I'm setting aside any discussion of the Lymerix vaccine for now and just posting this statement from Dr. Vijay Sikand, an MD who practiced in Lyme, Connecticut... (items of interest are in bold)
UNITED STATES OF AMERICA
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE MEETING
Tuesday, May 26, 1998
The meeting took place in Versailles Rooms I and II, Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland at 9:00 a.m., Patricia L. Ferrieri, M.D., Chair, presiding.
VIJAY SIKAND, M.D., Sponsor Rep :
"...As I was just saying, I included research in Lyme disease as part of a primary care practice for a number of years. In early 1995, 1,200 volunteers came to my office to enroll in the SmithKline Beecham vaccine trial which we are discussing today. Almost three and a half years later now, greater than 92 percent of those patients are still providing me with clinical follow-up.
Why do we need a vaccine for Lyme disease? It has been almost a quarter century since Lyme disease was first described as an emerging infection in this country. During these years a number of factors, epidemiologic factors and clinical factors, have resulted in considerable morbidity in burgeoning numbers of patients.This burgeoning load of disease as well as the increasing number of patients thus set the stage for prevention of this disease with a vaccine.Today, I will present to you some of the factors in a brief synopsis illustrating the need for a vaccine for Lyme disease.The illustrations which I will present to you, some of them are from my private practice and some of them are from the vaccine study.
The first factor is an epidemiologic factor,and this has already been discussed by Dr. Schoen. And that is that there is indeed a progressive increase in incidence of Lyme disease. The second factor also epidemiologic is the relentless geographic spread of this disease. There are new endemic areas being created annually and the disease burden is indeed growing.
The ineffectiveness of preventive measures which we attempt to practice is another important factor. We have tried various chemical and other means. Why have preventive measures, which are indeed important, not been effective in preventing an increase in cases of Lyme disease? And before I answer that question, let me underline the fact that I indeed believe it is important that we continue to practice preventive measures because of co-infection with other illnesses besides Lyme disease.
One obvious reason is that it is very impractical to practice certain protective measures. This individual in the Lyme, Connecticut area desires to do some outdoor work and does not want to be bitten by a tick. But the point is it is very difficult to ask children or anybody else for that matter to tuck pants into socks, et cetera, in the middle of July and August when the ticks are questing. We can certainly check our pets, but checking one's dog is indeed a Sisyphean task when the dog goes in and out of the house all day long. Probably the best protective measure, I think, in preventing Lyme disease is checking for ticks. Unfortunately, kids will only allow you to do this up to a certain age. And of course one must be vigilant with oneself.
More specifically, I think one of the important reasons to consider when thinking about why protective measures are difficult to utilize and be effective in preventing this disease is simply the nature of the Ixodid tick bite itself. The bite of this tick when it is infected transmits not only saliva infected with Borrelia burgdorferi, but the saliva also contains certain anti-inflammatory substances which have an anesthetic effect.The end result of that is that tick bites in general are not noticed. In one study, over 80 percent of the patients who presented with definite Lyme disease did not remember a tick bite. It is therefore very hard to correlate the incidence of definite Lyme disease cases with preceding tick bites, and this is well known.
Furthermore, as has been eluded to earlier, the recurrence of disease in individuals is also well known. Unfortunately, in the majority of patients, the vast majority of patients, natural infection with Borrelia burgdorferi does not confer protective immunity.
Difficulties in clinical diagnosis of this disease are also well known, and it is not my place today to give you an overview or detailed presentation of the clinical aspects of Lyme disease.However, a couple of issues that do spring up and which I would like to address are as follows. In particular, the specter of asymptomatic infection is something that troubles me a great deal and troubles a great number of my colleagues who need to treat Lyme disease. The obvious analogy with syphilis infection with Treponema pallidus is there to consider. It is well known that Borrelia burgdorferi indeed after asymptomatic infection can lurk or secrete itself in certain areas of the body, perhaps the central nervous system or perhaps the joint spaces, only to reappear months or maybe years later in the form of late stages of illness which are harder to diagnosis and treat.
In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection. In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to.Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.
Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection. Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember.
The next slide is the electrocardiographic tracing of a 37-year-old mom from Lyme, Connecticut, mother of three. Generally healthy and no medical problems. Early on the day that this electrocardiogram was taken, she went to her local health club and did her usual work-out, which went fine. However, when she came home that day, she noticed that she had some palpitations, a little shortness of breath, malaise, and things just didn't seem quite right, but she wasn't sure what. When her husband came home, she told him that maybe she had worked out a little bit too hard at the club. A few minutes later, he was reading the newspaper in an armchair and he heard a thump on the floor above. He ran up the stairs to find his wife unconscious briefly on the floor and called 911. On arrival at the emergency department, the patient presented with this tracing, which in retrospect was a superventricular tachycardia representing an escape rhythm.
