Co-administration of certain DNA vaccine combinations expressing different H5N1 influenza virus antigens can be beneficial or detrimental to immune protection

► Vaccine efficacy can be improved through systematic evaluation of optimal antigen combinations. ► Combining variable and well-conserved H5N1 antigens can improve DNA vaccine efficacy. ► Protection against divergent H5N1 viruses is achievable by mixing two different influenza antigens. ► The addition of three or more related and unrelated antigens reduces protection. ► Combining multiple antigens can be beneficial and detrimental.