The H5 subtype of highly pathogenic avian influenza (HPAI) viruses pose a serious challenge to public health and the poultry industry in China. In this study, we generated a chimeric QH/KJ recombinant virus expressing the entire haemagglutinin (HA)-1 region of the HPAI virus A/chicken/China/QH/2017(H5N6) (clade 2.3.4.4) and the HA2 region of the HPAI virus A/chicken/China/KJ/2017(H5N1) (clade 2.3.2.1). The resulting chimeric PR8-QH/KJ virus exhibited similar in vitro growth kinetics as the parental PR8-QH and PR8-KJ viruses. The chimeric PR8-QH/KJ virus induced specific, cross-reactive haemagglutination-inhibition and serum-neutralizing antibodies against both QH and KJ viruses, although PR8-QH and PR8-KJ exhibited no cross-reactivity with each other. Furthermore, the chimeric PR8-QH/KJ vaccine significantly reduced virus shedding and completely protected chickens from challenge with HPAI H5N6 and H5N1 viruses. However, the Re-8 vaccine against clade 2.3.4.4 viruses provided specific-pathogen-free chickens only partial protection when challenged with QH virus. Our results suggest that the antigenic variation of these epidemic viruses occurred and they can escape the current vaccine immunization. The Re-8 vaccine needs an update. The chimeric PR8-QH/KJ vaccine is effective against H5 HPAI virus clades 2.3.4.4 and 2.3.2.1 in chickens.