Genome sequences and supercomputers are fueling today’s breakthroughs in vaccine science, a field that emerged more than 200 years ago after Edward Jenner discovered that a case of cowpox protected milkmaids from smallpox. Using a new approach called “reverse vaccinology,” researchers are mining the genome sequences of microbes to develop potential vaccines for a variety of treacherous diseases including hepatitis C, meningitis, chlamydia and the plague — a potential bioterror weapon.
Scientists describe these developments in a special report on genomic medicine, in Friday’s issue of the journal Science published by the American Association for the Advancement of Science, the nonprofit science society.
Researchers have now sequenced the genomes of 140 bacteria and 1,600 viruses, according to Science authors Rino Rappuoli and Antonello Covacci of the Immunological Research Institute of Siena and Chiron Vaccines.
In this quantity there is also quality.
“In all cases, the new technology has identified treasure troves of novel vaccine candidates,” Rappuoli and Covacci report. They cite the rapid sequencing of the virus that causes Severe Acute Respiratory Syndrome, or SARS, as an example of the speed with which genomic information can provide answers to pressing questions.
Moving foward in reverse
In their Science article, Rappuoli and Covacci describe how scientists around the world are using the genomic information from harmful bacteria and viruses to make vaccines that could not be made using standard techniques.
Conventional vaccine development requires researchers to grow microbes in the lab and harvest proteins that they hope will lead to a vaccine. Some microbes, such as hepatitis B, won’t grow in test tubes, however. Through a reverse-vaccine-development approach, the virus’ genome sequence finally yielded the information needed to make the hepatitis B vaccines now used around the world.
In the reverse approach, scientists armed with gene-sifting computer programs identify slices of genomes that might code for a microbe’s surface proteins. If a surface protein elicits the right immune response, it can be used make a vaccine. Vaccines introduce the immune system to a specific pathogen and give it the information it needs to be ready for a real invasion.
To move from databases of microbe genomes to vaccines, scientists insert highlighted pathogen genes into E. coli bacteria. These living factories manufacture proteins based on the genetic instructions the scientists give them. Next, researchers collect the proteins from E. coli and test the immune systems of mice to see if the vaccine protected the mice from the disease.
“With reverse vaccinology, you can discover things you’d never find with conventional methods,” Rappuoli said.
A crop of new vaccines for diseases caused by bacteria could be available for people in the next 10 years, Rappuoli said. His team is working on a vaccine for meningococcus B, the bacteria that cause meningitis.
“Within 18 months of the beginning of the sequencing of meningococcus B, we far surpassed 40 years of conventional vaccine work,” Rappuoli said. He noted, however, that the reverse-genomic approach does not shorten the time required for clinical trials.
Genomes for security
“The potential of genomic information is enormous for combating microbial agents (both through vaccines and through antimicrobials) that could be used as weapons of bioterror,” Rappuoli and Covacci write in their article.
Rappuoli and colleagues are also using genomic information in their search for a vaccine for Yersinia pestis, the bacteria responsible for both the bubonic and the pneumonic plagues. The bubonic plague is often transmitted through flea bites, while the pneumonic plague spreads from person to person through airborne bacteria. This bacterium occurs naturally in the environment and could be grown in large quantities in a lab, thus making it a potential weapon of bioterrorism.
“In our view, the awareness that we have the technology to develop vaccines that will render any biological weapon inoffensive is a strong deterrent for bioterrorism,” Rappuoli and Covacci write.
They argue that restrictions on sharing genomic information from pathogens would represent a recognition of weakness and only serve to encourage the development of biological weapons.
Reverse vaccinology, phase 2
In the next phase of reverse vaccinology, researchers will increasingly rely on powerful computers to ask specific questions involving the comparison of many genomes at once, Rappuoli explained.
Using the reverse vaccine approach, researchers don’t need to work in laboratories specially designed to contain infectious diseases and other dangerous microbes. In Rappuoli and Covacci’s vision of the future, grids of computers will require only a number of hours to process complex genomic problems that now require weeks to answer.
Looking at the genomes of multiple pathogens highlights similarities or “homology” in surface proteins across species and evolutionary time. These similarities help scientists make better predictions of which genes might code for proteins that would make promising vaccine candidates.
With genomics, biologists are now encountering computing challenges similar to the problems that info-crunching physicists have faced for years.
“If we understand how the physicists process massive data loads, we can adapt their solutions to our problems,” said Rappuoli.