There’s a lot of innovative work being done to develop new ways to jumpstart our immune systems, both in the “immune system trigger” part, and the packaging. For instance, there are efforts focused on virus-like particles (VLPs), liposomes, and various nano-structures (a couple of examples). This week in Science, a team including Eckard Wimmer, famous for de novo synthesis of poliovirus, reports its work in exploiting “codon pair bias” to create weakened poliovirus strains with great vaccine potential. Science mentions two teams currently exploring this method—Wimmer’s at Stony Brook University, and a team led by Olen Kew at the CDC.
We currently have a live poliovirus vaccine that is not without risk of causing the illness it is supposed to prevent. The thinking on this new strategy is that the genetically crippled virus could never mutate in such a way to overcome all of its flaws; further, the methodology could possibly be applied to any virus to create new vaccines.
Here’s the abstract:
Virus Attenuation by Genome-Scale Changes in Codon Pair Bias
J. Robert Coleman,1 Dimitris Papamichail,2* Steven Skiena,2 Bruce Futcher,1 Eckard Wimmer,1† Steffen Mueller1
As a result of the redundancy of the genetic code, adjacent pairs of amino acids can be encoded by as many as 36 different pairs of synonymous codons. A species-specific “codon pair bias” provides that some synonymous codon pairs are used more or less frequently than statistically predicted. We synthesized de novo large DNA molecules using hundreds of over- or underrepresented synonymous codon pairs to encode the poliovirus capsid protein. Underrepresented codon pairs caused decreased rates of protein translation, and polioviruses containing such amino acid–independent changes were attenuated in mice. Polioviruses thus customized were used to immunize mice and provided protective immunity after challenge. This “death by a thousand cuts” strategy could be generally applicable to attenuating many
kinds of viruses.
Because everyone wants to coin a catchy phrase I guess, they call the method “synthetically attenuated virus engineering” or SAVE. The paper sums the potential benefits:
…these results suggest that synthetic attenuated virus engineering (SAVE) could play a role in creating new vaccines for various types of viruses. By deoptimizing codon pair bias, one could systematically attenuate a virus to variable but controllable and predictable extents. This approach has four key features: (i) It produces a virus encoding precisely the same amino acid sequences as the wild-type virus, and therefore eliciting the same immune response. (ii) It is a systematic method apparently applicable to many viruses, and possibly not requiring detailed, virusspecific research. (iii) The attenuation is not subject to reversion, simply because of the sheer number of mutations. (iv) It can be combined with other attenuating changes (such as amino acid changes from adaptation of the virus to low temperatures or alternative species) or with other synthetic biology approaches to attenuation (18, 19), thus taking advantage of additional modes of attenuation while providing the unique advantage of limited reversion.
Codon pair bias is a little more complicated twist on codon usage bias (or just codon bias) which is a principle that has been applied in codon optimization for synthetic genes. Greatly simplified, in the genome there are multiple three-letter codons that can result in single amino acids, but some just seem to translate better than others. This preference can be used to promote high levels of gene expression in a selected organism, for instance. If you do the opposite, though, you can produce an organism that the body recognizes as a threat, but it really isn’t because it just can’t quite get the job done. It’s like an instruction manual written in Engrish. You know it’s an instruction manual but damned if you can understand it.
Here’s another writeup at ArsTechnica.