SAFETY/EFFICACY CONCERNS RE: LYME VACCINE: LYMErix
Joel M. Shmukler, Esquire
Jmspaesq@aol.com
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BACKGROUND:
Lyme disease is a multi-systemic infection caused by infection with the spirochetal bacteria, Borrelia Burgdorderi. It is the most common vector borne illness in the United States. It is one of the leading infectious diseases in the United States. The actual incidence of lyme disease is unknown, but it is known that the reported statistics which are based on surveillance criteria, underreports the actual incidence of the disease by excluding known cases which do not meet the criteria. Surveillance criteria are used simply to get a sense of the rate of growth of an infection, not the true incidence of it.

A recent study in NEJOM reported that doctors routinely fail to report even cases that meet the surveillance criteria because of cumbersome reporting procedures and a distaste for paperwork. That study estimated this underreporting would result in 10 times more cases being reported than are currently reported. In addition, misdiagnosis of the disease is prevalent, increasing the impact of underreporting by an unknown factor. Almost 100,000 cases have been reported to the CDC from 1982-1996. During that time the reported incidence of the disease increased by at least 32 fold!

The disease has been reported in almost all states, although certain regions of the country are considered endemic, and some considered hyperendemic--there appear to be geographic clusters of higher infection. Infection varies from state to state, and even within states from county to county. While the surveillance of the disease leaves a great deal to be desired, two trends are clear--first, the incidence of the disease is increasing rapidly; and, second, there appears to be a spread of the organism to new areas.

LYMErix is a first generation, recombinant OSPa based vaccine. It has a unique mode of action for vaccines. It stimulates specific protective antibodies to be produced in the person vaccinated against OSPa, immunogenicity (the process of triggering protective antibodies). However, OSPa is not usually found in the human host, and it is thought that the bacteria changes its outer surface (triggered by heat) when moving from the tick vector to the human, this is called "upregulation" and "antigenic shifting."

So theoretically OSPa would not be a good candidate for a vaccine in humans, in whom OSPa is not generally found or detectable. It is thought that the mechanism of action is that when a tick bites an infected host and consumes a blood meal where the blood contains antibodies to OSPa that these antibodies kill the bacteria in the midgut of the tick where OSPa is not only detectable, but the dominant outer surface protein. Thus, the bacteria are killed before transmission occurs. Theoretically.

I. EFFICACY ISSUES:

A. EFFICACY UNIMPRESSIVE/OVERSTATED:
The commercials (that we have all seen) for LYMERix state that the vaccine, like all vaccines, may not be 100% effective. That much is true. How effective is the vaccine? The commercial, the literature and news reports have cited an 80% efficacy rate in preventing "definite" and "aymptomatic" lyme disease. However, if you include the category of "possible" lyme disease as well, the overall efficacy rate is 68%. If you include the category of "unconfirmed" lyme disease, in which the vaccine has negative efficacy, or some percentage of those cases, the efficacy rate is even lower, closer to 50%. The reported efficacy figures depend upon a semantic/definitional game--by creating different categories of vaccinees for the statistics Smith Kline has hidden the overall poor efficacy of this vaccine. The category of "unconfirmed" cases is the best example. The vaccine had negative efficacy in these categories, and by excluding this category they have effectively artificially inflated the efficacy numbers--a disturbing number of people got sick with something but due to the absence of laboratory confirmation Smith Kline did not count any of these people as having gotten lyme, though they may have had every symptom. Does this make sense when lyme is a clinical diagnosis? And, perhaps this tells us something about people who don't develop a rash, or detectable antibodies. Perhaps the vaccine is altering the natural presentation of the disease. These unimpressive rates are only achieved after the third shot, now schedulled a year after the first shot is taken. Accelerated dosing schedules are in trials, but reliable data has not been reported. (See tables 1 and 2).

It is interesting to note that the Smith Kline study did prove that lyme disease is hyperendemic, and seriously underreported. Vaccine recipients live(d) in endemic areas. The group receiving vaccines and placebos showed per capita infection rates in the study exceeding 1000 per 100,000, both in year 1 and year 2, even following vaccination!

Another interesting tidbit arose from the study. While the data has not been published it has been presented showing that 35-40% of people in both the Smith Kline study and the Connaught study who developed lyme disease with confirmation by PCR testing and/or culture, were negative by conventional serologic antibody testing. In addition, there is obviously an additional percentage of people without any laboratory evidence of lyme disease, who contracted the disease--given the problems with all lyme testing, a known population of seronegative patients, and the fact that the diagnosis of lyme is ultimately a clinical one given the unreliability of the testing.

