Saturday, May 4, 2013

The Bacteriophage as a Vaccine Platform?

Vaccines are a cornerstone of modern public health, and have been successfully used to control diseases such as Polio and Measles, and have also led to the successful eradication of smallpox.  Despite this success, many current vaccines still have room for improvement, and other modern diseases require vaccine development.  To address this need for further development in the vaccine field, Tao et al, from Venigalla Rao's Laboratory, reported an incredibly interesting bacteriophage T4 based technology that allows for concurrent delivery of desired DNA and proteins to mammalian cells [1].  By allowing for concurrent delivery of DNA and proteins, something other technologies do not currently offer, this phage T4 technology could provide novel approaches for vaccination.

Picture of bacteriophage T4 from Dr. Rao's lab website.
Bacteriophage T4 is a well-studied virus that infects the E. coli bacterium, and does not infect humans or other eukaryotes.  During its infectious life cycle, T4 leads production of phage heads (protein capsids) that are filled with phage genomic DNA.  After assembly of viruses, the bacterium is lysed and the new phages go on to infect new bacteria.  Tao et al took advantage of this process by generating phages that, upon genomic DNA insertion into the head, become unstable and release the genomic DNA back out of the head, leaving the empty head intact.  The group then used a DNA packaging motor to fill the empty head with their DNA of interest, with a capacity of up to ~170kb (a substantial increase over another common vector, Adenovirus, which has a capacity of 28kb).  In addition to the incorporation of DNA into the phage head, proteins of interest could be added to decorate the head surface.  The phage particles were collected and, when exposed to mammalian cells, delivered both DNA and protein.

The group went on to show that their phage particles are indeed taken up by mammalian cells, that the proteins and DNA encoded proteins are functional when delivered, and that the proteins on the surface can also be used for targeting phage delivery to specified cell types.  Finally, because this technology has implications in vaccination, as discussed above, the group immunized mice with a phage-based plague vaccine (which was compared to a vaccine with protein alone) and showed that they were able to induce robust responses through both adaptive immunity arms (humoral and cellular).  These results suggest that their technology warrants future investigation as a vaccine and/or therapeutic gene delivery platform.

This potential vaccine platform has benefits over other existing platforms, including ease of preparation, its large DNA carrying capacity, and its ability to concurrently deliver therapeutic DNA and protein.  One likely next step will be to perform more robust and direct comparisons between the efficacies of this technology to the competing technologies (including other viral vectors and DNA vaccines [2]).  If this T4 phage platform is to become a valuable approach for vaccination or gene delivery, it should be an improvement over existing technologies.  It would also be interesting to see how a vaccine construct, that incorporated a DNA antigen and a protein adjuvant, would compare to other technologies.  Furthermore, this study showed efficacy through correlates of protection (meaning they showed it stimulated the desired immune responses), but it would be beneficial to show the vaccine platform’s efficacy in protecting an animal from disease as well.

Using bacteriophage T4 as a vaccine platform appears to be an appealing and interesting approach.  It offers advantages over other platforms, and appears to be effective at eliciting immune responses.  It will be very interesting to see how this technology, and its applications, progress in the coming years.

Works Cited

1     Tao, P. et al. In vitro and in vivo delivery of genes and proteins using the bacteriophage T4 DNA packaging machine. Proceedings of the National Academy of Sciences of the United States of America 110, 5846-5851, doi:10.1073/pnas.1300867110 (2013).

2     Kutzler, M. A. & Weiner, D. B. DNA vaccines: ready for prime time? Nature reviews. Genetics 9, 776-788, doi:10.1038/nrg2432 (2008).

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