**4. Vaccinia-based vaccines for human use**

The vaccina–rabies recombinant has never been approved for human use, even though vaccinia virus has been used widely across the world in our populations to eradicate smallpox, and the vaccinia–rabies recombinant is very much attenuated compared to standard strains of vaccinia. Notwithstanding, intense efforts have been made to develop vaccinia as an anticancer agent for direct prophylactic or curative use in human [20–23], but for recombinants expressing viral antigens few clinical trials have been carried out (with some exceptions; e.g., [24]). Efforts in the 1990s were invested into the development of viral vectors based on vaccinia derivatives such as modified virus Ankara (MVA) [25], or fowlpox or canarypox [26]. More recently., high levels of protective antibodies have been obtained against SARS coronavirus using vaccinia recombinants in experimental animals (e.g., [27–29]), and, given the threat of COVID-19, MVA-based recombinants are being actively explored in California [30] and Germany (https://www.vfa.de/de/englische-inhalte/vaccines-toprotect-against-covid-19) as potential vaccines against SARS-COV-2, the etiologic agent of COVID-19.

One potential way to circumvent safety concerns may be to employ inactivated recombinant vaccinia virions that display viral antigens at their surface: very substantial levels of protection were observed with chemically inactivated recombinant vaccinia–rabies virus [7], and this might afford an entry route for new human vaccines based on vaccinia – perhaps even at some stage including Raboral® or further attenuated derivatives, given that rabies in human remains a major concern in several regions such as India [31].