B. EFFICACY ONLY ACHIEVED AFTER 3 SHOTS:
After only 2 shots the efficacy rates are even less impressive, 57% in preventing "definite" and "asymptomatic" lyme disease. If you include the category of "possible" lyme disease the overall efficacy rate is only 46%. If you include the category of "unconfirmed" lyme disease, in which the vaccine has negative efficacy, or some percentage of those cases, the efficacy rates are even lower than that. So after shot 1 and shot 2 and before getting shot 3 the benefits of the vaccine are especially dubious, especially when weighed against safety concerns. Until the third shot then, currently schedulled a year later, efficacy is unimpressive, dubious at best. After the third shot efficacy rates improve, however, protective antibodies begin to diminish quickly and we know that a year after shot 3 (whenever given--even on accelerated schedule) they have fallen to close to where they are after 2 shots, to unimpresive levels of protection. (See table 2).

C. DURATION OF PROTECTION UNCERTAIN/LIMITED:
We know that the protection conferred after 3 shots does not last, and Smith Kline has reported that protective antibody levels drop to the level achieved after 2 shots in less than a year after the third shot. So whatever protection is conferred, diminishes quickly. So additonal booster shots will definitely be needed, but the safety, efficacy and timing of such shots has not been studied, tested or approved so safety and efficacy of additional shots, which is of concern (additonal shots may trigger problems, aggravate problems from previous shots). No FDA approval has been sought or obtained for additonal shots. Data is being reported anecdotally only by Smith Kline. They may not seek FDA approval for boosters, instead relying on doctor's right to use approved medications for "off label," (unapproved) uses.

D. BOOSTERS WILL BE NEEDED/SAFETY/EFFICACY/TIMING NOT STUDIED/NOT APPROVED BY FDA:
As stated above, additional booster shots will be necessary following the 3rd shot. We do not know the optimal timing, safety or efficacy of such shots, and such shots have not been approved by the FDA. Safety and efficacy issues remain, and are potentially more dramatic than the same issues after 3 shots only. Safety concerns include additional boosters causing, aggravating problems caused by the first 3 shots and perhaps remaining undetected. A third booster could overwhelm the immune system, or overcome tolerances to side effects that lasted through the first 3 shots. Nor do we know whether additional boosters will provide the same level of protection as the 3rd shot does. Why, knowing that boosters would be needed, did Smith Kline seek approval based on studies that did not address these issues? Perhaps they are aware of problems, frightened by what formal data may show? The unanswered questions abound.

E. VACCINE DOES NOT PROTECT AGAINST ALL STRAINS OF LYME:
Lyme disease, caused by the bacteria Borrelia Burdorferi, has exhibited genetic variations, known as strains. While there are three major strains of lyme disease found in the world, there are substrains by the hundreds. Limited research has been done but strain variation has been associated with variant symptomatic presentation. In the United States where one major strain is found, almost 300 variant substrains have been identified. Smith Kline states that the vaccine has not showed substantial variability in efficacy against strains tested. How many strains have they tested? What safety issues are involved with variant strains and the vaccine? Connaught, which is developing a recombinant OSPa vaccine, similar to that which Smith Kline is marketing, has recently entered into an agreement with MedImmune to co-develop a vaccine based upon DbPa, to address the problems of strain variation. The reports from MedImmune indicate that OSPa is not protective against many "wild" strains found in the field. It is thought that DbPa may protect against most/all strains. Whether this is true or not, it is clear that OSPa is problematic in this regard. Also, Smith Kline and Pasteur Meriux Connaugt (PMC) were in a race to market with their OSPa vaccines for several years. One has to wonder why Connaught has not sought final approval for their OSPa vaccine? The studies have been finished for a long time. No new data is being collected in trials. Has PMC abandoned their OSPa vaccine because of safety and efficacy issues, not to mention lawsuits arising out of the trials? Does the deal between PMC and MedImmune indicate that PMC recognizes that OSPa vaccine is a failure (although maybe a good first step in developing a vaccine that will be safe and effective in the future).

F. VACCINE NOT EFFECTIVE IN PEOPLE > 70 YEARS OF AGE:
Older people were included in the study but the vaccine proved to be less effective in them than 15-69 years old so the vaccine was not approved for use in this age group. It is uncertain why this variant result occurred.

