As TrialSite has monitored allergic vaccine reactions associated with mRNA-based COVID-19 vaccines under U.S. Food and Drug Administration (FDA) emergency use authorization (Pfizer/BioNTech and Moderna), such allergic reactions can range from mild to severe and dangerous forms of anaphylactic reactions. Although no deaths reported thus far have been tied directly to the vaccines, deaths have been reported after individuals have in fact been vaccinated. A new clinical trial disclosed and sponsored by the public National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health (NIH), has been organized to learn more about adverse reactions associated with the mRNA-based vaccines. Now with a focus on allergic reactions NIAID is clearly concerned given reported incidences of adverse reactions post vaccination to commence another major clinical trial involving the mRNA-based vaccines from both Pfizer-BioNTech and Moderna vaccines. Acknowledging that these allergic reactions can range from the mild to the severe and life-threatening anaphylactic reactions a new study is in place to investigate the following: 1) estimate the proportion of systemic allergic reactions to the Pfizer-BioNTech COVID-19 Vaccine as well as the Moderna COVID-19 Vaccine in a High-Allergy/Mast Cell Disorder (HA/MCD) population, and 2) If the risk in the HA/MCD is demonstrable, determine whether the proportions are higher in the HA/MCD compared to non-atopic population. The NIAID is now using publicly financed clinical trials to better understand the risk associated with these mRNA-based vaccines.
Vaccine Safety—Overall Yes
In a recent TrialSite piece titled “Side Effects and More: COVID-19 Vaccines Unlikely Cause of Reported Deaths,” this media platform suggests, “Everything in life is a balance, and in the COVID-19 context, millions of folk need to decide if the risk of severe COVID outweighs any risks from the available vaccines.” While clearly the vaccines are safe for the great majority, edge cases do exist.
The risk profile for an 80-year old with a history of allergic reaction is very different than for a healthy 30 year old. TrialSite looked into a Swiss Policy Research piece that investigated post-vaccination deaths based on adverse event reporting systems in America, the UE and the UK and found that RNA-based vaccines have been associated (i.e. not established as a cause) with over 1,000 deaths and many thousands of non-trivial adverse events including anaphylaxis and miscarriages.
As vaccine reporting systems typically only cover a fraction of actual events, this could represent an undercount. Despite reports that deaths are occurring here and there, the government explanation now is that the mRNA-based vaccines have caused no deaths. That is, none of these deaths have been proven as directly correlated to the vaccination.
However, relative to the tens of millions of vaccines already administered the rate of serious adverse events is extremely small. Yet not much is known about the long-term impact of experimental RNA treatments. In a recent piece in Nature by Ariana Remmel data from CDC’s U.S. Vaccine Adverse Event Reporting System (VAERS) shows about 372 non-serious safety events out of every million administered doses of the mRNA vaccines. The Nature report shares that this is a lower figure than would be expected from the clinical trials data.
What is Anaphylaxis?
This condition results from a serious allergic reaction that occurs fast and can cause death. Common causes can include insect bites and stings, certain foods and medication. Other causes can include latex exposure and exercise. At times, this phenomenon can occur without any obvious reason. Worldwide anywhere from 0.05 to 2% of the population is estimated to experience anaphylaxis at some point in life but rates appear on the increase. Often occurring with young and females, those that are hospitalized in America 99.7% survive.
According to the American Academy of Allergy, Asthma and Immunology, a Mast Cell Activation Syndrome involves situations when a patient experiences repeated episodes of anaphylaxis symptoms—that is everything from the hives and swelling to low blood pressure, difficulty breathing or severe diarrhea for example. During those episodes an individual experiences high levels of mast cell mediators released and often responds to treatment with inhibitors or blockers of mast cell mediators.
The diagnosis of Mast Cell Activation Syndrome, a relatively new diagnosis is believed to be under-diagnosed.
The Study Overview
Sponsored by NIAID in collaboration with the Immune Tolerance Network (ITN) and a contract research organization, Rho Federal Systems Division, Inc., this study seeks to estimate the proportions of systemic allergic reactions to both of the COVID-19 mRNA-based vaccines in a High-Allergy/Mast Cell Disorder (HA/MCD) population and if the study sponsor deems the risk in this population demonstrable, to determine whether the proportions are higher in the HA/MCD compared to a non-atopic population.
Targeting 3,400 participants and scheduled to start in March, this multicenter, randomized, initially blinded (masked), Phase 3 trial assesses COVID-19 vaccination reactions in two populations including 1) individuals with a history of allergic reactions or Mast Cell Disorder and 2) One non-atopic population (e.g. population not reporting history of allergy).
The study plans on enrolling 2,040 HA/MCD participants and 1,360 non-atopic participants across participating 30 sites (primarily academic medical centers that are part of ITN) across America. As the female population experiences anaphylaxis more frequently, the study protocol calls for approximately two-thirds of the participants enrolled in each of the two groups to be female—and a majority of cases of the condition involving COVID-19 vaccines have also occurred in women. The study protocol limits to 300 those individuals who qualify only on the basis of reactions to multiple unrelated drugs.
The MCD group will include at least 200 participants but not more than 300 of them. The participants in each population are then randomized 2:2:1:1 to receive the Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, placebo + Pfizer BioNTech COVID-19 Vaccine, or placebo + Moderna COVID-19 Vaccine.
