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  • Low-Dose Avian Flu Vaccine May Be Safe, Immunogenic



    Low-Dose Avian Flu Vaccine May Be Safe, Immunogenic

    News Author: Laurie Barclay, MD
    CME Author: Penny Murata, MD

    September 7, 2006

    September 7, 2006 ? All 4 formulations of the low-dose avian influenza A virus H5N1 vaccine are safe and not associated with serious adverse events, according to the results of a stratified, randomized, placebo-controlled, double-blind study published in the September 7 Early Online Publication issue of The Lancet.

    "Avian influenza A virus H5N1 has caused widespread infections that have resulted in severe disease or death in poultry and wild birds as well as human beings," write Jiangtao Lin, MD, from Chinese-Japanese Friendship Hospital in Beijing, China, and colleagues. "This virus has the potential to emerge as a pandemic threat and H5N1 vaccines are being developed in many countries. Our aim was to assess the safety and immunogenicity of an inactivated adjuvanted whole-virion H5N1 vaccine."

    In this phase 1 clinical trial, 120 volunteers aged 18 to 60 years were randomized to receive 2 doses of placebo (n = 24) or an inactivated whole-virion influenza A (H5N1) vaccine with one?25 μg (n = 24), two?5 μg (n = 24), 5 μg (n = 24), or 10 μg (n = 24) hemagglutinin per dose with aluminum hydroxide adjuvant on days 0 and 28. Hemagglutination inhibition and virus neutralization assays were performed on serum samples on days 0, 14, 28, 42, and 56.

    All 4 formulations of vaccines were well tolerated, with no serious adverse events reported. Most local and systemic reactions were mild and transient. All vaccine formulations induced antibody responses after the first dose. The highest response of 78% seropositivity was seen in the 10-μg group after 2 vaccine doses. One volunteer in the one?25-μg group withdrew consent; one in the 10-μg group discontinued; and one additional volunteer was also excluded from the final analysis.

    "A two-dose regimen of an adjuvanted 10 μg inactivated whole-virion H5N1 vaccine met all European regulatory requirements for annual licensing of seasonal influenza vaccine," the authors write. "Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO [World Health Organization] for protection against an influenza pandemic."

    The Ministry of Science and Technology of the People's Republic of China funded this study. The authors have disclosed no relevant financial relationships.

    In an accompanying comment, Iain Stephenson, MD, from Leicester Royal Infirmary in the United Kingdom, notes that if pandemic H5N1 emerges, the consequences could be worse than those of the 1918 pandemic, and that vaccination will be central to our response. Dr. Lin's study identified a potential dose-sparing approach that could be crucial for a global supply of pandemic vaccine.

    "Although vaccine manufacturing capacity has had substantial investment from industry, global production capacity remains insufficient to meet pandemic demands," Dr. Stephenson writes. "Although developments including cell-culture systems, live attenuated vaccines, new adjuvants, and DNA approaches will be important in future planning, studies of dose-sparing vaccine formulations in children, adults, and elderly people should be international health priorities to optimize current immunization strategies."

    The Lancet. Published online September 7, 2006.

    Learning Objectives for This Educational Activity
    Upon completion of this activity, participants will be able to:

    Compare the immunogenicity of 4 formulations of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine following first and second doses.
    List local and systemic reactions of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine.

    Clinical Context

    In the March 30, 2006, issue of The New England Journal of Medicine, Treanor and colleagues reported that a 2-dose regimen of a US-manufactured 90-μg nonadjuvanted split-virion H5N1 vaccine was immunogenic. In the May 20, 2006, issue of The Lancet, Bresson and colleagues found that a 2-dose regimen of a 30-μg split-virion H5N1 vaccine adjuvanted with aluminum hydroxide was immunogenic per the European Union Committee for Medicinal Products for Human Use (CHMP) licensing criteria for interpandemic influenza vaccines: more than 40% seroconversion (proportion of individuals with seroconversions or at least 4-fold increase in antihemagglutinin antibody titers); more than 70% seropositivity (proportion of individuals with hemagglutinin inhibition antibody titer of at least 40); and more than 2.5 seroconversion factor (ratio of postvaccination geometric mean titer to prevaccination geometric mean titer). It is speculated that the most effective immune response in an immunologically naive population will require a 2-dose regimen of an adjuvanted whole-virion vaccine.

