On March 6-7, I was one of seven Lyme disease advocates selected to attend the “Lyme Disease Vaccine—Technical Consultation” at the CDC in Atlanta.

The purpose of this meeting was to bring together experts and advocates to develop a list of questions about the potential arrival of the new Pfizer/Valneva Lyme disease vaccine candidate called VLA-15.

Let me be clear, attending this meeting was not an endorsement of VLA-15. Quite the opposite—it was a chance for the Lyme advocacy community to raise our serious concerns.

Other advocates in attendance were Wendy Adams, Bonnie Crater, Bruce Fries, Holiday Goodreau, Olivia Goodreau and Patricia Smith. (Click links to find out more about them.)

My goal in this column is to share the theme of the questions we developed so that the public can at least know what was presented to Pfizer during our technical consultation. My next task will be to help gather answers to those questions and share them with the public.

And something I simply must state at the outset: I worry that a vaccine is being developed when there STILL is no accurate test for Lyme disease. How will they know someone does or doesn’t have Lyme, to begin with? How can Pfizer prove the vaccine even works? Honestly, if you want ALL the controversy to go away, develop an accurate test!

What I learned before the meeting

Prior to the meeting, I spoke with many scientists, researchers and entomologists who work with Borrelia and the ticks that transmit Lyme disease. Most of them had seen scientific presentations on VLA-15, and told me they likely would have designed the vaccine differently (eg. using mRNA or adding another protein like OspC) or gone for an anti-tick vaccine instead.

One researcher who had tested the vaccine in their animal lab told me “it worked” and while they maybe would have designed it differently, “something that reduces the number of Lyme cases is better than nothing” at this point.

I also reached out to several members of the Lyme community to get their input. I arrived at the meeting with a long list of questions, which I have included below.

The week before the meeting, we were given copies of Valneva/Pfizer press releases, which I will link to below for anyone interested in reading them. I was disappointed that we were not given anything more recent, nor access to the scientific presentations that the researchers I spoke with had seen.

In addition to the press releases (which had already been published) I read several of Pfizer’s references as I tried to drill down into the science. Among many things, I learned that VLA-15 is an aluminum-containing adjuvant formulation. (Adjuvants increase the immune response to the vaccine. Many people with Lyme and/or mast cell activation syndrome are highly sensitive to certain additives. They need to know all the ingredients to avoid a serious reaction.)

How VLA-15 reportedly works

The VLA-15 vaccine does not create a traditional immunity to Lyme disease. The vaccine is based off of a single outer-surface protein of Borrelia burgdorferi known as OspA. OspA is primarily expressed by Borrelia spirochetes when they are attached within the midgut of the blacklegged tick. The vaccine relies on the tick to feed on a fully vaccinated human and thus to ingest a human byproduct of the vaccine (OspA antibody). In theory that antibody will kill the Borrelia spirochetes in the midgut of the tick before it can be transmitted to the human. In order for this to work, Pfizer will likely recommend that people get three vaccines within the first year and annual boosters thereafter.

Let me say, I am not anti-vaccine. However, due to the history of the previous Lyme vaccine, called LYMErix, I came with a lot of questions about the safety of VLA-15. (You can read my recap of the Lyme disease vaccine—separating fact from fiction here.)

Who from the CDC met with us

There were several high-ranking members of the CDC present during both days of the meeting, including Dr. Susanna Visser, Dr. Lyle Peterson, Dr. Paul Mead, and Dr. Grace Marx. (There was also a team of kind women who worked behind the scenes to arrange for our travel, hotel, meals, taking notes of our meeting and allowing Pat Smith to participate virtually, as she was not able to attend in person.)

Dr. Nirav Shah, Principal Deputy Director of the CDC, started the first day’s meeting by reiterating that 90% of vector-borne disease in the U.S. are transmitted by ticks, with the majority (80%) of tick-borne infections being Lyme disease. One goal of the CDC’s Division of Vector-Borne Diseases latest National Strategy to Protect People is to reduce the number of Lyme disease cases (laboratory confirmed) 25% by 2035, compared to 2022. Part of their strategy to reduce Lyme is to find a safe and effective vaccine.