What will participants in the placebo groups receive?
These participants will receive a placebo as the first dose and then will receive two doses of their assigned active vaccine at subsequent visits.
Is the study fully blinded?
No. It starts out that way as during the first visit all participants are initially-blinded (they don’t know) whether they are receiving a placebo or vaccine and for that matter when they receive the vaccine they don’t know which vaccine they are receiving.
However, during the follow up visit for vaccination visit, it will become apparent to both site staff and study participants which vaccine was assigned. While the blind over placebo versus vaccine remains in effect till after the second visit, during a follow-up call—that is scheduled 3 days after the second injection, participants will be unblinded as to whether they received placebo or active vaccine.
What is the study duration?
If vaccinated with the Pfizer-BioNTech COVID-19 vaccine, those participants randomized and vaccinated will complete the study in 29 days and 36 days if vaccinated with the Moderna COVID-19 Vaccine and 50 or 64 days if administered placebo before receiving two doses of either one of the mRNA-based vaccines currently under Emergency Use Authorization (EUA). The total duration oft this study is about 17 weeks.
Trial Site Locations with PI
This important clinical trial will be conducted at the following trial site locations.
|Research Center||Principal Investigator|
|Mayo Clinic, Arizona||Matthew A. Rank, MD|
|University of Arizona Health Sciences||Tara Carr, MD|
|Arkansas Children’s, University of Arkansas for Medical Sciences||Stacie M. Jones|
|University of California, Los Angeles Medical Center||Maria I. Garcia-LIoret, MD|
|Stanford Medicine, Sean N Parker Center for Allergy & Asthma||Sayantani B. Sindher, MD|
|National Jewish Health (Denver, CO)||Donald Leung, MD|
|University Health, University of Miami Health System||Gary I Kleiner, MD, PhD|
|University of South Florida, Morsani College of Medicine||Thomas B. Casale, MD|
|Children’s Healthcare of Atlanta||Merin E. Kalangara, MD|
|The Sinus & Allergy Center, Northwestern University||Anju T. Peters, MD|
|NorthShore Medical Group (Skokie, IL)||Giselle S. Mosnaim, MD|
|University of Iowa Health Care||Mary Beth Fasano, MD, MSPH|
|Johns Hopkins Bayview Medical Center||Melanie C. Dispenza, MD, PhD|
|Massachusetts General Hospital||Kimberly Blumenthal, MD, MSc|
|Brigham and Women’s Hospital||Mariana C. Castells, MD, PhD|
|University of Michigan Health||James R. Baker, Jr, MD|
|Henry Ford Health System||Edward M. Zoratti, MD|
|Saint Louis University Care, Center for Specialized Medicine||Mark Dykewicz, MD|
|Mount Sinai Hospital, Dept of Med, Division of Clin. Immunology||Paula J. Busse, MD|
|Columbia University Irving Medical Center||Magdalena E. Sobieszczyk, MD, MPH|
|Rochester Regional Health||Allison C. Ramsey, MD|
|University of North Carolina||David B. Peden, MD, MS|
|Cleveland Clinic, Allergy & Clinical Immunology||David Lang, MD|
|Penn State Health & Allergy/Milton S. Hershey Med Center||Timothy Craig, DO|
|Vanderbilt University Medical Center||Elizabeth Phillips, MD|
|University of Texas Southwestern Medical Center||David A. Kahn, MD|
|Baylor College of Medicine Medical Center||Sanjiv Sur, MD|
|University of Virginia Health System||Michael R. Nelson, MD, PhD|
|Virginia Commonwealth University||Lawrence B. Schwartz, MD|
|University of Wisconsin||Mark Moss, MD|
The Immune Tolerance Network
The Immune Tolerance Network (ITN) is a collaborative network for clinical research, funded by NIAID to pursue a mission to accelerate the clinical development of immune tolerance therapies. This trial site network has conducted 75 clinical trials (18 allergy, 32 autoimmunity and 25 transplant), represents 250+ clinical sites and investigators at leading academic hospitals worldwide. To date the network has enrolled over 3,500 patients in ITN trials all the while collecting 708,805 clinical specimens for the ITN repository (like a biobank).
The group’s current leadership includes Gerald Nepom, MD, PhD, Network Director; E. William St. Clair, MD, Network Deputy Director, Clinical Affairs and Dawn Smilek, MD, PhD, Chief Medical Officer, Clinical Trials Group.
The ITN’s main areas of focus include:
∙ Acceleration of clinical development of immune tolerance therapies
∙ Develop, fund and conduct clinical trials in immune tolerance
∙ Test the safety and efficacy of methods that can induce the immune system to tolerate certain antigens for the treatment of immune-mediated disorders
∙ Conduct studies of immune tolerance in autoimmune disease, asthma and other allergic diseases, organ transplantation and type 1 diabetes
Lead Research/Investigator (Study Chairs)
∙ James R. Baker Jr., MD, Mary H. Weiser Food Allergy Center, University of Michigan, Study Chair
∙ Rebecca S. Gruchalla, MD, Division of Allergy and Immunology, University of Texas Southwestern, Study Chair
∙ N Franklin Atkinson Jr., MD, Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Study Chair