G. EFFICACY RATES MAY HAVE BEEN INFLATED BY AWARENESS:
Those who participated in the trials were obviously aware of, and concerned about lyme disease (or they wouldn't have volunteered for the trials--they were not paid). Part of the study design called for vaccine recipient education--thus these people may have taken more precautions than the ordinary person, thus lowering infection rates overall. H. WERE ADVERSE EVENTS FAIRLY REPORTED/DOCUMENTED: Both the Smith Kline and Connaught trials resulted in the filing of a number of lawsuits. One of those suits alleged, among other things, that adverse events were not promptly and honestly reported to the FDA. Anecdotally, many participants who developed illness reported that the doctors involved in the studies were dismissive of their complaints, rather than thorough in evaluating the question of whether an event was related or unrelated to vaccination.

II. SAFETY ISSUES:

A. PEOPLE WITH A PRIOR HISTORY OF LYME MAY BE AT RISK:
This may be the most serious safety issue associated with the vaccine. The target group for this vaccine is people who live in endemic areas. We know that these areas feature high incidences of infection, including "asymptomatic" infection, undiagnosed infection, and misdiagnosed infection. It is impossible because of the unreliability of laboratory testing to screen candidates for the vaccine for lyme disease effectively. People with a recent history of lyme were excluded from the study. People with a more remote history of simple infection were included, but comprised only a small percentage of people in the study ( total of 11% self-reported prior history--only 2% with serologic evidence for their prior lyme). These people were not studied as a seperate high risk group but the Smith Kline study does admit that people with a prior history of lyme did suffer from a higher incidence of adverse effects from the vaccine. These side effects were greater in number following the 2nd and then the 3rd shot. What the effect of additional booster shots will be is unknown. Analytically it is obvious that the study design, and data reported, deliberately glossed over this vital safety issue.

B. VACCINE NOT SAFE FOR CERTAIN TISSUE TYPES:
Two tissue types, HLA DR2 and HLA DR 4 have been specifically associated with a risk for chronic, destructive arthritic symptoms caused by lyme. These seem to be unresponsive to "adequate" antibiotic treatment, even when initiated promptly. It is theorized that this is due to an autoiimune mechanism, triggered by the infection, and likely because of molecular mimicry--the bacteria shares certain genetic traits with our own tisse; antibodies formed to attack the bacteria, attack our tissue. Similar associations have been made with a smaller percentage of people with other tissue types as well. Recently a specific mechansim for this autommunity has been proposed, and documented, for people with the tissue type HLA DR4. There is a link between OSPa and this mechanism and it is feared that OSPa vaccination may trigger this process, even in the absence of bacterial infection. OSPa vaccination in animals has triggered severe destructive lyme arthritis. Studies of other tissue types relative to this concern have not been performed. Dr. Steere, principal investigator for the vaccine has expressed "concern" over this general issue. Additional booster shots may exacerbate the problem. The vaccine was approved without even a warning concerning this issue, and without instructions to screen candidates for tissue type and not vaccinate people with affected tissue types. Other tissue types may be at similar, or lesser risk--this is unknown. A number of lawsuits were filed against both Smith Kline and Connaught during the trials claiming adverse events. However, the study reports no such adverse events. What happened to those people? Anecdotal reports have been received about such events, and some are reported in the Lyme Alliance News Letter. Other information may be found on the ... web site. If such incidents occur, report them there, and, even more important, make sure they are reported the the FDA Vaccine Adverse Events Reporting System (VAERS).

C. PEOPLE WITH OTHER HEALTH CONDITIONS MAY BE AT RISK:
People with health conditions including arthrtitic condtions, muscoloskeletal disorders, certain cardiac problems, neurologic problems, immunodeficiencies, a history of alcohol or drug abuse, and those receiving long term antibiotic treatment for any illness, along with those with hypersensitivity reactions to previous vaccinations were excluded from the study. So were those who had received treatment for lyme disease within three months of the study. Pregnant mothers were also excluded. Thus, the safety and efficacy of the vaccine in these groups has never been studied, and the vaccine cannot be said to be safe for them.

D. VACCINE NOT APPROVED FOR CHILDREN < 15 YEARS: Children were not included in the original study and the vaccine has not been approved for use in children. Trials involving children are under way now. I would not permit a child of mine to participate.

E. VACCINE NOT EFFECTIVE IN PEOPLE > 70 YEARS OF AGE:
Older people were included in the study but the vaccine proved to be less effective in them than 15-69 years old so the vaccine was not approved for use in this age group. It is uncertain why this variant result occurred.

