Originally published May 17, 2023 on TrialSiteNews.
By Laura Hovind, CEO, TruthCures
Why is there so much controversy surrounding Lyme disease? Why does it seem you can't get an accurate Lyme disease test?
The State of Lyme
The incidence of Lyme disease is approaching half a million cases per year in the United States, according to a 2021 Centers for Disease Control & Prevention (CDC) report based on data from commercial insurance claims. Yet fewer than 40,000 cases are reported to the CDC in any given year, exposing a massive discrepancy between the actual prevalence of the disease and the few cases that meet the CDC's surveillance reporting definition.
Despite its alarming incidence rate and often catastrophic effects on human health, there has been little advancement in diagnostic and therapeutic technologies for Lyme in the last 40 years. The CDC and Infectious Diseases Society of America (IDSA) continually support only the use of outdated serological techniques that are known to be inadequate, while simultaneously acknowledging that better tests are needed. The reasons for such double-speak and neglect are inextricably intertwined with the sordid history of Lyme disease vaccines.
Lyme vaccine development has continued for the last three decades despite evidence that the causative organism—the spirochetal bacteria Borrelia burgdorferi—evades immunity in multiple ways that may make it impossible for a vaccine to prevent infection. The most recent effort, a candidate known as VLA-15 from Pfizer and French biotech Valneva, is now in phase III trials. Last February it was revealed that due to alleged violations of good clinical practice, Pfizer had shut down all trial sites run by contractor Care Access, eliminating roughly half of the enrolled participants.
Pfizer's record of "engaging in illegal and corrupt marketing practices, bribing physicians and suppressing adverse trial results" may alone warrant suspicion about their recent actions. But in the context of a Lyme vaccine, suspicion should be heightened. The last Lyme vaccine on the market, SmithKline Beecham's LYMErix, was withdrawn in 2002 amid numerous injury claims, federal agency hearings, and class action lawsuits. Which begs the question, is history repeating?
Stepping back three decades
In June 1994, the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) devoted a lengthy meeting to the three companies that had Lyme vaccines in development. According to the official meeting transcript, the primary order of business was to answer the question, "Is the CDC case definition for Lyme disease appropriate for a pivotal efficacy trial?"
Why would this even be a question? The standard diagnostics at the time—mainly the ELISA, a serologic assay that measures antibodies produced against the bacteria—were known to produce a large proportion of false negatives. When the CDC discontinued routine testing of samples in its labs in 1988, it stated in a letter to the Oregon Public Health Laboratory that the sensitivity of the ELISA ranged from 13% to 27% in clinically recognized cases. Obviously, this would hamper any trial operator's ability to assess possible Lyme infection and the vaccine's overall effectiveness. If you can't diagnose cases, how can you determine whether your vaccine works?
The outcome of the VRBPAC meeting was that, no, the case definition of Lyme disease was not "appropriate" for use in the vaccine trials, and as such a new diagnostic standard was proposed. It required a two-tier approach, relying on the existing ELISA tests for initial screening, followed by a supposedly more specific Western blot for any positive or equivocal first-tier results. One might reasonably wonder how the ELISA's dismal sensitivity could possibly be improved by retesting the few positive and borderline specimens (which excludes even more cases) and completely disregarding a large proportion known to test falsely negative.
The two-tier testing methodology had been conceived by a consortium of federal employees, academics, public health professionals and industry representatives, known as the "CDC/ASTPHLD Work Group." ASTPHLD was the Association of State and Territorial Public Health Laboratory Directors, rebranded since then as the Association of Public Health Labs, or APHL. Conflicts of interest, financial and otherwise, were rampant among the work group.
CDC employees owned patents with SmithKline, maker of LYMErix. SmithKline had a Cooperative Research and Development Agreement (CRADA) with the CDC and Yale to develop their vaccine and companion diagnostics. The CDC employee in charge of the CRADA, David Dennis, also served on the data and safety monitoring board (DSMB) for LYMErix and presented at the June 1994 VRBPAC meeting in favor of the manufacturers.
