In human observational studies, the 2008�C09 TIV was still shown to be protective overall against homologous seasonal influenza. Spring-summer 2009 observations of increased risk of heterologous A09 illness were identified six or more months after TIV receipt. In that regard, lower vaccine-induced antibody titers in ferrets at our three-week post-immunization Apdm09 challenge time point may better replicate end-ofseason antibody conditions when vaccinated humans were exposed to Apdm09 virus. A prior ferret study to assess the same 2008�C09 Fluviral also suggested disease enhancement but was able to induce homologous HI antibody response to the H1N1 component with mean antibody titre exceeding 100 within two weeks of a single 0.5 mL vaccine dose, higher even than induced in the pediatric study population cited above. Such variability in serologic responses may reflect lot-to-lot or laboratory differences. Not knowing the precise mechanisms involved in vaccine-associated enhanced respiratory disease, and unable to exactly know or replicate the human immunologic context in spring-summer 2009, we did not adjust the human vaccine formulation, dose or schedule to force higher ferret vaccine responses. Instead we focused on clinical parameters, recording the observed effects according to standard immunization practice. In general, ferret studies to date have suffered from small Gomisin-D sample size and insufficient power. Our study was powered for clinical comparison and follow-up to 14 days post-challenge. Failure to reach statistical significance for other consistent indicators should not prompt their dismissal but should stimulate further investigation. It may be argued that lung findings at Ch+5 were chance occurrences among few ferrets poorly-representative of the full group experience. However, animals in both groups were randomly and blindly selected for Ch+5 sacrifice, the comparison of baseline and Ch+5 characteristics showed no significant within-group differences according to scheduled endpoint, and Ch+5 lung findings in vaccinated animals were consistent with overall clinical patterns. Nevertheless, future experiments should be powered with more animals to specifically examine these early acute clinical, immunologic, and pathologic findings and explore their possible mechanisms in greater detail. We assessed only influenza-na? ��ve animals whereas most humans, other than young children, will have prior potentially cross-attenuating influenza infection history. The use of influenzana? ��ve animals in previous swine and the current ferret studies may be relevant to the increased severity highlighted in vaccinated animals but to a lesser extent noted with the association in Albaspidin-AA people. Further experiments are needed to explore nuances related to infection and/or immunization history which additionally and variously complicate the human experience. In a recent publication, disease enhancement was included among possible hypotheses to explain greater 2009 pandemic H1 morbidity in the Americas compared to Australia, New Zealand or Europe, with reference to findings in vaccinated swine interpreted ecologically in the context of regional differences in prior heterologous seasonal H1N1 virus circulation; given findings in vaccinated ferrets and swine, however, regional differences in prior heterologous seasonal H1N1 vaccine coverage may also be relevant to consider. Of note, mechanisms such as ADE, if explanatory, require a precise balance of low-level, crossreactive, non-neutralizing antibody to be manifest, a particular but sliding immunologic scale that may not have been captured in all animals or humans at the time of Apdm09 exposure.