8. Live attenuated vaccines
The strategy of creating attenuated strain of real pathogens through in vitro manifold passages has already been used successfully in manufacturing attenuated live viral vaccines such as measles, mumps, and rubella (MMR), oral polio vaccine (OPV) and vaccine for rotaviruses [82]. Over the processing of this vaccines’ generation, the virulence genes are mutated or deleted, and thus the pathogen reproduce in a limited extent in the live host without causing serious disease. The manipulated viral particles generate long-acting antibody and cellular immune responses by replicating in the host and are therefore important for achieving herd immunity and disrupting the transmission cycle (Fig. 2) (Table 3). Similarly, several structural and non-structural genes that are not involved in viral reproduction have been nominated to create attenuated forms of zoonotic coronaviruses [83-85]. Protein E is one of the structural proteins which has been deleted to produce attenuated coronaviruses [83, 84], but there have been reports of conversion to virulent strains [86]. In addition to the preferential deletion of virulence genes, another mechanism for producing attenuated phenotypes of pathogenic viruses is applying codon deoptimization approach. In this strategy, due to the changes in the coding sequence of certain viral proteins, their in vivo translational speed is significantly slowed down, but the virus can still continue to multiply [87, 88]. However, the feasibility of this largely depends on proving the genetic irreversibility of the modified species. This is challenging especially for coronaviruses because, at least in theory, it is possible for a combination to occur between the in vitro attenuated and wild-type viral species, re-forming novel pathogenic strains [89]. Besides, the transport of these vaccines requires a cold chain, which limits their use over long distances. That’s why only three research institutes including Indian Immunologicals Ltd and Griffith University, Turkish Mehmet Ali Aydinlar University and Codagenix and Serum Institute of India exploited codon deoptimization technology in order to attaining SARS-CoV2 attenuated vaccine and now they pass through preclinical stage [90]. COVI-VAC is the only first-in-human live attenuated COVID-19 vaccine that was developed in collaboration between the Serum Institute of India and Codagenix company and is currently in a phase I clinical trial.