Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response

Abstract

IMPORTANCE Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.OBJECTIVE To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03-and MF59-containing formulations and of adjuvanted and unadjuvanted formulations. DESIGN, SETTING, AND PARTICIPANTS Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015. INTERVENTIONSThe H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 μg, 7.5 μg, 15 μg, and 45 μg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site. MAIN OUTCOMES AND MEASURESProportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.RESULTS Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 μg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI,; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001). CONCLUSIONS AND RELEVANCEThe AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.

Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults

“…Several H7 inactivated influenza vaccines and live-attenuated influenza vaccines are in clinical development, but have not been highly immunogenic in humans [8–10]. Adjuvanted vaccines have shown improved immunogenicity [11–14]. A recent mix-and-match study demonstrated that a monovalent H7N9 vaccine adjuvanted with AS03 induced a better immune response than the nonadjuvanted or MF59-adjuvanted formulations, when administered to adults according to a 2-dose schedule [14].…”

“…Adjuvanted vaccines have shown improved immunogenicity [11–14]. A recent mix-and-match study demonstrated that a monovalent H7N9 vaccine adjuvanted with AS03 induced a better immune response than the nonadjuvanted or MF59-adjuvanted formulations, when administered to adults according to a 2-dose schedule [14]. Here, we present the findings of a study that evaluated H7N9 vaccine formulations with hemagglutinin (HA) antigen doses of 2.78 and 5.09 µg, given with AS03 adjuvants of different potency and a nonadjuvanted formulation.…”

Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania: Preclinical evaluation of split virion inactivated H5N1 vaccine with adjuvant

“…7 There are 2 main lines of evidence indicating that the respiratory tract of ferrets closely resembles that of humans; first, ferrets possess a predominance of a-(2-6)-linked sialic acids on the upper airway epithelia and second, avian H5N1 and human H3N2 influenza viruses exhibit similar patterns of virus attachment to tissues from both species. [8][9][10][11][12] The primary goal of the ferret studies described below was to evaluate the antigen sparing capacity of the adjuvant; in this regard and consistent with clinical study designs addressing the same question, 13 the most efficient use of animals called for an experimental design with a high dose antigen alone group compared to lower dose antigen groups with or without adjuvant.…”

Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

“…H5N1 and H7N9 vaccines have proven to be poorly immunogenic in these trials, often requiring multiple doses of vaccine with high hemagglutinin (HA) content or the use of adjuvants to achieve the desired neutralizing antibody titers (7)(8)(9)(10)(11). A 2006 H5N1 vaccine trial showed that two doses, each con-taining 90 g of HA, were able to generate microneutralization (MN) titers of Ն1:40 in just half of the subjects (7).…”

“…A 2006 H5N1 vaccine trial showed that two doses, each con-taining 90 g of HA, were able to generate microneutralization (MN) titers of Ն1:40 in just half of the subjects (7). Similarly, a 2015 H7N9 vaccine trial demonstrated that two AS03-or MF59-adjuvanted doses were required to achieve desired MN titers in the majority of patients (9).…”