Just for background, the CDC has not been involved in the clinical trials and has no intellectual property tied to the Pfizer Lyme vaccine candidate. However, if the vaccine is approved by the FDA, and if the Advisory Committee on Immunization Practices (a panel within the CDC) recommends it, the CDC will take the lead for developing and implementing the Lyme disease vaccination program.

Later, Drs. Marx and Mead gave presentations on the government’s relative roles in vaccine development and monitoring for adverse events.

Then, the Lyme advocates presented our many questions (summarized below) and grouped them into logical categories. It was a long, worthwhile process.

After the meeting, we got to see the CDC museum, one of the only places at the complex where you are allowed to take photographs. We then headed to dinner where we continued our deep discussions about vector-borne diseases and why we each have a passion for why we do what we do.

Day 2

The next day, we met Pfizer representative Christine Hanson. She is not a scientist and thus could not answer any of our technical questions. She was there to hear and document our concerns and then get back to us with answers at a later date.

Sue Visser asked each of us to give our full personal stories of how we or a family member were affected by Lyme and/or co-infections. All of us had stories about missed and delayed diagnoses.

Pat Smith’s recollection was the most detailed—going back to the 80s when the cause of Lyme disease was first discovered. She documented her real-life experience as community members reported serious side effects of the LYMErix vaccine as it rolled out in the late 90s until it was taken off the market in 2002.

See here for more on the complicated history of the LYMErix vaccine.

Summary of Questions

Many of my technical questions (besides those in my vaccine Fact/Fiction recap) came after reading the publication entitled “Broadly Protective Multivalent OspA Vaccine against Lyme Borreliosis, Developed Based on Surface Shaping of the C-Terminal Fragment.”

The paper details how Valneva designed the vaccine off of six different outer surface protein A (OspA) derived from the five most common species of Borrelia found in Europe and one species found in the U.S.

Being from California, I immediately had several specific questions about whether this vaccine would offer any protection to the many species of Borrelia we have on the West Coast (see my question #7 below).

I asked Pfizer if they could explain why, in the above paper, the vaccine appeared to be roughly three times better against the five European strains (3.2 fold) versus the single U.S. strain which showed only a 1.9 fold increase in antibodies as compared to baseline.

Wendy Adams and I also wanted to know how (or if) Pfizer had modified the OspA proteins to prevent auto-immune reactivity to HLA-DR4, as was theorized with the previous OspA vaccine, LYMErix.

We all wondered how Pfizer is testing patients for Lyme disease considering the standard laboratory tests for Lyme miss approximately 50% of cases.

We all had concerns about whether a Lyme vaccine might create a false sense of security regarding tick bites. After all, Lyme disease is only one of nearly 20 tick-borne pathogens transmitted to humans in the U.S.

We asked how quickly it takes for someone to develop antibodies following the vaccine, and how long those “protective” antibodies last. And what is the overall effectiveness of this vaccine? Reportedly, the prior vaccine was only 70% effective, if everything went right. Would this one be any better?

The absolute need for transparency

We asked about the inclusion/exclusion criteria for their phase 2 and 3 clinical trials, which did not include pregnant women. We also wanted access to the detailed reports of adverse events (VAERS).

I wanted to know specifically why both of the VALOR clinical study sites located in Nantucket and Marthas Vineyard were shut down during the Phase 3 clinical trial.

And we all stressed the need for 100% transparency.  Without it, we warned both the CDC and Pfizer, you’ll never gain trust from the Lyme community. Complete transparency is a must!

Above all, we want to know if the proposed Lyme vaccine is safe.

It was an intense couple of long days. I am honored to have been invited and I hope that I am able to make the Lyme community proud by reporting my experience as the facts roll in.

Once the CDC has compiled our questions in written form, I will share them with you. Stay tuned for updates as I learn more.

