Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.

BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. METHODS: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. RESULTS: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. CONCLUSIONS: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).

Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial.

IMPORTANCE: The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine. OBJECTIVES: To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). DESIGN, SETTING, AND PARTICIPANTS: Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults. INTERVENTIONS: Participants who were previously vaccinated with 90 µg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 µg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 µg [n = 55 with MF59 and n = 59 without], 7.5 µg [n = 51 with MF59 and n = 57 without], 15 µg [n = 48 with MF59 and n = 44 without], 45 µg [n = 47 with MF59 and n = 47 without], or 90 µg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28. MAIN OUTCOMES AND MEASURES: The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events. RESULTS: Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 µg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 µg (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 µg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 µg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups. CONCLUSIONS AND RELEVANCE: Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00680069.

Safety and immunogenicity of a subvirion inactivated influenza A/H5N1 vaccine with or without aluminum hydroxide among healthy elderly adults.

A total of 600 healthy adults > or =65 years were randomized to receive 2 vaccinations 1 month apart of a subvirion avian influenza A/H5N1 vaccine containing 3.75, 7.5, 15, or 45microg of hemagglutinin (HA) with or without aluminum hydroxide (AlOH). All formulations were safe. Groups given the vaccine with AlOH had more injection site discomfort. Dose-related increases in antibody responses were noted after the second vaccination. Antibody responses to the vaccine were not enhanced by AlOH at any HA dose level. A microneutralization titer > or =40 was observed in 36% and 40% of subjects who received 45microg of HA with or without AlOH, respectively.

Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults.

BACKGROUND: Influenza A H5N1 viruses pose a significant threat to human health. METHODS: We conducted a multicenter, randomized, double-blind study in 394 healthy adults. Subjects were randomly assigned to receive 2 intramuscular doses of either saline placebo; influenza A/Vietnam/1203/2004(H5N1) vaccine alone at 45, 30, or 15 microg per dose; vaccine at 15 or 7.5 microg per dose with MF59; or vaccine at 30, 15, or 7.5 microg per dose with aluminum hydroxide. Subjects were followed up for safety and blood samples were obtained to determine antibody responses. RESULTS: The vaccine formulations were well tolerated but local adverse effects were common; the incidence of these effects increased in a dose-dependent manner and was increased by the addition of adjuvants. The addition of MF59 increased the antibody response, whereas the addition of aluminum hydroxide did not. The highest antibody responses were seen in the group that received 15 microg of vaccine per dose with MF59, in which 63% of subjects achieved the predetermined endpoint (hemagglutination-inhibition titer > or =40) 28 days after the second dose, compared with 29% in the group that received the highest dose (45 microg per dose) of vaccine alone. CONCLUSIONS: A 2-dose regimen of subvirion influenza A (H5N1) vaccine was well tolerated. The antibody responses to 15 microg of A/H5 vaccine with MF59 were higher than the responses to 45 microg of vaccine alone. TRIAL REGISTRATION: ClincalTrials.gov identifier: http://www.clinicaltrials.gov/ct2/show/NCT00280033?term= NCT00280033&rank=1 NCT00280033 .

Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects.

To improve immune responses to influenza vaccine, a trivalent inactivated vaccine containing 60 microg of the HA of each component (A/H3N2, A/H1N1, B) was compared to a licensed vaccine containing 15 microg of the HA of each. More local and systemic reactions were reported by subjects given the high dosage but only local pain and myalgias were significantly increased. The high dosage vaccine induced a higher frequency of serum antibody increases (> or =4-fold) in both hemagglutination-inhibiting (HAI) and neutralization tests for all three vaccine viruses in the total group as well as subjects vaccinated and those not vaccinated the previous year. Mean titers of antibody attained, the magnitude of antibody increases and the frequencies of persons with final HAI antibody titers > or =1:32, > or =1:64, and > or =1:128 were all greater for the high dosage group in both serologic tests, for all groups, and for all vaccine viruses. These increased immune responses should provide increased protection against influenza in the elderly.

Comparative immunogenicity of trivalent influenza vaccine administered by intradermal or intramuscular route in healthy adults.

The present study was undertaken with controls using equal doses ID and IM plus the standard full dose IM to assess the role of route of vaccine in immunogenicity of inactivated influenza vaccine. The study was a prospective, randomized, active-controlled, open label clinical trial conducted in healthy young adult outpatients to compare the effect of route (IM versus ID) on antibody responses to influenza vaccine. Volunteers received 3, 6 or 9 microg of vaccine by ID or IM route; 15 microg IM was also studied. Low doses of vaccine given by either route were almost as immunogenic as the standard 15 microg IM dose of influenza vaccine. ID route was not superior to IM vaccine at inducing antibodies. ID vaccine induced significantly more local inflammatory response than IM vaccine.