Dr. Allen Steere also presented at VRBPAC on behalf of SmithKline, was a member of the CDC/ASTPHLD Work Group, became the chief investigator for the LYMErix trial, and his 1993 paper, "Western Blotting in the Serodiagnosis of Lyme Disease," was cited as a "predicate device" in the FDA applications for the new diagnostic tests that emerged from these events.
By definition, a predicate device is one that has previously received authorization through the pre-market notification process. Obviously, a journal report is no such device. That didn't seem to bother the FDA reviewers, though. Two of them participated extensively in the efforts to make the CDC case definition for Lyme disease "appropriate for a pivotal efficacy trial."
In October 1994, in Dearborn, Michigan, the CDC held another event to discuss the topic of Lyme diagnosis, promoted as a "consensus" meeting for adoption of a new testing algorithm. Diagnostic manufacturers were invited to present their laboratory evaluation results of the proposed method. They returned a broad range of results, with some reporting sensitivity lower than 10%.
The June 1994 VRBPAC meeting and its outcome were not mentioned in the published proceedings of the October 1994 Dearborn conference. Dearborn went ahead as if its organizers were seeking input, but a consensus had already been reached. Dearborn simply cemented in place the two-tier diagnostic algorithm: a wildly insensitive ELISA (Remember the letter to the Oregon Public Health Lab?) followed by a questionably sensitive Western blot for the few samples testing positive or borderline on the ELISA.
Implementation Despite Objections
Multiple objections were raised. Dr. Paul Fawcett, along with co-authors, presented at the 1995 Rheumatology Symposia that the two-tier method caused a false-negative rate of 69%. In another objection, the New York State Department of Health in a 1996 letter to the CDC wrote, "If we followed a case confirmation scheme which incorporated the new two-test requirement for serologic confirmation on our 1995 cases, 1237 cases (81%) of our non-EM [erythema migrans, or bullseye rash] cases would not have been confirmed." This is significant because the CDC recognizes the EM rash as a sign of infection which alone confirms a reportable case of Lyme disease.
The most serious accusation, though, came from Dr. Nick Harris, founder of the Igenex specialty laboratory, the very next day after the conference ended. His letter to organizers, a copy of which was obtained from the records of Dr. Willy Burgdorfer, Borrelia burgdorferi's namesake, implied financial conflicts of interest drove the CDC's decision. He claimed the patient samples provided by Yale, SUNY-Stony Brook and New York Medical College (NYMC), known as the Academic Reference Centers (ARCS) Panel, had been pre-screened to ensure positivity and had been provided to one of the participants in particular.
That participant, MarDX Diagnostic, reported the highest accuracy of all the labs, claiming up to 100% sensitivity and specificity in certain disease stages. MarDX also happened to have the contract to provide tests for the LYMErix phase III trial.
MarDX submitted FDA applications in April 1995 for clearance of their Western blot tests intended to be used as second-tier confirmatory tests. In these applications, obtained through the Freedom of Information Act (FOIA), MarDX cited not only Steere's western blotting report as a predicate device; they also claimed the ARCS panel to be a predicate, in addition to their own ELISA tests.
The two FDA officials who had been involved in the proceedings appear multiple times each in the heavily redacted applications. Perhaps as a signal they were unwilling to assume any liability associated with these events, the FDA passed a regulation in December 1994 requiring submitters of pre-market notifications "to provide a statement that the submitter believes, to the best of his or her knowledge, that all data and information submitted in the premarket notification are truthful and accurate and that no material fact has been omitted." Initially MarDX failed to include the statement and their application was put on hold until it was provided. After several rounds of revisions, MarDX's second-tier Western blot tests received FDA clearance.
After its use in the phase III LYMErix trial, the manipulated two-tier diagnostic standard was rolled out for public use via a 1997 FDA advisory. If any manufacturer wanted to continue marketing their already-cleared tests, they would have to submit data demonstrating accuracy in the context of the two-tier method. Any new diagnostics submitted for FDA clearance must also prove "substantial equivalence" to the tests and algorithm developed on behalf of SmithKline for their vaccine trial.
“Lyme disease” would now be defined as a small subset of Borrelia burgdorferi infections deemed genetically competent to mount a strong antibody response, because ensuring that only a minority of cases could test positive benefitted the vaccine developers.
