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.