Thursday, December 8, 2016

The Vaccines of the Future: Influenza’s New Opponent

As the days get shorter and shorter, we are not only reminded of the impending winter weather but we are also reminded of the dreaded spread of the flu. The scientific name for the flu is Influenza, which is a RNA virus that often is replicating and infecting the cells in your respiratory tract.  The flu, as there is a yearly occurrence of infection due to slight mutations in the virus strain, has been the focus of lots of research to create effective vaccines to distribute every year to the public. From the extensive research on this process, Influenza has in some senses become a model for creating vaccines that could potentially be used to produce vaccines for different viruses. One issue, however, is that inactive and attenuated virus vaccines for Influenza often have a loss of productivity and efficacy. (1) Nevertheless,  in a recent Science paper titled, Generation of Influenza A Viruses as Live but Replication-Incompetent Virus Vaccines by Si Longlong et al, (2) the authors demonstrate how they were able to generate live but replication incompetent vaccines for Influenza by genetically expanding the genome.  In other words, the author proved that they could make genetic alterations to Influenza that would usefully replicate in a cell line but would be replication incompetent in vivo.

Before we start of the details of the paper, I am sure you are wondering what it means to be a replication incompetent vaccine? A replication incompetent vaccine is a vaccine that is full of virus particles but these particles have had the coding regions for the genes necessary for additional rounds of virion replication and packaging deleted. These viruses are capable of infecting their target cells and delivering their viral payload, but then fail to continue the typical lytic pathway that leads to cell lysis and death. This is rare to have for vaccines in some sense because in order to make a vaccine you need it to replicate itself and have the virion replication but to lack this when it is injected into you.

What makes this paper rare is that they do not remove any of the viral genes they alter the genetics so the replication is dependent on an UAA (unnatural amino acid). This is seen in their Figure 1 A below:

This figure demonstrates how they used plasmids to generate cell lines with premature termination codon Influenza viruses that function in transgenic cells with UAA but do not function in conventional cells. After this they went through the process of checking to make sure the vaccine has everything that is desirable in a vaccine. They found that the replication of their PTC virus did not affect the genetic stable that made it incompetent, and probably most important to any vaccine is how safe it is to use in vivo. For this aspect of the vaccine, the authors did a fantastic job and utilized three animal models. They test the PTC virus on mice, ferrets and guinea pig and found the virus not only to be effective for offering protection against influenza but also to be able to elicit a robust humoral, mucosal and T cell mediated immunity. Both of these can be seen below. The safety of the in vivo is demonstrated in Figure 3A and the robust immune response is displayed in Figure 4A:

Overall, the question always comes to why do we care about these findings? These findings are important because of the potential they hold. It is great that this is very effective vaccine against Influenza but as I mentioned earlier there is already the existence of them.  The intrigue of this paper is really the future directions.  You could take this method of genetically expanding the genome of the virus and making them cell line dependent to maybe create a vaccine for a virus that doesn’t have one yet. You could maybe even apply this to something like HIV, where you introduce the virus to the patient then when they are actually infected the immune response might be so great that it lowers the set point to a point where they don’t develop AIDS. Such generation of PTC virus vaccines can be adapted as long as the virus genome can be manipulated and packed in a cell line. According to a recent Science article the most desirable vaccine is for Ebola. (3) So maybe the next research that should be attempted is use this technique for that purpose. This is a new approach to making vaccines and definitely one you should check out.

Source paper:
1.Si, L. et al. "Generation Of Influenza A Viruses As Live But Replication-Incompetent Virus Vaccines". Science 354.6316 (2016): 1170-1173. Web.

Additional Research:
2. Jang, Yo Han and Baik-Lin Seong. "Principles Underlying Rational Design Of Live Attenuated Influenza Vaccines". Clinical and Experimental Vaccine Research 1.1 (2012): 35. Web.
3. Cohen, J. "Unfilled Vials". Science 351.6268 (2015): 16-19. Web.

All Figures were taken from the paper.

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