Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single–dose influenza vaccine protection

Abstract

Neonates are at high risk for influenza morbidity and mortality due to immune immaturity and lack of priming by prior exposure. Inactivated influenza vaccines are ineffective in infants under six months and to provide protection in older children generally require two doses given a month apart. This leaves few options for rapid protection of infants, e.g. during an influenza pandemic. We investigated whether Advax™, a novel polysaccharide adjuvant based on delta inulin microparticles could help overcome neonatal immune hypo-responsiveness and also whether it was possible to obtain single-dose influenza vaccine protection of babies against lethal infection. Inactivated influenza A/H1N1 vaccine (iH1N1) combined with Advax™ adjuvant administered as a single immunization to 7-day-old mouse pups significantly enhanced serum influenza-specific IgM, IgG1, IgG2a and IgG2b levels in association with a 3–4 fold increase in the frequency of splenic influenza-specific IgM and IgG antibody secreting cells versus pups immunized with iH1N1 alone. Pups immunized with Advax-adjuvanted iH1N1 had significantly higher influenza-stimulated splenocyte production of IFN-γ, IL-2, IL-4, and IL-10 and a 3–10 fold higher frequency of T cells IFN-γ secreting IL-2, IL-4 or IL-17 by ELISPOT. Immunisation with iH1N1+Advax adjuvant induced robust protection against influenza virus challenge 3 weeks post-immunization, whereas pups immunized with iH1N1 alone had no protection. Protection by Advax-adjuvanted iH1N1 was mediated by serum antibody and memory B cells rather than memory T cells as protection was lost in neonatal µMT mice that are B-cell deficient. Hence, Advax adjuvant overcame neonatal immune hypo-responsiveness and enabled single-dose protection of pups against otherwise lethal influenza infection, thereby supporting development of Advax™ as a neonatal vaccine adjuvant.

Advax4 delta inulin combination adjuvant together with ECMX, a fusion construct of four protective mTB antigens, induces a potent Th1 immune response and protects mice against Mycobacterium tuberculosis infection

“…9 Advax is an adjuvant derived from delta inulin, a polysaccharide found in the roots of plants of the Compositae family. 10,11 Advax adjuvant has shown high levels of efficacy in vaccines against respiratory syncytial virus, 11 West Nile virus and Japanese encephalitis virus, 12,13 influenza, [14][15][16] severe acute respiratory syndrome coronavirus, 17 Listeria, 18 onchocercosis 19 and anthrax, 20 amongst others, consistent with its having broad efficacy across viral, bacterial and parasitic vaccines. An advantage of delta inulin adjuvant is that it enhances both Th1 and Th2 T cell responses.…”

“…It has also been shown to be safe and effective in pregnant mothers and newborns in addition to the general population. 14,16,[21][22][23] This prompted us to test the suitability of Advax adjuvant for formulation with TB subunit vaccines.…”

IgG subclass co‐expression brings harmony to the quartet model of murine IgG function

“…The production of all four IgG subclasses has been reported after animals have been challenged with widely varying antigens including DNA vaccines, 32 recombinant Ascaris suum antigens, 33 recombinant Plasmodium antigens 34 and bacterial adhesins, 35 as well as after infection with bacteria 36 and a range of viruses 37 , 38 , 39 . The four subclasses have also been reported in response to T‐independent antigens.…”

Advax Adjuvant

“…Immunization of 7-day-old pups with a single dose of influenza antigen with Advax increased serum IgM and IgG1 levels, memory B and T cell frequency, and protected against influenza challenge at 28 days of age. 31 Remarkably, given that neonatal T cells have been described to have a fixed defect in the ability to make IFN-g irrespective of stimulus, 32 Advax restored the ability of neonatal T cells to make IFN-g recall responses. The benefits of Advax are not just restricted to seasonal influenza vaccines as in a ferret H5N1 challenge model, Advax enhanced protection against high-pathogenicity H5N1 avian influenza.…”