Abstract
There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation.Trial RegistrationAustralia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709
Highlights
Poor vaccine immunogenicity remains a major challenge in influenza vaccine development
As hypothesized based on previous animal studies where delta inulin adjuvant enhanced generation of antigen-specific memory B cells and plasma cells [6,25], administration to human subjects of influenza vaccine formulated with Advax adjuvant resulted in an increased plasmablast peak post-immunization, surprisingly this effect was more evident at the lower Advax 5mg dose
The finding that Advax adjuvant was associated with an increased peak plasmablast response post-immunization, may at least partially explain the finding of higher antibody titers in human subjects receiving Advax-adjuvanted influenza vaccine the modest effect size on plasmablast frequency, at the higher Advax 10 mg dose, suggested that some other mechanism of humoral enhancement might be operating
Summary
Poor vaccine immunogenicity remains a major challenge in influenza vaccine development. Advax has previously been shown to enhance seasonal and pandemic influenza vaccine protection in murine [6] or ferret models [7], respectively. When combined with a poorly immunogenic avian influenza antigen, Advax adjuvant reduced virus shedding and provided robust protection of immunized ferrets against H5N1-associated mortality and clinical disease [7]. Advax adjuvant has been shown to have similar beneficial effects on antibody production in humans, as shown in clinical trials of a pandemic influenza vaccine [9] and a hepatitis B vaccine [10]. In this study we sought to characterize the effect of Advax on human plasmablasts [11] using cryopreserved 7dpv PBMC from a subset of subjects in a previously conducted seasonal influenza vaccine study (FLU006). The results reveal unique adjuvant-related effects on plasmablast frequency, AID gene expression and B-cell receptor usage when subjects that received TIV vaccine alone were compared to those that received vaccine formulated with Advax adjuvant
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