|“With a genome, you have a dictionary of every potential protein the bacteria can make."
While vaccines are already available for prevention of 4 of the 5 strains (serogroups) of Neisseria meningitidis, a bacterium that causes meningitis and infections of the bloodstream, developing a vaccine for serogroup B (MenB) has presented a nearly insurmountable challenge over the last 25 years. Responsible for approximately 50 percent of cases in the United States and more than 90 percent of cases in Europe, the MenB bacterium causes aggressive infection, and results in death in 5 to 15 percent of cases, mostly in adolescents.
For the first time, however, significant gains have been made in the development of a universal vaccine for MenB that has the potential to control this devastating disease once and for all.
“It’s been an enormous amount of work by a very large number of people,” explains CHORI scientist Dan Granoff, MD, whose lab has been an important part of the international effort described in a recent publication by Giuliani et al in the Proceedings of the National Academy of Sciences (PNAS) (Giuliani, 2006).
|“This is the first successful recombinant protein vaccine to confer MenB immunity in humans against multiple strains.”
An international collaboration of such magnitude was required because traditional methods for vaccine development couldn’t be utilized. MenB, unlike other meningococcal strains, has a complex sugar that forms a capsule on its surface that is identical to a structure widely distributed in human tissues. Thus, using the capsular material as the vaccine risked eliciting an autoimmune response. As a result researchers had, for the past 25 years, been trying to identify a protein that might work instead, but to no avail.
“None of the proteins were really ideal, and you were limited by what proteins you could actually identify in the bacterial cell.” explains Dr. Granoff. “What was needed was a new approach.”
That new approach, referred to as “reverse vaccinology” and pioneered by Rino Rappuoli, Chief Scientific Officer of Novartis Vaccines and Diagnostics (formerly Chiron Corporation), can identify every single protein in the bacteria, even proteins no one knew existed.
“It’s basically utilizing the MenB genome and working backwards,” Dr. Granoff says. “With a genome, you have a dictionary of every potential protein the bacteria can make. You can then use a computer to predict which of the more than 2500 genes present in bacteria might encode proteins useful to include in a vaccine.”
Recombinant proteins from more than 250 genes were prepared at the Novartis Research laboratories in Siena Italy and were used to vaccinate mice. The sera from the mice were then tested by scientists at Novartis and at Dr. Granoff’s laboratory at CHORI. Of the approximately 30 resulting proteins identified as new promising vaccine candidates (Pizza et al, 2000), Novartis, CHORI and other laboratories have over the last 5 years narrowed the number of candidates to five, from which Novartis prepared a multicomponent vaccine.
The vaccine was well-tolerated and stimulated protective serum antibodies. As Dr. Granoff says, “This is the first successful recombinant protein vaccine to confer MenB immunity in humans against multiple strains.”
While the combination vaccine has the potential to cover 70 to 80 percent of MenB strains, Dr. Granoff’s lab is already undertaking studies to make the vaccine even more universal. For example, the meningococcal bacteria normally produce only small amounts of the proteins that are used in the combination recombinant vaccine. By engineering the bacteria to produce more of one of the proteins, called factor H binding protein, (Madico, 2006), Dr. Granoff’s laboratory has made a membrane vesicle vaccine from the MenB bacteria. As reported in the journal Vaccine (Koeberling, 2006), this vaccine approach has the potential to broaden protection even further.
The results also have greater implications beyond Neisseria meningitidis. Creating vaccines using reverse technology is now proven and the door has been opened to use the same methods on other, equally tenacious bacterial infections that have to date remained elusive.
“The cocktail looks highly effective,” says Dr. Granoff of the vaccine, called 5CVMB. “It produces a protective response in animals, and in September, Dr. Rappuoli presented the preliminary results of the vaccine in humans at an international congress held in Australia.”
Monday, May 16, 2011 11:33 PM