Preparing for a Pandemic—Bloomberg School Tests Potential Avian Flu Vaccine (web article)

Scientists continue to detect the H5N1 influenza virus in migratory birds from Asia to Eastern Europe, raising concerns about a potential pandemic. Since 2003, the H5N1 virus, or “bird flu,” has infected 117 people resulting in 60 deaths, according to the World Health Organization. However, there is no evidence that the virus can be easily spread from person to person.

Ruth Karron, MD, is an influenza vaccine expert and a professor in the Department of International Health at the Johns Hopkins Bloomberg School of Public Health. The Office of Communications and Public Affairs spoke with her about the growing concerns over an influenza pandemic and her research to develop an avian flu vaccine.

Office of Communications and Public Affairs: You are in the midst of evaluating a potential vaccine against a strain of avian flu. Tell me about your work.

Two avian influenza A (H5N1) virons (Courtesy CDC)

Ruth Karron: We are working with the National Institute for Allergy and Infectious Diseases (NIAID) to evaluate a number of live viral vaccines, including a series of live attenuated vaccines to protect against avian influenza. The avian influenza vaccine candidates will be tested in our isolation unit at the Center for Immunization Research over the next several years. In addition to conducting the clinical trials, we are developing the laboratory assays needed to support the clinical work.

In the summer of 2005, our unit tested a live attenuated H9N2 influenza virus vaccine. H9N2 viruses infect humans on rare occasions and cause typical influenza illnesses. The H9N2 vaccine that we tested was well tolerated among the people who received it, and we are in the process of evaluating the antibody response to the vaccine. In the spring of 2006, we plan to begin evaluation of live attenuated H5N1 influenza vaccines. These vaccines are being jointly developed by the NIAID (NIH) and MedImmune Inc. They contain modified versions of the avian H5 gene, the avian N1 gene, and a ‘backbone’ (internal genes) that are the same as those contained in FluMist®, the licensed live attenuated influenza virus vaccine.

Potentially, we will be conducting vaccine trials using a number of live attenuated avian influenza virus vaccines, each containing the avian hemagglutinin (H) and neuraminidase (N) genes of interest and the FluMist® ‘backbone.’ Obviously, the vaccine candidates we test down the road will be dictated by what is going on in the world. Based on current developments, it’s likely that we’ll spend a lot of time evaluating H5 vaccines.

OC&PA: Isn’t there already an H5N1 vaccine available?

RK: Yes, there is one other vaccine for H5N1 that has been evaluated in clinical trials in the U.S. It is an inactivated vaccine that was developed using a recombinant form of the virus. The vaccine was tested at several institutions earlier this year and was shown to produce an antibody response when very large doses were administered. The federal government is buying doses of the recombinant H5N1 vaccine in preparation for a potential pandemic, but relatively small quantities of vaccine are available. Clinical trials are currently being done in which this inactivated vaccine is administered with an adjuvant (substance used to boost the immune response) to see whether this would allow lower doses of the vaccine to be administered.

One difficulty with preparing for an influenza pandemic is that individual influenza strains undergo antigenic drift, in which nucleotide changes in the viral hemagglutinin and neuraminidase lead to small antigenic changes. These changes could mean that a vaccine made against a strain in one year may not be as protective in subsequent years. It’s because of antigenic drift that the components of our standard influenza vaccine are updated yearly. We know that H5N1 is undergoing antigenic drift. For example, the H5N1 virus that caused disease in Hong Kong in 1997 is different from the H5N1 viruses that have been circulating recently in Asia. So, one concern is that an H5N1 vaccine that we stockpile now may not be optimally protective against a virus that could ultimately emerge as a pandemic strain.

One potential advantage of the live attenuated vaccine is that it is possible that it would induce broader protective immunity against these drifted strains than an inactivated vaccine. We have evidence that this is true for some of the human influenza viruses that circulate each year—FluMist® seems to work better against drifted strains than inactivated influenza vaccine, though we don’t know why.

OC&PA: Why is everyone so worried about the H5N1 virus?

RK: The H5N1 virus is of concern because it may have the potential to develop into a pandemic strain. For a pandemic to occur, three things need to happen. First, you need a novel virus that can infect humans. Secondly, a large proportion of the population has to be susceptible (lack immunity) to this virus. Finally, the virus must be able to spread easily from person to person. As of now, H5N1 has fulfilled the first two of these criteria, but it is still not readily transmissible from person to person.

Although no one can say with certainty that an H5N1 virus will cause the next flu pandemic, there are several qualities of this influenza subtype that are worrisome. What is really of great concern with H5N1 is that it can certainly cause lethal disease in humans. About half of the 117 confirmed cases have been fatal, although there may be additional, milder, unconfirmed cases. H5N1 infects many types of birds, but what is more worrisome is that it can now also infect a variety of mammals—ferrets, monkeys, leopards and tigers. Unlike typical flu, H5N1 also causes diarrhea, which may mean that it could be transmitted via contaminated water as well as the more typical respiratory route. In addition, H5N1 is resistant to two frontline antiviral drugs typically used to treat and prevent influenza, amantadine and rimantadine.

OC&PA: What can we do to prevent or prepare for an influenza pandemic? Should we be focusing our prevention efforts on antiviral drugs, or vaccines, or some other measures?

RK: Yes and yes and yes. If we were faced with a flu pandemic, we’d need all of these and more. Antiviral agents will be very important, particularly to limit spread in the early phases of a pandemic. We need to stockpile the two antiviral agents we have that do work—oseltamivir and zanamivir—but we also need to develop new antiviral agents, particularly in the face of a recent report of the development of oseltamivir resistance during treatment of H5N1 infection in a child. Vaccines will be needed to provide long-term immunity, and I believe that there will be a place for both inactivated and live vaccines. We’ll also need to develop methods to educate and inform the public.--Tim Parsons