Thus was created a decades-long "daisy chain" of diagnostics referencing predicate tests that appear to have been improperly cleared. Indeed, when representatives of nonprofit Lyme advocacy group TruthCures met with FDA investigators in October 2021, the investigators agreed that this appeared to be the case.
The real-world consequences for people subjected to this test method have been nothing short of devastating. There are potentially hundreds of thousands of people every year falling into a black hole of under-diagnosis, withholding of treatment, and utter denial of their illness.
Improved Testing: A Mirage
Fast forward nearly 30 years: the two-tier diagnostic methodology which Lyme disease patient-advocates say has caused immeasurable harm, remains the standard. In 2019 a seemingly regressive "modified two-tier method" was implemented. The only difference is that first-tier tests may be used in both the screening and confirmation steps instead of the customary ELISA-then-Western blot scheme.
Despite calls for better diagnostics by everyone from the patients themselves to the HHS Tick Borne Disease Working Group, the state of Lyme diagnostics appears to be an infinite loop of finger-pointing. The CDC will not recommend a new test method unless it is cleared by the FDA. To be cleared by the FDA through the pre-market notification pathway, a test must demonstrate "substantial equivalence", i.e., it has little chance of becoming available to consumers unless it is a serological assay, just like the tests in place now.
Few test developers have the interest or the resources to utilize the more complex and considerably more expensive FDA pathway. At least one who tried—Sin Hang Lee, M.D., Director of Milford Molecular Diagnostics in Milford, Conn.—faced years of lawsuits that remain ongoing. Dr. Lee's expertise includes 36 years on the faculty at Yale while practicing hospital-based pathology. Dr. Lee noted via email, "Lyme disease is an infectious disease, just like COVID-19. You do not wait for the patients to develop antibodies before diagnosing SARS-CoV-2 infections."
Good Enough for Thee but not for Clinical Trials
Is it possible that after decades of controversy over the accuracy of Lyme diagnostics, we are witnessing history repeating? Lyme disease activist Carl Tuttle, whose years-long petition on Change.org has garnered nearly 100,000 signatures, made a stunning discovery.
Lyme disease researcher and renowned expert Dr. Gary Wormser disclosed in a recent publication that he received a research grant "from Pfizer, Inc. for developing Lyme diagnostics for a Lyme vaccine trial." Evidently the two-tier method that was developed on behalf of a pivotal efficacy trial still isn't good enough for the latest pivotal efficacy trial.
According to the Centers for Medicare & Medicaid Services (CMS) Open Payments website, Wormser's institution, New York Medical College (NYMC) received a payment of $156,000 from Pfizer in 2021 for "Borrelia strain genome sequencing and sera analysis." He is listed as Principal Investigator (PI). This payment appears to match up with his published disclosure, however, an August 8, 2022 Associated Press article that quoted Wormser notes he "isn’t involved with the new research."
If he was paid $156,000 as PI for "developing Lyme diagnostics for a Lyme vaccine trial" as per his own written disclosure, and that work consisted of "Borrelia strain genome sequencing and sera analysis," does that not constitute "involvement" with Pfizer's vaccine research? Dr. Wormser was contacted for clarification of these conflicting details and was told that the information was for an article to be published the following day. He was quick to reply but offered additional information that raised even more questions.
The initial request for clarification received the following reply (all punctuation his own):
i was asked to be a participant in the clinical trial of a new Lyme vaccine candidate but declined. NYMC, with me involved, did provide some materials from past Lyme cases as requested by Pfizer in order for them to be get ready for the future trials. I was never given any more specifics. The funding was given to NYMC. is this clear or still confusing?
I clarified that I was "trying to understand whether a new test was developed for Pfizer’s Lyme vaccine trials, as seems straightforward in your disclosure." I then asked five pointed questions and received the following answers:
1. Does your disclosure, "...research grants from...Pfizer, Inc. for developing Lyme diagnostics for a Lyme vaccine trial" refer to the $156,000 CMS Open Payments record of payment to NYMC in 2021?"
YES but i have no idea what tests specifically
2. Are you saying that your disclosure is not an accurate description of the work you conducted, after all? If so, how was an inaccurate description submitted for publication?
not sure i follow, 1 disclosure is from the journalist and 1 from me
3. CMS Open payments describes the work as "Borrelia strain genome sequencing and sera analysis”. Is this related to test development for Pfizer’s Lyme vaccine clinical trial?
