Using modern methods for synthesizing long DNAs, and using computer algorithms, we have recently synthesized several totally novel variants of polio virus in vitro from oligonucleotides, and we have converted these nucleic acids into infectious virus. These viruses preserve the exact protein coding capacity of wild- type polio, but use synonymous codons in various ways to target translation. Two of the viruses were designed to have poor codon bias, or poor codon pair bias, respectively, and both of these viruses were inviable (i.e., cannot form plaques on cultured cells). Here, we seek to understand exactly why the altered viruses are attenuated;to find ways of generating still other, novel polio viruses attenuated to predictable extents;and to extend this approach of synthesizing predictably-attenuated viruses to other classes of viruses. The most important longer term implication of these studies is that the predictable synthesis of attenuated virus should provide a rapid, safe, inexpensive, general and reliable method of creating the raw material for viral vaccines. In principle, vaccines could be created quickly even for very poorly characterized viruses, as long as a nucleic acid sequence is available.

Public Health Relevance

Vaccination has been humankind's main most robust defense against viral disease. We describe an entirely novel and rapid method to generate anti-virus vaccine candidates that might prove applicable to most if not all human pathogenic viral systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075219-05
Application #
8238127
Study Section
Vaccines Against Microbial Diseases (VMD)
Program Officer
Park, Eun-Chung
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$552,986
Indirect Cost
$196,221
Name
State University New York Stony Brook
Department
Genetics
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Wang, Bingyin; Yang, Chen; Tekes, Gergely et al. (2015) Recoding of the vesicular stomatitis virus L gene by computer-aided design provides a live, attenuated vaccine candidate. MBio 6:
Wimmer, Eckard; Paul, Aniko V (2011) Synthetic poliovirus and other designer viruses: what have we learned from them? Annu Rev Microbiol 65:583-609
Sitaraman, Varsha; Hearing, Patrick; Ward, Charles B et al. (2011) Computationally designed adeno-associated virus (AAV) Rep 78 is efficiently maintained within an adenovirus vector. Proc Natl Acad Sci U S A 108:14294-9
Mueller, Steffen; Coleman, J Robert; Papamichail, Dimitris et al. (2010) Live attenuated influenza virus vaccines by computer-aided rational design. Nat Biotechnol 28:723-6
Mueller, Steffen; Coleman, J Robert; Wimmer, Eckard (2009) Putting synthesis into biology: a viral view of genetic engineering through de novo gene and genome synthesis. Chem Biol 16:337-47
Coleman, J Robert; Papamichail, Dimitris; Skiena, Steven et al. (2008) Virus attenuation by genome-scale changes in codon pair bias. Science 320:1784-7