Pfizer/Valneva Press Releases

Sept. 28, 2021: Valneva and Pfizer Report Further Positive Phase 2 Results, Including Booster Response, for Lyme Disease Vaccine Candidate

Feb. 4, 2022: Valneva and Pfizer Report Further Positive Phase 2 Data for Lyme Disease Vaccine Candidate

April 28, 2022: Pfizer, Valneva Report Positive Phase 2 Pediatric Date for Lyme Disease Vaccine Candidate

Aug. 8. 2022: Pfizer and Valneva Initiate Phase 3 Study of Lyme Disease Vaccine Candidate VLA15

Dec. 1, 2022: Valneva and Pfizer Report Six-Month Antibody Persistence Data in Children and Adults for Lyme Disease Vaccine Candidate

Aug, 8, 2022: Pfizer and Valneva Initiate Phase 3 Study of Lyme Disease Vaccine Candidate VLA15

Feb. 17, 2023: Pfizer and Valneva Issue Update on Phase 3 Clinical Trial Evaluating Lyme Disease Vaccine Candidate VLA15

Sept. 7, 2023: Valneva and Pfizer Report Positive Pediatric and Adolescent Phase 2 Booster Results for Lyme Disease Vaccine Candidate

Dec 4, 2023: Pfizer and Valneva Complete Recruitment for Phase 3 VALOR Trial for Lyme Disease Vaccine Candidate, VLA15

 

Full List of My Personal Questions to Pfizer

Vaccine development requires a clinically testable disease definition to pass clinical trials and garner FDA approval.

1. What testing method is Pfizer using to find a patient population free of Lyme disease, vaccinate it, and then prove the vaccine has worked by retesting those patients?
2. Have you followed up with VLA15 vaccinated patients who’ve been bitten by ticks to see if they were in fact protected from Lyme disease? How are you determining efficacy considering standard laboratory tests for Lyme miss approximately 50% of actual cases?
3. Lyme disease is the most common vector-borne disease in the US. How do people who’ve already had Lyme disease react to VLA15?
4. Growing evidence suggests that Borrelia can be present at subclinical levels leading to mild symptoms or asymptomatic infection. Similarly, people may have been previously exposed to the bacteria and have a resolved infection. This infection status and immune history could dramatically impact vaccine response. How will you determine if trial participants have a past or present infection?

A similar question holds for other subclinical co-infections. How will you assess infection status for common Lyme co-infections?

Are Pfizer scientists aware of advances in direct detection that may help stratify patients for clinical trials? E.g., Nanotrap, digital PCR, etc.

Will Pfizer/Valneva release raw data from the clinical trials and be transparent about adverse reactions?

Why exactly were the two VALOR VLA15 study sites at Nantucket and Martha’s Vineyard halted “representing approximately half of the total recruited”? At the time thoses sites were shut down, how many US. patients versus how many European patients were enrolled in the trial? How many US patients remained in the trial after Nantucket and Martha’s Vineyard were shut down? 

How was OspA “modified” to prevent auto-immune reactivity with HLA-DR4?

What modifications were made to better stimulate protective immunity? Can you provide any evidence pointing to improved efficacy in children and seniors, a short-coming of the previous vaccine?

Valneva began the research for VLA15 in Europe utilizing “four Borrelia species presenting six different outer surface protein A (OspA) serotypes (ST) that are responsible for the majority of human clinical cases: Borrelia burgdorferi (OspA ST1), Borrelia afzelii (OspA ST2), Borrelia garinii (OspA ST3, OspA ST5, and OspA ST6), and Borrelia bavariensis (OspA ST4).” In VLA15 “The protein backbones of all six chimeric variants were based on the sequence of the C-terminal fragment of afzelii OspA ST2, which represents the most prevalent OspA ST causing LB in Europe.” My questions:

1. How protective will VLA15 be against other forms of Borrelia found in the United States? (eg. B. mayonii, americana, CA5, CA382, CA-11-2A, CA8 and B. miyamotoi a relapsing fever species found in the same blacklegged ticks that carry Lyme).
2. According to Bob Lane’s research significant variations exist in the major outer surface proteins (OspA and OspB) and other proteins (21kDa to 25kDa) in fresh tick-derived isolates of B.burgdorferi from Northern California. Isolate CA5 possessed abundant proteins with relative mobilities of ca.21.5 and 24 kDa that were not present in several other fresh isolates from ticks or in the B31 strain. How effective is VLA15 against the many strains of Borrelia found on the West Coast of North America?
3. One “study of California patients who were tested for tick-borne disease suggests there may be similar exposure risks for Lyme disease and relapsing fever borrelia (33% vs. 27%), and evidence for dual exposure to Lyme disease and relapsing fever borrelia (RFB) was found in 11% of patients.” How is Pfizer going to educate the public about the lack of protection to RFB?
4. In your phase 2 clinical trial, patients produced three times as many antibodies to the European strain ST2 versus the US strain ST1 (Geometric mean fold rise 3.2 fold increase over baseline, versus 1.9 respectively). Can you explain this?

