Stanford Report, February 1, 2006

New avian flu vaccine to undergo test at Stanford

BY MITZI BAKER

Cornelia Dekker

The School of Medicine will soon begin the first trial in the United States of a new vaccine against avian influenza. With three other medical centers, Stanford scientists will be testing the safety and effectiveness of a vaccine based on the H5N1virus responsible for the current avian influenza outbreak.

Although there have not been any cases of avian flu reported in the United States, it has claimed the lives of 85 people in Asia, almost entirely from contact with birds. The concern is that as the virus mutates it may become easily transmissible between humans, creating a pandemic. With a nearly 60 percent fatality rate so far in Asia, this might mean that millions of deaths could result.

Congress has earmarked almost $4 billion for combating avian flu. The National Institutes of Health contracted in 2004 with St. Jude's Hospital in Memphis to engineer a viral strain based on virus isolated from an avian flu victim in Vietnam. The NIH also contracted with both Sanofi Pasteur and Chiron Corp. to develop H5N1 vaccines based on the engineered construction.

Last year, the NIH reported favorable results from the Sanofi Pasteur trial. The problem was that its vaccine used six times more antigen than the annual flu vaccines to generate sufficient antibodies—and had to be delivered twice.

Cornelia Dekker, MD, an associate professor of pediatric infectious diseases and director of the Stanford-Lucile Packard Children's Hospital Vaccine Program, explained that having to use a high dose means that there is less vaccine to go around. "If it take six times more antigen, there is six-fold less vaccine that can be administered," she said. Antigens are the parts of the virus that provoke an immune response.

One way to stretch out the available vaccine is to use an adjuvant, an additive that can make vaccines more potent. An effective adjuvant may not only allow a smaller vaccine dose to deliver effective immunity, but it also may trigger a more complete immune response than the vaccine alone.

For years, Chiron has used an adjuvant mixture, called MF59, in its European flu vaccine and in other vaccines that have been tested in the United States. Scientists believe it can be used to bolster the H5N1 vaccine. "That's what this trial is going to be able to shed some light on," said Dekker, who was a clinical research executive at Chiron before leaving in 1997. The other adjuvant that will be tested is alum, which has been used for years in licensed vaccines in the United States.

In this vaccine trial, led at Stanford by Dekker, the vaccine is manufactured from inactivated virus so there is no chance of participants coming down with avian flu from the vaccine.

During the course of the seven-month study, up to 100 adults aged 18 to 64 will be inoculated with one of eight varying dose combinations of the vaccine with one of the two adjuvants, or no adjuvant or with a placebo.

Study participants will receive the vaccine in two doses by intramuscular injection in the arm about one month apart and then continue to be followed for safety and immune response. Common symptoms may include pain at the injection site, mild fever and achiness. These symptoms can happen with any flu vaccine, said Dekker, and therefore they may happen with this one.

The researchers will draw blood from participants over seven clinic visits and will test the blood samples to see if antibodies to avian flu strain develop. "We don't have a way—nor would we ever want to—challenge individuals with live avian flu virus, so looking at antibodies is the best test we have," explained Dekker. "Testing the blood for immunogenicity has been shown to be pretty predictive for the annual flu vaccine, so we think it will also apply for avian flu."

Dekker emphasized that most of the participants will not get the optimal dose to innoculate them against avian flu. "We can never guarantee protection," she said. "While there is a small chance that they may receive a vaccine that ends up being the chosen combination, people shouldn't volunteer for this thinking that they are going to walk out of clinic being protected against the avian flu."

This study will help define the best formulation to use if H5N1 vaccine is needed to protect against human-to-human transmission. After completing the study, Dekker said the next step will be testing what has been determined to be the optimal dose in larger numbers of people, especially the elderly and very young children.