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Four randomized phase III trials conducted recently in melanoma patients in the adjuvant setting have been based in part on the correlation between antibody responses in immunized patients and improved survival. Each of these randomized trials demonstrated no clinical benefit, although again there was a significant correlation between antibody response after vaccination and disease free and overall survival. To better understand this paradox, we established a surgical adjuvant model targeting GD2 ganglioside on EL4 lymphoma cells injected into the foot pad followed by amputation at variable intervals. Our findings are (1) comparable strong therapeutic benefit resulted from treatment of mice after amputation with a GD2-KLH conjugate vaccine or with anti-GD2 monoclonal antibody 3F8. (2) The strongest correlation was between antibody induction in response to vaccination and prolonged survival. (3) Antibody titers in response to vaccination in tumor challenged mice as compared to unchallenged mice were far lower despite the absence of detectable recurrences at the time. (4) The half life of administered 3F8 monoclonal antibody (but not control antibody) in challenged mice administered was significantly shorter than the half life of 3F8 antibody in unchallenged controls. The correlation between vaccine-induced antibody titers and prolonged survival may reflect, at least in part, increased tumor burden in antibody-negative mice. Absorption of vaccine-induced antibodies by increased, although not detected tumor burden may also explain the correlation between vaccine-induced antibody titers and survival in the adjuvant clinical trials described above.

The recent appearance of a novel H1N1 (nH1N1) virus has highlighted the importance of rapid response to emerging pandemic threats. VaxInnate has developed an influenza vaccine production system that permits rapid response on a global scale. The vaccine comprises the protective globular head subunit of HA fused covalently to the TLR 5 ligand flagellin. Using animal models that have successfully predicted the tolerated dose range in humans we have identified an optimal position for the HA globular head. Three constructs evaluated the globular head fused to the C terminus of flagellin (C-term), in place of domain 3 (R3) and in both positions (R3.2x). The three formats were tested in mouse immunogenicity and rabbit reactogenicity models. HAI assays were performed using CA/07/2009 virus. Rabbits were monitored for body temperature, food consumption and CRP. In mice, HAI titers >1:40 were achieved with 1 μg doses of all vaccines, but R3 and R3.2x vaccines yielded higher titers. In rabbits, the C-term vaccine elicited elevated temperature and CRP levels and reduced food consumption at doses well below R3 and R3.2x. Replacement of domain 3 of flagellin with the HA globular head, either R3 or R3.2x, proves safe and immunogenic in mice and rabbits. Our clinical experience with other flagellin-linked vaccines has correlated well with the rabbit model. The results predict that the R3 or R3.2x nH1 vaccines would be both safe and efficacious in humans.

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