Each influenza season, a set of wild-type viruses, representing one H1N1, one H3N2, 1-2 influenza B isolates, are selected for inclusion in the annual seasonal influenza vaccine. In order to develop broadly reactive subtype specific influenza vaccines, a methodology called computationally optimized broadly reactive antigens (COBRA) was used to design novel hemagglutinin (HA) vaccine immunogens. COBRA technology was effectively used to design HA immunogens that elicited antibodies that neutralized H5N1 and H1N1 isolates. In this report, the development and characterization of seventeen prototype H3N2 COBRA HA proteins were screened in mice and ferrets for the elicitation of antibodies with HAI activity against human seasonal H3N2 viruses that were isolated over the last 48 years. The most effective COBRA HA vaccine regimens elicited antibodies with broader HAI activity against a panel of H3N2 viruses compared to wild-type H3 HA vaccines. The top leading COBRA HA candidates were tested against co-circulating variants. These variants were not efficiently detected by antibodies elicited by the wild-type HA from viruses selected as the vaccine candidates. The T-11 COBRA HA vaccine elicited antibodies with HAI and neutralization activity against all co-circulating variants from 2004-2007. This is the first report demonstrating broader breadth of vaccine induced antibodies against co-circulating H3N2 strains compared to the wild-type HA antigens that were represented in commercial influenza vaccines.IMPORTANCE There is a need for an improved influenza vaccine that elicits immune responses that recognize a broader number of influenza virus strains to prevent infection and transmission. Using the COBRA approach, a set of vaccines against influenza viruses in the H3N2 subtype were tested for the ability to elicit antibodies that neutralize virus infection against not only historical vaccine strains of H3N2, but also a set of co-circulating variants that circulated between 2004-2007. Three of the H3N2 COBRA vaccines recognized all the co-circulating strains during this era, but the chosen wild-type vaccine strains were not able to elicit antibodies with HAI activity against these co-ciruclating strains. Therefore, the COBRA vaccines have the ability to not only elicit protective antibodies against the dominant vaccine strains, but also minor circulating strains that can evolve into the dominant vaccine strains in the future.