study, 756 infants were randomized in approximately equal numbers to receive 0.5mL intramuscular dose of diptheria-tetanus-pertussis-polio-Haemophilus influenzae type b+hepatitis B vaccine, or 1 of 3 double-blind investigational formulations. All formulations included a hepatitis B surface antigen (HBsAg) concentration of 10µg/0.5mL. The three hexavalent vaccine formulations used in this study contained either Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus toxoid [PRP-T, 12µg] or Neisseria meningitidis outer membrane protein complex [PRP-OPMC, 3µg or 6µg]): a minimum acceptable postdose 3 antibody response rate for each antigen was defined by the lower limit of a 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited vaccine-related injection-site reactions (pain, erythema, swelling) with increasing PRP-OMPC dose. No serious vaccine-related AEs were reported in the investigational groups. Both PRP-OMPC formulations met prespecified acceptability criteria for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and poliovirus. The PRP-T formulation met the acceptability criterion for antibody responses to all antigens other than PRP at postdose 3. Postdose 4 responses were adequate for all antigens in all formulations. All vaccine formulations were well-tolerated. Both PRP-OMPC formulations met prespecified immunogenicity criteria of PRP-OMPC evaluation.

AF03-adjuvanted and non-adjuvanted pandemic influenza A (H1N1) 2009 vaccines induce strong antibody responses in seasonal influenza vaccine-primed and unprimed mice.

Pandemic influenza vaccines have been manufactured using the A/California/07/2009 (H1N1) strain as recommended by the World Health Organization. We evaluated in mice the immunogenicity of pandemic (H1N1) 2009 vaccine and the impact of prior vaccination against seasonal trivalent influenza vaccines (TIV) on antibody responses against pandemic (H1N1) 2009. In naïve mice, a single dose of unadjuvanted H1N1 vaccine (3 microg of HA) was shown to elicit hemagglutination inhibition (HI) antibody titers >40, a titer associated with protection in humans against seasonal influenza. A second vaccine dose of pandemic (H1N1) 2009 vaccine strongly increased these titers, which were consistently higher in mice previously primed with TIV than in naïve mice. At a low immunization dose (0.3 microg of HA), the AF03-adjuvanted vaccine elicited higher HI antibody titers than the corresponding unadjuvanted vaccines in both naïve and TIV-primed animals, suggesting a potential for antigen dose-sparing. These results are in accordance with the use in humans of a split-virion inactivated pandemic (H1N1) 2009 vaccine formulated with or without AF03 adjuvant to protect children and young adults against influenza A (H1N1) 2009 infection.

Safety and immunogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine at 2, 3, 4, and 12-14 months of age.

Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections. In a Phase 2, randomized, double-blind, multicenter study, we compared four formulations of a liquid, hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B virus (DTaP-IPV-Hib-HBV) vaccine in 708 infants immunized at 2, 3, 4, and 12-14 months of age. The formulations contained identical DTaP and IPV components, differing in the contents of Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus-toxoid [PRP-T, 12microg] or Neisseria meningitidis outer-membrane-protein-complex [PRP-OMPC, 3microg or 6microg]), and in hepatitis B surface antigen (HBsAg, 10microg or 15microg). A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited injection-site reactions (pain, redness, swelling) with increasing PRP-OMPC and HBsAg concentration. Serious AEs reported by eight subjects were not considered to be vaccine related. All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and polio. Apart from the Hib response, the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen. Postdose 4 responses were acceptable for all antigens in all formulations. All vaccine formulations were well tolerated. The three PRP-OMPC formulations met prespecified immunogenicity criteria, and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity.

Improving seasonal and pandemic influenza vaccines.

Challenges facing seasonal and pandemic influenza vaccination include: increasing the immunogenicity of seasonal vaccines for the most vulnerable, increasing vaccination coverage against seasonal influenza, and developing vaccines against pandemic strains that are immunogenic with very low quantities of antigen to maximize the number of people who can be vaccinated with a finite production capacity. We review Sanofi Pasteur's epidemic and pandemic influenza research and development programmes with emphasis on two key projects: intradermal influenza vaccine for seasonal vaccination of both elderly and younger adults, and pandemic influenza vaccine.

Lot-to-lot consistency of a combined hexavalent diptheria-tetanus-acellular-pertussis, hepatitis B, Inactivated polio and haemophilus B conjugate vaccine, administered to healthy chilean infants at two, four and six months of age.

