AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.

Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion

Adjuvants are substances added to vaccines to improve their immunogenicity. Used for more than 80 years, aluminum, the first adjuvant in human vaccines, proved insufficient to develop vaccines that could protect against new challenging pathogens such as HIV and malaria. New adjuvants and new combinations of adjuvants (Adjuvant Systems) have opened the door to the delivery of improved and new vaccines against re-emerging and difficult pathogens. Adjuvant Systems concept started through serendipity. The access to new developments in technology, microbiology and immunology have been instrumental for the dicephering of what they do and how they do it. This knowledge opens the door to more rational vaccine design with implications for developing new and better vaccines.

https://www.tandfonline.com/doi/pdf/10.1080/21645515.2016.1225635

From discovery to licensure, the Adjuvant System story

Studying the spread of influenza in human populations and protection by influenza vaccines provides important insights into immunity against influenza. The 2009 H1N1 pandemic has taught the most recent lessons. Neutralizing and receptor-blocking antibodies against hemagglutinin are the primary means of protection from the spread of pandemic and seasonal strains. Anti-neuraminidase antibodies seem to play a secondary role. More broadly cross-reactive forms of immunity may lessen disease severity but are insufficient to prevent epidemic spread. Priming by prior exposure to related influenza strains through infection or immunization permits rapid, potent antibody responses to immunization. Priming is of greater importance to the design of immunization strategies than the immunologically fascinating phenomenon of dominant recall responses to previously encountered strains (original antigenic sin). Comparisons between non-adjuvanted inactivated vaccines and live attenuated vaccines demonstrate that both can protect, with some advantage of live attenuated vaccines in children and some advantage of inactivated vaccines in those with multiple prior exposures to influenza antigens. The addition of oil-in-water emulsion adjuvants to inactivated vaccines provides enhanced functional antibody titers, greater breadth of antibody cross-reactivity, and antigen dose sparing. The MF59 adjuvant broadens the distribution of B-cell epitopes recognized on HA and NA following immunization.

Influenza vaccine immunology.

17 – Inactivated influenza vaccines

Importance Human infections with avian influenza A/H7N9 have resulted in high morbidity and mortality in China. Objective To compare safety and immunogenicity of different doses of influenza A/Shanghai/2/13 (H7N9) vaccine mixed with or without the MF59 adjuvant. Design, Setting, and Participants Multicenter, randomized, double-blind, phase 2 trial at 4 US sites enrolled 700 adults aged 19 to 64 years beginning in September 2013; 6-month follow-up was completed in May 2014. Interventions The H7N9 inactivated virus vaccine was administered intramuscularly on days 0 and 21 at nominal doses of 3.75, 7.5, 15, or 45 µg of hemagglutinin (actual doses approximately 50% higher) with or without the MF59 adjuvant. A total 99, 100, or 101 participants were randomized to each group (7 groups; N = 700). Main Outcomes and Measures Proportions achieving day 42 antibody titer of 40 or greater or seroconversion (a minimum 4-fold increase to titer ≥40) with the hemagglutination inhibition assay; vaccine-related serious adverse events through month 13; and solicited postvaccination symptoms through day 7. Results Hemagglutination inhibition antibodies were minimal after participants received an unadjuvanted vaccine. After receiving 2 doses of H7N9 vaccine at a dosage of 3.75 µg plus the MF59 adjuvant, day 42 seroconversion occurred in 58 participants (59%; 95% CI, 48%-68%). The peak seroconversion occurred at day 29 in 62 participants (62%; 95% CI, 52%-72%). The day 42 geometric mean titer was 33.0 (95% CI, 24.7-44.1). Higher antigen doses were not associated with increased response. For the neutralizing antibody assays, after receiving 3.75 µg of H7N9 vaccine plus the MF59 adjuvant, day 42 seroconversion occurred in 81 participants (82%; 95% CI, 73%-89%). The day 42 geometric mean titer was 81.4 (95% CI, 66.6-99.5). There was no statistically significant difference in day 42 hemagglutination inhibition seroconversion after mixing adjuvant with either the first or both 15 µg doses (n = 34 [35%; 95% CI, 25%-45%] vs n = 47 [47%; 95% CI, 37%-58%], respectively; P  = .10). Recent receipt of seasonal influenza vaccination and older age were associated with attenuated response. No vaccine-related serious adverse events occurred. Solicited postvaccination symptoms were generally mild with more local symptoms seen in participants who received the adjuvant. Conclusions and Relevance Point-of-use mixing and administration of 2 doses of H7N9 vaccine at the lowest tested antigen dose with MF59 adjuvant produced seroconversion in 59% of participants. Although these findings indicate potential value in this approach, the study is limited by the absence of antibody data beyond 42 days and the absence of clinical outcomes. Trial Registration clinicaltrials.gov Identifier:NCT01938742

https://jamanetwork.com/journals/jama/articlepdf/1911327/joi140126.pdf

Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial.

Background The tocopherol-based oil-in-water emulsion adjuvant system family (AS03) improves antigen sparing with split-virion H5N1 influenza vaccines, representing an important development for pandemic preparedness. In this phase 1/2 randomized, controlled, observer-blinded study in 680 adults, we assessed the immunogenicity and safety of A/Indonesia/5/05 H5N1 (IBCDC-RG2, clade 2.1) prepandemic candidate vaccines produced at 2 separate manufacturing sites. Methods Two doses, each of which contained 3.75 microg of hemagglutinin antigen, were given 21 days apart either without adjuvant or with an adjuvant system containing 11.86 mg or 5.93 mg of tocopherol (AS03). Results The AS03-adjuvanted A/Indonesia/05/2005 (NIBRG-14) vaccines were significantly more immunogenic than nonadjuvanted vaccine in homologous assays. Neutralizing cross-clade immunogenicity against clades 1, 2.2, and 2.3 was demonstrated at day 42 with all vaccines; at 6 months, seroconversion rates were highest for clade 2.2 (60.7%) and for clade 1 (38.3%). Adjuvantation was associated with increased short-term injection-site reactions (pain) in 80% of participants, with such reactions assessed as being of grade 3 severity for 4.0% of doses. No other safety or reactogenicity concerns were identified over 6 months of follow-up. Conclusions Humoral responses against the adjuvanted 3.75-microg hemagglutinin antigen vaccines from both manufacturing sites fulfilled European and US licensure criteria for immunogenicity for influenza vaccines.

Safety and Cross-Reactive Immunogenicity of Candidate AS03-Adjuvanted Prepandemic H5N1 Influenza Vaccines: A Randomized Controlled Phase 1/2 Trial in Adults

Casey Johnson

Papers

Safety and Cross-Reactive Immunogenicity of Candidate AS03-Adjuvanted Prepandemic H5N1 Influenza Vaccines: A Randomized Controlled Phase 1/2 Trial in Adults