There was fortunately a very vigilant emergency physician who didn't understand quite why a 37-year-old healthy woman had completely passed out, and she had what was a relatively benign rhythm at that point. But he was wise and admitted her to the coronary care unit for further monitoring. Late that night and the early hours of the following morning, the CCU nurse noted that the patient had gone through progressive degrees of AV block culminating in complete atrial ventricular dissociation. A cardiologist was summoned. He inserted a temporary transvenous pacemaker. The patient was started on intravenous antibiotics for about a week in the hospital followed by a few more weeks as an outpatient.This patient also had no history of a tick bite.
Besides the difficulties in clinical diagnosis, we are all aware that quandaries in laboratory diagnosis are rife.We rely pretty much on serologic testing in the United States today to assist us in diagnosing Lyme disease. Unfortunately, serologic testing, as with other infectious diseases, provides only indirect evidence of infection. When we order a serologic test, it just tells us that the patient has been exposed to Borrelia burgdorferi and doesn't tell us whether the infection is active or whether it is a past infection. It is probably worth noting, since I have learned a lot, that we don't have the clinical luxury in private practice that we had in the SmithKline Beecham trial in which we had baseline sera on all the patients who enrolled so that when they presented with symptoms, we could draw acute and convalescent serologies so as to compare them with each other and with baseline to better understand what symptoms they are presenting with. But your average physician in the office just can't do this. A patient comes in with symptoms or signs of Lyme disease and you have to make a clinical diagnosis and it is not always easy and serology doesn't help. The fact that in particular the ELISA creates a great deal of false positive results is also problematic.
In particular and commonly in infectious mononucleosis and other spirochetal disorders, even healthy people, juvenile rheumatoid arthritis and other autoimmune disease all can produce false positive results. Indeed, even with Western blotting recent reports have shown that infection with the agent of human granulocytic Ehrlichiosis can cause false positive Western immuno-blots.The false negatives that we deal with are generally caused by use of serology testing in patients who have early Lyme disease and in whom the serologic response with immunoglobulin M has not occurred to the extent to which it can be measured.
What do we have in the way of direct testing to try to see if the organism itself is actually there or evidence of it? Well, culture and PCR are what are out there right now. However, these are unreliable and impractical. Culture and PCR are certainly not warranted for the diagnosis of erythema migrans. The polymerase chain reaction is indeed sensitive in joint fluid. However, the diagnosis of Lyme arthritis does not require PCR testing since serology is almost invariably positive at that stage. Clinical conditions such as complex neurological conditions when a test like sensitive PCR would be useful, unfortunately cannot be diagnosed that way because PCR and indeed culture are not sensitive for cerebrospinal fluid, nor are they sensitive for urine, blood, and other body tissues when later in the disease one might care to employ these techniques.
Finally, there are indeed many dilemmas in therapy. In particular, untreated or inadequately treated Lyme disease may lead to the chronic morbidity with which we are very familiar. Most commonly arthritis and the not common but complex neurological syndromes are what often result and which confront the primary care physician in the office diagnostically and therapeutically.These particular outcomes result in much more intensive, long-term expensive therapy, often in the form of long-term intravenous antibiotics. These are the patients who often are refractory to treatment. Indeed, these are the patients in whom symptoms seem to persist despite what we have given in terms of adequate antibiotic therapy by any known measure.
In conclusion, we need a vaccine for Lyme disease because it is increasing in incidence and geographic spread.We need a vaccine for Lyme disease because there are problems in clinical diagnosis, its laboratory evaluation, and its treatment. We need a vaccine for Lyme disease because preventive measures are unfortunately ineffective. Lyme disease is indeed vaccine preventable. Availability of this vaccine would lead to a significant reduction in chronic sequelae and substantive morbidity. Lyme vaccine is thus a critical new public health approach to the primary prevention of Lyme disease in the United States. Thank you very much."
Dr. Sikand and Dr. Steere were at the same meeting. It's obvious Sikand knew Lyme disease could lead to serious late stage Lyme disease and chronic persistent symptoms of infection. If it could be easily resolved with 2-3 weeks of antibiotics, would they have spent this much time, effort, and money on developing a vaccine and running clinical trials?
Everyone at this meeting - including Lyme disease patient advocates - wanted a vaccine. That it would lead to adverse events in some patients and be pulled from the market later was not what everyone thought at first - at first it was welcomed as a solution to preventing the worst of what Lyme disease could do to a person because it was hard to diagnose and treat.
1998. Thirteen years ago.
How much have things changed since then?
Why are we still looking at the same problems and issues?