OBJECTIVES: To assess the safety, immunogenicity and lot consistency of a liquid hexavalent combined vaccine (DTaP-IPV-PRP approximately T-HBs, HEXAVAC) (Sanofi-Pasteur MSD, France) administered to infants at two, four and six months of age. METHODS: A total of 1028 infants were vaccinated with one of three vaccine lots, in a randomized, double-blind fashion. Equivalence testing was used to compare post-vaccination seroprotection/seroconversion rates and geometric mean titers (GMTs) for each antigen between the three lots. Blood samples were drawn before vaccination and one month after the third dose. Local and systemic adverse events were monitored for three days following each injection. RESULTS: Equivalence between lots was demonstrated for all antigens, on post-dose 3 seroprotection/seroconversion rates and GMTs. Reported rates of local and systemic adverse events tended to increase with subsequent doses. Altogether, 11.8% of the infants reported at least one adverse local event (mainly redness and induration/swelling) after the first dose and 36.1% after the third dose. Systemic adverse events (mainly irritability and fever) were reported by 39.2% of the infants after the first dose and by 57.5% after the third one. CONCLUSION: Three separate lots of the liquid hexavalent combined vaccine induced consistently protective antibody responses against all antigens. These results and the well established clinical tolerability of this combined vaccine make it suitable for primary immunization of infants at two, four and six months of age.

Safety and immunogenicity of two formulations of a hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae conjugate-hepatitis B vaccine in 15 to 18-month-old children.

Combination vaccines decrease the number of injections and improve parental satisfaction and vaccination schedule compliance. In a phase 1, randomized, partially-blinded, single-dose booster study, we evaluated two formulations of an investigational liquid hexavalent vaccine containing diphtheria, tetanus, acellular pertussis (5-component), inactivated poliovirus, Haemophilus influenzae b conjugate and hepatitis B surface antigen (DTaP-IPV-Hib-HBV) in 60 healthy toddlers, 15 to 18 months of age, who had been primed with three doses of a licensed pentavalent diphtheria, tetanus, acellular pertussis (5-component), inactivated poliovirus, Haemophilus influenzae b conjugate (DTaP-IPV//PRP-T) vaccine. The DTaP-IPV//PRP-T vaccine was used as a control in 30 subjects. The investigational formulations, which contained the same DTaP-IPV components, differed only in Hib (content and conjugate) and HBV (content) (PRP-T/HBV10 = 12 mug Hib tetanus toxoid conjugate with 10 microg HBsAg; PRP-OMPC/HBV15 = 6 microg Hib Neisseria meningitidis outer membrane protein complex with 15 microg HBsAg). Injection-site pain, redness and swelling were reported by 46.7%, 46.7%, and 20.0% of the licensed vaccine recipients, 43.3%, 43.3%, and 26.7% of PRP-T/HBV10 recipients and 70.0%, 46.7%, and 46.7% of PRP-OMPC/HBV15 recipients, respectively. Fever > or = 37.8 degrees C and irritability were reported by 0% and 16.7% of licensed vaccine recipients, 10.3% and 23.3% of PRP-T/HBV10 recipients and 30.0% and 16.7% of PRP-OMPC/HBV15 recipients, respectively. There were no apparent differences between the groups in the proportion of participants achieving predefined, threshold or seroprotective immune responses. Geometric mean antibody levels for all antigens were similar except for anti-PRP levels, which were 19.0 microg/mL in recipients of the licensed vaccine, 40.8 microg/mL in PRP-T/HBV10 recipients and 9.4 microg/mL in PRP-OMPC/HBV15 recipients. We conclude that the hexavalent formulations appear generally well tolerated and immunogenic as a booster dose in these toddlers.

A liquid hexavalent combined vaccine against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type B and hepatitis B: review of immunogenicity and safety.

To reduce the number of injections needed to comply with paediatric vaccination requirements, a liquid, hexavalent vaccine (DTaP-IPV-PRP-T-HBs; Hexavac; Aventis Pasteur MSD) has been developed for primary and booster vaccination of infants and toddlers. In extensive clinical studies, Hexavac has been shown to be highly immunogenic. Seroconversion or seroprotective titres of antibodies against all antigens were achieved in the majority of infants following a primary series of three doses administered at 1-2-month intervals from 2 months of age. Hexavac also induced immunologic memory, as evidenced by the anamnestic response to booster vaccination at 12-18 months of age. These responses were comparable with those seen following concomitant administration of Pentavac (DTaP-IPV//PRP-T) and monovalent hepatitis B vaccine (H-B-Vax II), and were also within the ranges observed for other relevant licensed vaccines. Clinical studies comparing the immunogenicity of Hexavac administered at either 2, 3 and 4 months or 2, 4 and 6 months demonstrated that it can be used by either vaccination schedule. A further study also supported the use of primary doses of Hexavac at 3 and 5 months with a booster at 12 months of age. Hexavac demonstrated a good reactogenicity and tolerability profile. The most frequently reported adverse events after both primary and booster doses were local reactions of redness and swelling/induration and a systemic response of mild fever, irrespective of the vaccine used for priming. Hexavac provided immunity against six important childhood diseases with a single injection at each visit.