The invention discloses a non-
human animal integrated with a double-derived VH subclass
fusion gene as well as a construction method and application of the non-
human animal. The method comprises the following steps: firstly, constructing a
gene construct containing human IGHV1-69 and IGHV3-23 fragments, a specific spacer region, a functional element and a rat
heavy chain 3'
enhancer, and microinjecting the
gene construct into a C57BL / 6J fertilized egg with an endogenous
heavy chain and a kappa light chain knocked out to obtain a transgenic mouse; through identification, after a mouse endogenous
antibody is inactivated, a human
gene is stably integrated, a human
IgM antibody is expressed and H5N1 HA immunization is carried out, the use frequency of IGHV1-69 is remarkably increased, the mouse produces a high-
titer specific antibody, and serum has neutralizing activity. The mouse can generate a target bnAbs aiming at the HA stem and the RBS in parallel, so that the
antibody screening efficiency is improved, and an in-vivo screening and evaluation platform for simulating
human body fluid response is provided for research and development of influenza antibodies and vaccines.