a special program of the National Emergency Medicine Association (NEMA)

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Week: 575.7
Guest: Dr. Solomon Langermann, MedImmune, Inc., Gaithersburg, MD

Topic: Research into an E. Coli vaccine

Host/ Producer: Steve Girard

NEMA: UTI's...or urinary tract infections. A big problem...which may have an ingenious answer sometime soon. Dr. Solomon Langermann of MedImmune is with us today to talk about work into finding a vaccine that will prevent UTI's, rather than treating them after they've taken hold....

LANGERMANN: The urinary tract infections are a significant problem in women in this country. In fact, the statistics show that 50% of women, by the age of 30, will have had at least one urinary tract infection. And overall, it accounts for 7 to 8 million physician or hospital visits per year, and amounts to medical costs exceeding 1 billion dollars per year. It's particularly a problem in adolescent women, and in young adults. And a recent study in theNew England Journal of Medicine, by Doctors Hooten, Stapleton and Stamm at the University of Washington in Seattle, has demonstrated that increased sexual frequency also contributes to increased urinary tract infections.

NEMA: What's the usual course of treatment today?

LANGERMANN: Many urinary tract infections are fairly easily treated with an antibiotic, and that antibiotic regimen can vary, depending upon what types of antibiotics are used from single day treatment to 3 to 7 days. However, what we're seeing in the case of urinary tract infections is a large number of antibiotic resistent strains,which is typical for many bacterial infections. And there are many women who have recurring urinary tract infections, which do not seem to be cleared by antibiotics. So, as with many other diseases, the emergence of antibiotic resistent bacteria are making thedisease more difficult to treat, and furthermore, women who have recurrent UTI's are particularly succeptible to multiple infections.

NEMA: Are there certain categories of people, women, more predisposed to getting UTI's?

LANGERMANN: There is no real, definitive genetic correlation, for example...I mean, it's typically...it can affect most young women. And in the case of URI in women, unlike the pediatric population, where it's associated with anatomic abnormalities...in women, this is something that's really quite prevalent throughout the population. What I would mention, also, is that there are...in a small subset of these cases, a yet significant number of ascending infections, where the E.coli will ascend from the bladder into the kidney, and cause severe pylonephritis, or swelling of the kidney. And in some cases, that can lead to the bacteria invading the bloodstream, and in a small number of cases...or I should say 5% of those cases, can be fatal.

NEMA: Let's talk about the vaccine in the works which may help prevent these infections....

LANGERMANN: Most bacterial infections, in order to be able to initiate, the bacteria need to be able to bind or attach to the cell surface that lines various mucosal tissue, in this case, the bladder. And we know through work done by our collaborators at Washington University in St. Louis...led by Dr. Scott Holquin...that these bacteria that cause the urinary tract infections, make an adhesion protein at the very tip of a structure called the pillus organelle. And that adhesion protein is absolutely required for the bacteria to stick to the tissue, and to cause an infection. What we have done is we've taken these adhesion proteins and used them as a vaccine, and forced the body...in this case in our mouse model, for the mice to make an antibody response against the adhesion, and that now blocks the infection from happening. So, the strategy has been to block infections before they happen, rather than to treat infections after they've already set in.

NEMA: So it's more against the adhesion process rather than the E. coli itself?

LANGERMANN: Well, it is against E. coli because these proteins are present on the E. coli surface. If you can imagine, the bacteria that make these pilli-proteins, the E. coli bacterium, have these hairlike projections off of this surface - it looks like a hairy bacteria. And these hairlike proteins are the pillus proteins. At the very tip of these hairlike proteins, or pillus proteins, is the adhesin...and that is like the sticky paper that allows the bacteria now to attach to the bladder tissue. So, our approach has been to raise the antibody, the protective antibody, against those sticky proteins to block them from attaching to the bladder.

NEMA: What's the collaboration between MedImmune and Washington University been like?