HAVE NO IDEA BUT MAYBE AND AM NOT SURE EXACTLY HOW
4. Your original reply to me states, "NYMC, with me involved, did provide some materials from past Lyme cases as requested by Pfizer in order for them to be get ready for the future trials. I was never given any more specifics.” Congratulations on the substantial award for a seemingly small project! You are listed on CMS Open Payments as Principal Investigator. Was this a reporting error? If so, is there someone else who had a higher level of involvement in the project, carrying out the genome sequencing, sera analysis, and reporting back to Pfizer?
I WAS THE PI BUT ONLY FOR ARRANGING THE MATERIALS TO BE SENT TO PFIZER; WHATEVER THEY DID WITH THE MATERIALS IS UNKNOWN TO ME
5. Why did you decline to participate in Pfizer’s clinical trial when invited?
MY RESOURCES NOT ENOUGH TO PARTICIPATE I FELT
ANY CHANCE WE COULD SPEAK BY PHONE SO I COULD GIVE YOU BETTER ANSWERS?
Sensing that a phone conversation would be unproductive and having already clarified that the $156,000 grant Pfizer paid to NYMC with Dr. Gary Wormser as PI to conduct "Borrelia strain genome sequencing and sera analysis" was, in fact, the same conflict disclosed as "developing Lyme diagnostics for a Lyme vaccine trial," I declined. I followed up with one final request, "since I was not explicit enough in my question," on number two.
2. Are you saying that your disclosure is not an accurate description of the work you conducted, after all? If so, how was an inaccurate description submitted for publication?
not sure i follow, 1 disclosure is from the journalist and 1 from me
I’m referring to your disclosure, "..."from Pfizer, Inc. for developing Lyme diagnostics for a Lyme vaccine trial." I'm assuming this description is in your own words, submitted for publication. Is there something inaccurate about it?
The reply confirmed my instinct that a phone conversation would be unhelpful.
Pfizer has not been contacted for comment, but any explanation would be welcomed and incorporated into this article.
In the absence of public disclosures or a transparent process, it looks as if Pfizer paid someone to create or validate a test that will make their vaccine appear effective. In light of Pfizer's recent withdrawal of numerous trial sites affecting nearly half of their U.S. enrollees, this opaque move does not inspire much-needed trust in a next-generation Lyme vaccine. It only raises more questions about the apparent need to customize a diagnostic test for clinical trials, and the expert contracted to carry out the necessary laboratory work.
History of Conflicts
Wormser's list of potential conflicts is lengthy. He is listed as an inventor along with CDC officers on patents for Lyme disease diagnostics. He previously has disclosed relationships with Lyme diagnostic manufacturers including Biomerieux, Diasorin, BioRad, Immunetics and Quidel. He owns equity in Abbott Labs, who once patented a Lyme test but never brought it to market. He has testified against patients and Lyme-treating physicians in legal proceedings. He has been a board member for the American Lyme Disease Foundation (ALDF), an organization notorious for promoting a decidedly anti-patient narrative about Lyme.
Moreover, Wormser served as lead author of the Infectious Diseases Society of America's (IDSA) 2006 Lyme disease diagnostic and treatment guidelines—the standard of care to which insurance providers and doctors unquestionably adhere. Notably, he served as principal investigator in phase III trials for the Connaught Lyme vaccine candidate, a LYMErix competitor that ultimately declined to seek FDA approval. Both Connaught and Wormser were named as defendants in lawsuits by trial participants claiming harm from the vaccines.
Wormser's institution, NYMC, purportedly was one of the providers of the ARCS samples to MarDX for the Dearborn conference, according the letter from Nick Harris, shared earlier. In their premarket notification paperwork for their second-tier Western blot tests, MarDX notes that the ARCS panel was being maintained by the CDC. Apparently this public-academic relationship continued, at least through 2015.
Between 2008 and 2015, NYMC was awarded contracts worth hundreds of thousands of dollars to provide various types of samples to CDC's Lyme serum repository, including "serial serum samples from patients diagnosed with Post-treatment Lyme disease symptoms and controls."