    This phase 1, stratified, randomized, placebo-controlled, double-blind trial assesses the immunogenicity and safety of an inactivated whole-virion influenza A (H5N1) vaccine adjuvanted with aluminum hydroxide.

    Study Highlights
    120 healthy adults aged 18 to 60 years (mean, 31.8 - 37.9 years) were enrolled.

    Exclusion criteria included allergic history and chronic illness.
    Vaccine produced in embryonated hens' eggs with H5N1 pandemic influenza reference reassortant strain and adjuvanted with aluminum hydroxide was used to prepare 4 antigen concentrations: 1.25, 2.5, 5, and 10 μg of hemagglutinin per 0.5-mL dose.

    Each of the 4 dosing groups had 30 subjects: 24 received 2 intramuscular doses of vaccine 28 days apart, and 6 received placebo.
    Subjects were observed for local symptoms, systemic symptoms, and axillary temperature for 3 days following vaccination.

    Medical history and adverse events were reviewed on days 3, 14, 28, 31, 42, and 56.

    Serum antibody responses (hemagglutinin inhibition and virus neutralization antibody response) were measured on days 0, 14, 28, 42, and 56.
    1 subject in the 1.25-μg group and 1 subject in the 10-μg group withdrew.
    Hemagglutinin inhibition assay results showed all groups had antibody response against H5N1 after 1 dose, but highest response was in 10-μg group on day 42 after 2 doses.

    CHMP criteria for seroconversion factors were met on day 14 by the 5-μg group (2.8) and 10-μg group (6.3); on day 28 by the 5-μg group (2.7) and 10-μg group (5.7); on day 42 by the 1.25-μg group (2.7), 2.5-μg group (2.7), 5-μg group (4.9), and 10-μg group (11.5); on day 56 by the 1.25-μg group (2.6), 5-μg group (4.5), and 10-μg group (10.3).

    On day 42, the 10-μg group also met CHMP criteria for seroconversion (78%) and seropositivity (78%).

    On day 56, the 10-μg group still met CHMP criteria for seroconversion (64%), but not seropositivity (64%).

    Neutralizing antibody titers of at least 40 were highest for the 10-μg group by day 42.

    Neutralizing antibody titers of at least 40 were measured on days 28, 42, and 56:

    1.25-μg group (4% vs 9% vs 9%);
    2.5-μg group (17% vs 21% vs 21%);
    5-μg group (25% vs 33% vs 42%);
    10-μg group (30% vs 65% vs 50%).

    No serious adverse events were reported during 56-day study period.

    Most common local reaction after 2 doses was mild pain, which occurred most often in the 1.25-μg group (16 [67%] of 24 subjects).

    The groups showed no significant differences in other local reactions: moderate or severe pain, more than 15-mm erythema, more than 15-mm induration, and swelling.

    Most commonly reported systemic reaction was fever, then headache, myalgia, fatigue, nausea, arthralgia, and diarrhea, but the groups showed no significant differences vs placebo.

    Myalgia was more common in the 2.5-μg group vs 1.25-μg and 5-μg groups.
    Fever more than 37.5?C axillary was measured in 4 subjects.
    Reactions were significantly fewer after second dose vs after first dose in all groups.

    Pearls for Practice

    A 2-dose regimen of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine containing 10 μg of H5 hemagglutinin meets seroconversion factor, seropositivity, and seroconversion criteria per CHMP guidelines.
    An inactivated adjuvanted whole-virion influenza A (H5N1) vaccine results in mild, transient reactions, the most common of which is pain.
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