http://www.biomedcentral.com/news/20030513/02/

Unblocking the vaccine pipeline

New approaches for speeding vaccine discovery and development proposed

By John Dudley Miller
 

A pair of ideas discussed at the Sixth Annual Conference on Vaccine Research in Arlington, Va., promises to dramatically shorten the frustrating, decades-long process of discovering and testing new vaccines. Proponents believe the approaches could make it possible to develop a variety of vaccines years before they would otherwise become available.

Dramatically cutting initial discovery time can be accomplished by searching for potential antigens in the genome using a computer rather than in the lab using traditional methods, according to Rino Rappuoli, head of research and development at Chiron Vaccines in Sienna, Italy.

"The genome has provided us all we need, for every pathogen," said Rappuoli, the technique's pioneer. The "old method" of conducting years of painstaking basic lab research to understand a pathogen before creating its vaccine is no longer necessary, he claimed.

Speeding up vaccine development can also be accomplished by improving researchers' basic understanding of the manufacturing end of the process to prevent the surprisingly common problem of creating vaccines that cannot be manufactured safely and reliably, according to Myron Levine, professor and director of the Center for Vaccine Development at the University of Maryland (UM) School of Medicine.

"A very large proportion of basic vaccine development involves antigens and approaches that can be dead ends [for human use]," he explained.

Scientists have never found a straightforward method to discover and develop new vaccines, so bringing one to market commonly takes 15 to 40 years or more, if it can be completed at all. But terrorism and the worldwide AIDS pandemic have only increased the pressure to create new vaccines quickly and predictably.

President Bush and Congress have tasked American science with creating new or improved vaccines for some dozen pathogens considered to be potential bioweapons. Although the kingpin in the government's biodefense effort, Anthony Fauci, director of the National Institute of Allergies and Infectious Diseases (NIAID), has set a goal of 10 years to discover all the vaccines, therapeutic drugs, and diagnostic tests to thwart those diseases, many scientists believe that his goal may be unrealistic.

Rappuoli, however, thinks vaccine candidates can be generated in just a couple of years. He and his Italian colleagues discover them using what he calls "reverse genomics"—studying the complete genome to select first genes, then proteins they express, and finally antigens the proteins create, which previous experience with other diseases and vaccines suggest may be immunogenic. Once these candidate antigens' actual immunogenicity has been tested in vitro and in animal models, the ones that provoke the largest and most varied immune responses are simply mixed together into a vaccine cocktail.

In just 4 years, from 1998 to 2002, the Sienna team moved from the genome for meningococcus B, a bacterium that causes cerebrospinal meningitis, to phase 1 clinical trials of their vaccine to protect against it. "This is a technique that was defined at that time as impossible," Rappuoli said in an interview at the conference.

The phase 1 results for the meningococcus B vaccine will be available in a few weeks. If it succeeds, the vaccine must still pass phase 2 and phase 3 trials before it can be licensed and manufactured.

Not everyone is convinced reverse genomics will work to create vaccines for all threatening pathogens. "[It's unclear] ...whether this could be a model paradigm for most or all vaccines, or whether one needs a tremendous amount of basic knowledge that only the old slow [laboratory-based] way can give you before you could even make the right decisions as you were going through [Rappuoli's process]," said Fauci.

Rappuoli countered, "If you focus, if you get the right people with the right expertise, [and] if you get the right funding… you will be able to make the right choices to select the antigens for the vaccine."

Another way to speed up vaccines is to reduce the time it takes to test, license, and manufacture them, which could be accomplished by simply sensitizing academic researchers to typical manufacturing problems, according to Stuart Shapiro, an AIDS project officer at NIAID. "Frequently we have people come in for the product development money with products that are not feasible," he remarked during a symposium on the global crisis in vaccine supplies.

For instance, some researchers' vaccines include molecules so large they cannot be chemically characterized, Shapiro said. That makes it impossible to manufacture them accurately in every new batch of vaccines. Other academic scientists develop "dirty vaccines," which are more immunogenic than normal because they are contaminated with cellular debris. But that very property also makes them difficult to analyze and manufacture consistently, he said.

Some academic researchers make the mistake of including ova albumen (egg white) and other inappropriate proteins in their vaccines "simply because there is a long history of having used those in mouse work," said Maryland's Levine. But "ova albumen...is a protein that could be actually quite harmful if put into a human," he explained.

The problem of insensitivity to manufacturing constraints is not limited to academics, added Peter Paradiso, senior director of scientific affairs at Wyeth. "Even within our group [of discovery-oriented vaccine researchers], it's something we have to work on."

Stuart Shapiro's office has taken its own steps to sensitize academics to manufacturing problems that could scuttle their vaccines.  NIAID's Division of AIDS has named four HIV Vaccine Design and Development Teams, "to support consortia of scientists with both ideas and product development experience, from industry and/or academia." Together, the four teams will receive a total of $70 million over 5 years.

NIAID has also funded a fellowship training program for MDs and PhDs to spend two years at the UM Center for Vaccine Development learning about the entire vaccine development process. With $240,000 a year in funding, the center has trained more than a dozen researchers in the past seven years and currently has four more enrolled.

Correction: Due to an editing error, the original version of this article included an inaccuracy in the second sentence of the first paragraph, which has been changed.