ADVAX (The Aaron Diamond AIDS Research Center)

Newborns represent over half of hospitalized pediatric influenza infection cases, with current influenza vaccines not effective in the first months of life. Advax® (delta inulin) is a polysaccharide particle that targets DC‐SIGN, whereas CpG55.2 is a potent murine and human toll‐like receptor (TLR)‐9 agonist. This study asked whether Advax or CpG alone, or combined, could enhance the protection of an inactivated influenza virus vaccine (IIV) in newborns. One‐day‐old mouse pups were immunized subcutaneously with a single dose of IIV alone or with Advax or Advax‐CpG55.2 adjuvants and then, at 28 days of age, challenged intranasally with a lethal dose of influenza virus. While IIV alone or with CpG adjuvant provided minimal protection, Advax alone or combined with CpG55.2 induced enhanced serum anti‐influenza IgM and IgG responses to IIV and protected the newborns against clinical disease. Protection induced by a single vaccine dose was highly durable and was still evident 6–9 months after a single neonatal immunization. Protection was lost in B‐cell‐deficient μMT pups but preserved in β2m knockout pups and in CD4+ and CD8+ T‐cell‐depleted pups, indicating the importance of intact humoral immunity to the enhanced protection. The neonatal benefits of Advax® and Advax‐CpG55.2 adjuvant were confirmed in newborn macaques, where they similarly enhanced serum anti‐influenza antibody responses to IIV. This raises the possibility that Advax® adjuvant alone or in combination with CpG55.2 may have utility in improving influenza vaccine protection in human newborns.

It would be advantageous if a strategy could be found to accelerate vaccine induction of anti-influenza adaptive immunity to more rapidly protect frontline workers and other vulnerable individuals during virus outbreaks. This study asked whether Advax® delta inulin adjuvant could accelerate the kinetics of protection afforded by a single dose of inactivated influenza vaccine (IIV) in two different strains of mice. A single dose of Advax®-adjuvanted IIV, but not IIV alone, gave complete protection if given 7 or 3 days before, and even when given at the same time as virus challenge (same day protection). Co-administration of both IIV and Advax® were critical to obtaining robust same day protection which was not seen with the individual vaccine components. Same day protection was lost in B-cell deficient μMT mice but was still evident in T cell-depleted mice, confirming its dependence on humoral but not T cell immunity. Day 6 post-challenge serum from protected mice demonstrated elevated influenza-binding IgM which had hemagglutination inhibition activity not seen in mice that received IIV alone. This confirmed that Advax® accelerated the kinetics of anti-influenza IgM production in response to IIV. Influenza protection could be transferred to naïve mice using day 6 sera or purified IgM from Advax®-adjuvanted IIV-immunised mice. Draining lymph nodes from protected mice showed increased CD138⁺ B220⁺ migratory and IgM⁺ extrafollicular, antibody secreting cells. These results show Advax® adjuvant accelerates the kinetics of anti-influenza IgM production in response to IIV thereby enabling the vaccine to protect against an infection acquired at the same time as the immunisation. While further studies are required to confirm that this ability to accelerate humoral immune kinetics extends to other species, including non-human primates, the phenomenon of adjuvant-accelerated IIV protection offers promise as a strategy for development of faster-acting vaccines.