These samples would fit in the same category as those provided to validate the manipulated diagnostic method in 1994. The CDC gives sample panels to researchers and industry labs to conduct validation studies of diagnostics, as well as for other research purposes. Therefore, Lyme disease research has been artificially focused on a narrow subset of cases for many years.
Notably, Dr. Wormser admitted in his email communication that Pfizer was seeking "cultured patient isolates of Borrelia burgdorferi that we have saved and have been evaluating genetically over many years." Such genetic characterization could indicate a propensity for certain samples to test positive by serology.
THE MATERIALS THEY WANTED FROM ME WERE TO DEVELOP OR VALIDATE CERTAIN LYME DIAGNOSTICS BY SCIENTISTS AT PFIZER BUT WAS NOT TOLD ABOUT EXACTLY WHAT TESTS AND HOW. I HAD SOMETHING TOTALLY UNIQUE THAT THEY NEEDED, I HAD CULTURED PATIENT ISOLATES OF BORRELIA BURGDORFERI THAT WE HAVE SAVED AND HAVE BEEN EVALUATING GENETICALLY OVER MANY YEARS. THEY WANTED THE ISOLATES BUT DID NOT ASK FOR ANY OF THE GENETIC TYPING WE HAD DONE.
Wormser's litany of conflicts might be interpreted by some as evidence of his vast expertise in the Lyme space. To Lyme sufferers who feel they've been trapped at the wrong end of an abusive medical relationship, it is seen as a form of regulatory capture. Wormser and his colleagues have maintained control of the dialogue ever since the events of 1994, showing "expertise" to be a self-fulfilling, self-magnifying prophecy. The more they insist the patients are simply making things up, the more credible they become in the eyes of the unaffected public.
The Fallout, Then and Now
Now we are facing a situation strikingly similar to the first Lyme vaccine trials in the 1990s. Pfizer is conducting a clinical trial on thousands of adults and children, with a product that shares a chemical structure similar to its harmful predecessor's formulation. They have paid an individual with an outrageous list of conflicts to help develop or validate diagnostics specifically for their trial just as the existing standard was developed specifically for the predecessor's trial.
Why must a new diagnostic standard be developed every time a vaccine enters phase III trials? Why aren't diagnostics developed, first, to be most accurate for diagnosing real-world patients, then applied to clinical trials? What behind-the-scenes LYMErix history has Pfizer been made privy to, that led them to conclude they needed a new test? And if, in fact, they have developed their own test, why is such a test allowed to be developed in a vacuum, without any oversight, transparency, or adherence to administrative processes and regulations?
Lyme disease has developed an ugly reputation over the years, with patients taking the brunt of the manufactured vitriol. The official narrative of "over-diagnosed and therefore controversial" places sick and disabled people in a harrowing position: They are forced to prove and justify their own illness to disbelieving family members, friends, employers, and even health care providers, without benefit of a diagnostic test that actually works.
The gap between reported Lyme disease cases and estimated actual cases represents more than 90% of the total. Ninety percent or more of the total cases are unable to test positive and receive proper care. So, it seems obvious that the controversy lies not in the over-diagnosis of Lyme, but in the staggering rate of under-diagnosis.
There is no ethical reality in which Pfizer and Valneva can be permitted to continue their trials. The existing, manipulated diagnostic standard misses 90% of cases. An individual and institution paid by Pfizer to develop "Lyme diagnostics for a Lyme vaccine trial" have helped perpetuate the manipulated standard over three decades. Trial subjects are unwittingly facing harm on multiple fronts—from the vaccine formulation itself, to a potential false sense of security, to a complete inability to be accurately diagnosed if symptoms develop.
We've been here before. We've seen the damage inflicted by the fiasco surrounding LYMErix. We have witnessed widespread medical abuse over the engineered inaccuracy of the tests developed for previous Lyme vaccine trials but foisted on the public. Yet, history is already in the process of repeating—unlikely to be stopped, with only the prior victims speaking up: "We told you."
We told you.
Visit truthcures.org for more information. TruthCures is a 501(c)3 organization dedicated to restoring an accurate Lyme disease case definition and securing justice for those who suffer the consequences of inaccurate testing.