Antibody-dependent cell-mediated cytotoxicity bridges humoral immunity and cellular immunity. Thus vaccine candidates which can elicit both broadly neutralizing antibodies and potent antibody-dependent cell-mediated cytotoxicity (ADCC) are recommended. Previously, a panel of functional epitopes that can elicit ADCC effects is isolated and characterized on the H1N1 Influenza Virus. Based on these identified epitopes, an epitope vaccine against H1N1 infection has been designed. The serum of vaccine immunized mice show potent ADCC activities in comparison with vector control group and HA ecto domain vaccinated group. However, the release of IL-6 and TNFα is higher in lung of epitope vaccine immunized mice. The viral load is also higher in epitope vaccine immunized mice. In addition, the epitope vaccine immunized mice showed lower survive rate than both empty vector immunized mice and HA ectodomain immunized mice. Passive transfer of serum from epitope vaccine immunized mice to healthy adult mice can decrease the survival rate of recipients after viral challenge. Our data suggested that ADCC epitope based vaccine has a mortality promoting effect rather than protective effect after H1N1 viral challenge. This result provides indications in future vaccine design with a consideration of balancing humoral immune response and cellular immune response.