How long does it take for human antibodies to OspA to develop after VLA15?

How long do human antibodies to OspA continue after VLA15 last?

What happens if someone is only partially vaccinated? For instance,

1. What happens if someone is infected with Lyme disease between the first and second vaccine?
   • Will the patient be more or less prone to infection?
   • Will the patient be more or less prone to false positive or false negative testing?
   • Will the patient be more or less prone to auto-inflammatory reactions?
   • What testing methods are you using to prove the above?
2. What happens if someone is bitten by a tick and infected with Lyme disease prior to receiving the third VLA15 vaccine? (same followup questions)
3. What happens if someone is infected with Lyme disease between annual boosters? (same followup questions)

According to the previous LYMErix vaccine package insert, it was 70% effective at preventing a rash but only 50% effective at preventing chronic Lyme. How effective is VLA15 at preventing chronic Lyme? What testing method are you using to prove this?

In your mouse model studies following vaccination with VLA15, all of the challenge tick inoculation was with B. afzelii, while all of the B31 challenge was via needle inoculation using cultured B31. Borrelia have a unique response to tick guts and tick saliva that does not occur in culture. In fact, approximately 90% of Borrelia burgdorferi die with needle inoculation, In addition, B31 does not produce OspA in culture. How can you prove VLA15 is truly effective against B31 when you did not include tick inoculation in your B31 vaccine challenge?

Have you done any non-human primate studies with VLA15?

VLA15 is expected to disable the outer surface protein A (OspA) of the Borrelia burgdorferi bacteria within the tick gut prior to transmission to humans.

1. Most Lyme infections are a result of bites from nymphal ticks. “Outer surface proteins A and B are two antigens coded on a bicistronic operon and abundantly expressed on the surface of spirochetes within unfed (flat) ticks. When nymphs feed, the majority of B. burgdorferi clear OspA and OspB from their surface and instead express OspC, a protein which is not expressed on spirochetes before tick engorgement.” How long does Bb continue to express OspA in the tick gut once it is exposed to human blood? How long does Bb continue to express OspA once it has migrated to the tick salivary glands?
2. In partially fed ticks Borrelia has migrated to the salivary glands and is no longer expressing OspA. Partially fed infected ticks are capable of transmitting infection in as little as 12 hours. Have you done any studies to demonstrate VLA15 works against partially fed ticks?

Some have expressed concern that a Lyme vaccine might promote a false sense of security against Lyme and other tick-borne diseases [See Understanding consumer and clinician perceptions of a potential Lyme disease vaccine]

The COVID pandemic has created a lot of anti-vaccine sentiment and will likely be a barrier for broad Lyme vaccine acceptance. How will you gain trust?

Since patient compliance was low with the previous OspA vaccine LYMErix, even outside of the fears related to autoimmunity, why was the decision made to continue with a 3-shot, plus annual boosters regimen? 

How will you convince patients and providers that this vaccine is a significant improvement over its predecessor?

Will the vaccine be safe for patients with pre-existing autoimmune conditions?

Will the vaccine be safe for patients with acquired immune deficiency (from AIDS, COVID, Lyme and co-infections or otherwise)?

Will the vaccine be safe for pregnant women? If so, to what extent have pregnant women been included in the clinical trials?

In VLA15 mouse studies, aluminum hydroxide increased the efficacy of the vaccine. What adjuvants are being used in the VLA15 human trials? Will this be the same adjuvant used when the vaccine goes public?

LymeSci is written by Lonnie Marcum, a physical therapist and mother of a daughter with Lyme. She served two terms on a subcommittee of the federal Tick-Borne Disease Working Group. Follow her on Twitter: @LonnieRhea  Email her at: lmarcum@lymefaces.com.