F. SHORT TERM FOLLOW UP/LIMITED STUDY:
Another serious issue involving study design is the short term follow-up of the study. Vaccinees were only followed during the study and then for less than a year afterwards. Thus, any mid to long term consequences of the vaccine, problems that might not be detected within the time frame of the study, could not have been recognized. Furthermore, while 11000 people were involved in the study, only half received the vaccine. It is very possible that adverse effects from the vaccine in the broader population might not have been detected. Remember that a serious adverse event that occurs to 1 in 1000 people sounds insignificant. However that figure translates into 1000 people in 1,000,000. Now it sounds more significant. One final note, the lack of long term follow up is of great concern in a disease that may become latent and then reemerge later as lyme is known to do.

III. OTHER ISSUES/CONCERNS:

A. VACCINE DOESN'T PROTECT AGAINST ALLCASES OR OTHER TICKBORNE DISORDERS/DON'T ABANDON OTHER PROTECTIVE MEASURES OR GET A FALSE SENSE OF SECURITY:
Since the vaccine does not protect against all strains of the vaccine, or 100% of recipients, and since protective levels are lower following shots 1 and 2, nor does the vaccine protect against Babesiosis, Ehrlichiosis, Rocky Mountain Spotted Fever, Tick Born Encephalitis, or a variety of other less common tickborne diorders spread by the bite of the same tick, it is vital that people in endemic areas not lower their vigilance with regard to other protective measures (i.e., property management, proper attire, personal repellents, and tick checks). A false sense of security could lead to serious consequences. These facts should be carefully explained to all vaccine recipients.

B. VACCINATION WILL CONFUSE ALREADY PROBLEMATIC TESTS MAKING DIAGNOSIS EVEN MORE DIFFICULT:
Because the vaccine itself will cause certan antibodies to be produced, the appearance of these antibodies will confuse existing testing geared to those antibodies--the tests will not be able to distinguish between antibodies caused by vaccination as opposed to those caused by infection. Rather than question people tested for lyme as to whether they have recieved the vaccine, the tests have been reconfigured to discount certain significant and unique antibody responses. Thus, already reliable testing has been rendered even less reliable--and this affects both those who recieve the vaccine, and those who don't. Diagnosis will be even more difficult, and people put at greater risk for a delay that worsens the prognosis for treatment. Prompt diagnosis and early treatment for proper duration, at proper dosage is essential in preventing sequelae of the disease. This will be more difficult now than it has been. Further, as mentioned above, a large number of patients in the vaccine trials developed illnesses that could not be confirmed as lyme. Perhaps this means that the vaccine alters the natural presentation of the disease, and perhaps the natural course of infection. We simply do not know without extensive additional study.

C. FDA/MEDICAL COMMUNITY HAS RESERVATIONS ABOUT LYMERix:
The vaccine was approved with a record number of reservations by the FDA and the approval came in record time, and in an atmosphere of pressure on the FDA to generally speed up their drug approval process. This atmosphere has been created by disease advocacy groups exerting political pressure, in particular , HIV/AIDS patients. Unfortunately, while HIV/AIDS patients have received new drugs in record time, the pressure has been applied across the board and numerous drugs have been approved but then pulled from the market recently due to safety issues.

IV. THE BOTTOM LINE:
Given all of the above it is apparent that the approval of the vaccine was premature. Dr. Steere, principal investigator for the vaccine, has expressed concern over its long and short term safety. The FDA approval came with a unique number of reservations and concerns. Other researchers have simply stated that this vaccine is not safe for human beings. Vaccines given to dogs have turned out to have previously undetected long term consequences, and have never been particularly effective. Dr. Steere himself has declined to receive his own vaccine. The vaccine is expensive ($60-80 per dose, with three doses needed in the first year or earlier, and boosters needed but no one knows when, or how often).

Study design glossed over the biggest safety issues with the vaccine. Anecdotal reports of adverse events are flowing in, but have been denied by Smith Kline, as they were during the trials, despite the fact that several ended up in litigation. All of the above data is based upon Smith Kline's own studies--there may be reason to doubt the accuracy of this data, especially because the integrity of many of the researchers has been questioned, and their aptitude for diagnosing lyme disease is a matter of some debate amongst patients and clinicians. There are at least two schools of thought when it comes to lyme disease issues; it is fair to say that the researchers involved represented only one school of those schools.

If there were a safe and effective vaccine, lyme advocates would be wholeheartedly endorsing this as an additional tool to add to the arsenal of protective measures available to guard against, or minimize the risk of contracting a potentially devastating illness. These advocates have no vested interest in preventing a good vaccine from getting to market. Smith Kline does have a vested interest in marketing the vaccine in which they have invested millions of dollars.

The dubious benefits conferred by vaccination with LYMErix are far outweighed by the known safety issues, and the many unanswered questions.