By Rich McManus

On the Front Page...

The original title of the STEP committee's Dec. 2 presentation on vaccines was subtitled, "Friend or Foe?" but when it came time for the actual event, the more optimistic, if indefinite, title "Changing Perspectives" was adopted. That's because one needn't have sat through more than half the morning-long presentations to have gleaned that vaccines, viewed historically as a whole, are not only stratospherically more beneficial than they are harmful, but also new ones, including those for such deadly viruses as HIV and Ebola, are on the launchpad and being readied for presentation to a world desperately in need of them.

Continued...

The panel opened with the heaviest topic on the global health agenda — HIV/AIDS. Vaccine authority Dr. Gary Nabel, who directs NIH's Vaccine Research Center, described the candidate NIH is betting on: a so-called "naked" DNA vaccine consisting of four components — a fusion protein combined with envelope immunogens from the three major clades, or families, of HIV most responsible for infections worldwide. "We need a globally relevant vaccine," Nabel said. "The strains [of HIV] in the developing world are different from the ones we see here." NIH's so-called "prime-boost" vaccine includes a prime designed to stimulate CD8 cells in the body to mount an infection-controlling defense, which is boosted by an adenovirus vector.

Nabel said his team's assumption is that CD8 cells can control infection; thus far no antibodies to HIV have proven capable of doing that. The vaccine may also induce neutralizing antibodies that react with some circulating strains in the population. CD8 cells seem to be effective in animal models of the disease, Nabel said, and scientists here are hoping that their candidate can delay disease progression, reduce the spread of HIV in people and, most ambitiously, prevent the disease. "Ultimately we'll need to test its efficacy in a natural setting."

Before getting there, however, the long slog toward success must include a safety test of the recombinant adenovirus component of the vaccine, scheduled to commence in March 2004. "The immune profile in animals is encouraging so far, with respect to CD4 and CD8 response," Nabel noted.

He said the molecular nature of the HIV envelope is under intense scrutiny at the VRC as scientists probe its 3-dimensional structure for targets of opportunity. Nabel foresees phase III (efficacy) trials of the candidate vaccine by 2005 or 2006, and said colleagues have already picked dozens of sites worldwide as test beds for trials that will take at least 3-4 years. "The earliest that we expect results is around 2009, so we need to settle in and be patient," he advised. A second-generation VRC candidate is about a year behind the first one, he disclosed, and the drug company Merck also has a horse in the race.

With respect to Ebola, Nabel said that the virus's envelope glycoprotein is responsible for its toxicity; his team has engineered this factor out of its vaccine. Like the HIV vaccine candidate, the Ebola vaccine consists of a DNA prime and adenovirus boost. Human trials of the Ebola vaccine are scheduled to start next year, Nabel said.

Touching briefly on SARS, Nabel observed that it took scientists only 10 days to identify the agent, once it was isolated, and another month to sequence its genome. With respect to a SARS vaccine, he said, "I'm relatively optimistic that we'll get there in a few years — the early signs look good."

Offering a sobering look at how long and hard — and expensive — vaccine development can be was Dr. Harry Greenberg, senior associate dean for research and professor of medicine at Stanford University, who spent a few years away from academia as he helped a company launch FluMist, a nasal flu vaccine. Since the early 1990s, he said, the company spent nearly $750 million bringing its product to market. "Vaccine development historically has been quite slow," he explained. "You don't make it in a day or two, and frequently not in a decade or two."

As with HIV, the SARS coronavirus, and Ebola, it's the surface or envelope proteins on the flu virus that are the targets of protective antibody responses. The recently licensed live attenuated intranasally administered flu vaccine (FluMist) was originally developed in the mid-1960s and consists of an attenuated master donor virus, coupled with the surface proteins relevant to immunity to the latest strain circulating in the community. The strains are actually named according to the characteristic envelope proteins hemagglutinin (H) and neuraminidase (N), hence a designation such as H3N2 to describe a season's flu bug.

The program's last two speakers took on the challenge of defending vaccine safety. Dr. Frank DeStefano of the CDC's National Immunization Program outlined the strengths and weaknesses of vaccine safety monitoring in the United States, both pre- and post-licensure, and gave evidence against a link between the MMR (measles, mumps and rubella) vaccine and autism, or between thimerosal (an organic ethyl mercury compound used as a preservative in vaccines) and neurodevelopmental disorders.

While evidence gathered internationally lets the MMR vaccine off the hook as a cause of autism, DeStefano acknowledged that concerns persist not only in the U.S., but also more strongly in the United Kingdom. He called for better education and communication in the area of risk. Because concerns persist and new data have become available, the Institute of Medicine, which last weighed in on the topic in a report issued in 2001, has another review of vaccines and autism due in February 2004.

The final speaker put vaccine safety in perspective; if your definition of safety is absolute, then nothing is safe, neither bathing, nor eating, nor walking in the rain. Dr. Paul Offit, professor of pediatrics at the University of Pennsylvania School of Medicine, used the histories of the polio, pertussis, rotavirus and smallpox vaccines to argue that vaccines can generally be considered safe so long as their benefits outweigh their risks. He acknowledged that vaccines do sometimes injure; early versions of the polio vaccine caused some cases of polio, the first whole-cell pertussis vaccine did cause some symptoms of fever, fretfulness and crying, and the rotavirus vaccine has lost a place in the world pharmacopeia because, while it is vastly more useful than harmful, it is still associated with rare cases of intussusception, or intestinal obstruction.

Offit said society is trending toward the irrational nowadays as emotional argument comes to outweigh the preponderance of data. "We are unduly influenced by anecdote," he said, lamenting that the removal of the Rotashield rotavirus vaccine from the marketplace demonstrates a wrongheaded apprehension of risk.

If we are going to define safety absolutely, he wondered, how do we handle the following facts: RSV (respiratory syncytial virus) causes about 90,000 hospitalizations and 5,000 deaths per year in the U.S. Would an RSV vaccine that prevented 90 percent of severe and fatal illness, but caused 5 deaths per year be considered safe? "I fear the answer would be no," said Offit. "We'd want to wait for a safer vaccine."

Such waiting around is justified, he noted, with respect to the smallpox vaccine. True, smallpox could theoretically be used as an agent of terror. But with no cases evident in the wild (the last case occurred in 1977 in Ethiopia), and a good but not great vaccine already stockpiled, why put yourself at any risk whatsoever? "The American medical profession has already voted with their arms on this one," Offit said.

To view the entire 3-hour seminar, visit http://videocast.nih.gov.