LANGERMANN: We've had an ongoing collaboration now for about a year and a half or two years with Dr. Scott Holquin's lab. And he had done, along with Stephen Normark in Sweden, some of the pioneering work, demonstrating that these proteins on the surface of the bacteria, these pillus proteins, are made up of a lot of different sub-units. And they had shown that one of these sub-units is the adhesin, or the portion of the overal structure that allows the bacteria to bind very specifically to the bladder. What we have done now in collaboration with Dr. Holquin is to look at these proteins as vaccine candidates, specifically for urinary tract infections, because E. coli cause 85% of UTI's in women. And what we found is that, not only does this strategy work to block infections, but that these adhesin proteins are present on greater than 95% of the bacteria that cause these infections. And it blocks greater than 95% of those strains from binding to human bladder cells in laboratory experiments that we've done. So, it looks like a very promising strategy to block a wide array of E. coli strains out there that cause the disease.

NEMA: What's the next step in the process?

LANGERMANN: The next step in the process is, we have ongoing now...some studies in monkeys with a collaborative group at the Karolinska Institute, led by Dr. Stephen Normark. And they've done a lot of work in the past where they've developed a very nice UTI model in monkeys, and of course, in monkeys, they are more anatomically similar to humans in terms of the proximity of the peri-urethral area to the bladder, which is normally how these infections occur in women. And what we would like to demonstrate in the monkeys is that this approach would work in terms of blocking urinary tract infections. So we've initiated some studies and we should have the readout on those experiments by the end of the summer.

NEMA: How far down the road are human trials with this vaccine?

LANGERMANN: Well, if all goes well with the monkey studies, by the end of the summer, our plans would be to initiate human studies as phase one clinical trials by the beginning of next year. Of course, it's a long process...in terms of the Food & Drug Administration approval to go through the whole process of phase one, two and three clinical trials, to go from demonstrating safety to efficacy. So the process, once it gets into humans, would probably take around 4 to 6 years.

NEMA: How would the vaccine be administered?

LANGERMANN: You know, that's a very good question. In the monkeys, we're giving it as an intramuscular vaccine, and what we've found in the case of our mouse studies is that a systemic immunization, or an intramuscular immunization will generate antibodies that are present in urinary secretions. And what we believe is happening is that you get something called transudation, or leakage of the antibodies onto the mucosal surface, or onto the lining of the bladder. And particularly during a UTI, you get a tremendous amount of inflammation caused by the E. coli bacteria that are stuck to the bladder. So, under those conditions, you get even more antibodies present into the bladder via the leakage of the antibody into the bladder... in the interior of the bladder. So, the presumption is that these antibodies are what block the binding of the bacteria to the bladder, and allow the bacteria to get flushed out by the normal mechanisms.

NEMA: And you mentioned this vaccine could eventually be used on a wider scale....

LANGERMANN: Most, if not all bacteria express similar types of proteins on their surface. And although we've initiated these studies looking at urinary tract infections, because it's a clearly significant problem and one that needs to be treated, this has broad applicability to a number of different bacterial infections, which also require the bacteria to attach to the host tissue before it can initiate an infection. And so, we believe that this has broad applicability to a number of bacterial diseases.

NEMA: What other problems, for example...might be targeted someday?

LANGERMANN: ...it's been shown that a bacteria like homoflous influenza, which causes middle ear infections in kids...a bacteria like clubsiopneumonia, that cause pneumonia...bacteria such as nycerigonorrhea, that are responsible for gonorrhea...as well as some other, what we call ground positive bacteria...which are ones that are associated with things like streptococcal pneumoneia, or pneumococcal infections, may also have similar types of proteins on their surface. So the potential application actually covers a wide range of diseases.

NEMA: Thanks to Dr. Sol Langermann of MedImmune, working with Washington University in St. Louis and the Karolinska Institute in Sweden on a vaccine against E. coli and other invasive bacterial agents. Some scientists have called the new angle of developing the vaccine the most important advance in that area in 20 years. The study results appear in a recent issue of the journal Science.

SPOT: Small pages....big advice on parenting...from infants to teens. What to expect, emotionally and physically, as your child grows. How to develop positive discipline,how to deal with kids and TV, adolescent issues, drug education, fighting, single and step parenting...it's all in the 'Little Book of Parenting, available through the National Emergency Medicine Association. Call 1-800-332-6362 for more information.

NEMA: Thanks for joining us for today's program. If you have any comments or suggestions, contact this station. Or visit our home page at: www.nemahealth.com/ ...for a look at transcripts of this or past programs, or to find out more about the National Emergency Medicine Association. I'm Steve Girard at The Heart of the Matter.



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