## 1 Introduction  
Since the 1960s, the technology of inactivated vaccine based on cell culture has developed rapidly. Because of its advantages including quick production process, fast development, low cost, high yields, and effective protection, it has gradually become the main form of vaccine against a variety of viruses [1], including varicella-zoster (VZV) [2], hepatitis A virus (HAV) [3], and rabies viruses (RABV) [4]. Recently, the COVID-19 inactivated vaccine based on cell culturing has been effective for the prevention and control of the epidemic situation in China [5]. Most inactivated vaccines are produced using Vero cells (African green monkey kidney cells), which have been used for more than 25 years for the production of vaccines against VZV, poliovirus, RABV, and most recently, COVID-19 [6; 7; 8; 9]. Hundreds of millions of doses of Vero cell-derived vaccines are being distributed worldwide due to high viral replication and large-scale productivity [10]. Vero cells are an interferon (IFN)-deficient cell line, which could be used for achieving the high productivity of these viruses [11]. High yields of RABVproduction using Vero cells of \(10^{8}\) fluorescence focus units (FFU)/mL under appropriate conditions have been achieved [12]. Due to these advantages, the inactivated vaccine based on Vero cells has become the mainstream product in the vaccine market. Since Vero cells are monkey-derived, concerns exist over non-human DNA contamination during vaccine production. The DNA contamination exhibits a potential carcinogenic risk and increase the burden of vaccine purification and detection [13]. At present, one solution includes replacing Vero cells with human diploid cells [14]. Inactivated vaccines based on Vero cells, such as vaccines against VZV and HAV, are not approved in European countries and the US; however, they are used in developing countries [15]. In the field of rabies vaccines, purified Vero cell rabies vaccine (PVRV) has not been approved for the prevention of rabies in humans in the US. Although PVRV is approved in France, it is mainly sold in developing countries such as Asia. The human diploid cell rabies vaccine (HDCV) is marketed in France and the US. In fact, the safety and effectiveness of human diploid cell inactivated vaccine have been fully demonstrated [16; 17]. For example, the human embryonic lung fibroblast cells (MRC-5) line has become the source of many vaccines including VZV, HAV, and enterovirus 71 (EV71) inactivated vaccines because of its advantages of safety and production, especially with regard to the removal of the DNA contamination from host cells in vaccines [2; 3; 17]. Since the production of vaccines against most viruses including HAV and RABV using MRC-5 cells does not result in high yields, their development is slow. Thus, these cells are not widely used for inactivated vaccine production, thereby resulting in high prices. The yields of VZV and HAV-inactivated vaccine using human diploid cells were much lower than those using Vero cells [2; 18]. At present, the output of HDCV in the Chinese market is \(1/10\)th that of PVRV, and the price is 10 times higher than that of PVRV. Since it is a safer choice, the demand for HDCV has been increasing over the years. The 2020 Chinese HDCV production was expanded 10-fold as compared to that in 2010. However, the low yield has made it difficult to inoculate more people with HDCV. If the low production hurdle of human diploid cell is overcome, it will be of great significance for the promotion of inactivated virus vaccine production based on human diploid cells in developing countries. Rabies is a fatal zoonotic disease that significantly impacts global public health, characterized by encephalopathy and generalized paresis [19]. Moreover, there are tens of thousands of human deaths annually, mainly in Asia and Africa [20]. Almost all cases of human rabies are caused by a bite from a rapid dog [21].