NIAID Investigators Demonstrate How Stress Responses Closely Mimic Allergic Reactions

Some responses to the mRNA COVID-19 vaccines reported as severe allergic reactions were likely a recently described, non-allergic condition called immunization stress-related response (ISRR), according to NIAID investigators. The symptoms of ISRR can closely mimic those of a severe allergic reaction known as anaphylaxis, a potentially life-threatening, systemic allergic reaction in which the immune system releases a dangerous flood of chemicals. These findings from a small study are being presented today at the 2023 Annual Meeting of the American Academy of Allergy, Asthma & Immunology in San Antonio. 

As defined by the World Health Organization, ISRR encompasses a range of signs and symptoms that may arise before, during or immediately after immunization and are related to stress from the process of immunization, not to the vaccine product. Some of the manifestations of ISRR are the same as those that occur during anaphylaxis, including a rapid pulse, throat tightness, lightheadedness, trouble breathing, and nausea.

The reported rate of severe allergic reactions to immunization with mRNA COVID-19 vaccines, while estimated to be on the order of just five cases per million doses administered, is still higher than that reported for conventional vaccines. To better understand this phenomenon, NIAID researchers assessed the safety of a second dose of an mRNA COVID-19 vaccine in people who had experienced a systemic allergic reaction after their first dose. The study was led by Muhammad B. Khalid, M.D., a clinical fellow in the NIAID Laboratory of Allergic Diseases, and Pamela A. Frischmeyer-Guerrerio, M.D., Ph.D., the laboratory chief.

The investigators enrolled 16 people ages 16 to 69 years who had a moderate or severe systemic allergic reaction to their first dose of the Moderna or Pfizer-BioNTech COVID-19 vaccine. The study participants were admitted for a minimum of four days to the Intensive Care Unit at the NIH Clinical Center in a closely supervised, safe and controlled environment. There, they received the Pfizer-BioNTech mRNA COVID-19 vaccine and a look-alike injection of placebo in a random order on different days. Neither the participants nor the investigators knew which shot was being given on which day. At admission and during the inpatient stay, participants underwent breathing tests and frequent blood draws so medical staff could discern the details of any allergic or other responses to the vaccine.

People who had an allergic reaction to the first dose of a vaccine would be expected to have an allergic reaction to subsequent doses with equal or greater severity. However, only three participants, or 19%, developed an allergic reaction within minutes of receiving the second dose of vaccine, and one reaction was mild while two were moderate. As expected, no one developed an allergic reaction to the placebo.

By contrast, nine study participants developed a non-allergic reaction within minutes of receiving the vaccine, and 11 developed a non-allergic reaction within minutes of receiving the placebo. The non-allergic reactions included numbness, tingling, dizziness, throat tightness, difficulty swallowing, and temporarily high blood pressure—signs and symptoms consistent with ISRR. Forty-five percent of these reactions were classified as moderate to severe.

To further probe the nature of the volunteers’ responses to mRNA COVID-19 vaccines, the study team administered an open-label booster dose of the Pfizer-BioNTech vaccine and performed skin testing for allergic reactions. Thirteen participants completed this part of the study and another three were scheduled to do so.

The skin testing began with a so-called skin-prick test. A tiny drop of the Pfizer-BioNTech vaccine, a vaccine component called polyethylene glycol (PEG), and a related chemical called polysorbate were placed on the skin, and a small prick was made through each drop into the skin. If this did not elicit a small, short-lived rash indicating an allergic response, the researchers injected a small amount of the vaccine into a superficial skin layer for an intradermal test.

The investigators found that none of the participants reacted to PEG or polysorbate. Two participants reacted to the vaccine during the intradermal test, but only one of these individuals had allergic reactions to every vaccine dose they received before and during the study. The other person had a reported allergic reaction only to the dose they received before entering the study. Taken together, these findings further support the hypothesis that some reports of allergic reactions to the mRNA COVID-19 vaccines were non-allergic responses, and that these methods of testing are not very predictive of who will have a reaction—whether allergic or ISRR—to the vaccine.  

People who have had a suspected allergic reaction to an mRNA COVID-19 vaccine should discuss it with their physician. If it was a true allergic reaction, then the individual should follow current medical advice regarding vaccination allergy. However, if the reaction was more consistent with ISRR, then the person can be reassured they have not had a severe immune reaction to the vaccine and can safely receive subsequent doses.

It is important to realize that ISRR can repeat at subsequent vaccinations. Physicians can suggest interventions that may reduce the symptoms of this condition.

The researchers expect to submit a complete and detailed report of their findings to a peer-reviewed journal for publication. An abstract of the study was published in a supplement to the Journal of Allergy and Clinical Immunology on February 3, 2023. For more information about this research, please visit ClinicalTrials.gov and search using study identifier NCT04977479.

References:

MB Khalid. COVID-19 mRNA vaccine-induced immunization stress-related response (ISRR) and anaphylaxis: an early look at COVAAR clinical outcomes. Presentation at the AAAAI 2023 Annual Meeting in San Antonio, Texas. Monday, Feb. 27, 2023, at 1 pm CT.

MB Khalid et al. COVID-19 mRNA vaccine-induced immunization stress-related response (ISRR) and anaphylaxis: an early look at COVAAR clinical outcomes. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2022.12.687 (2023).

NIAID scientists have found an association between widely used chemicals called diisocyanates and atopic dermatitis, a chronic inflammatory skin disease commonly known as eczema. The researchers also found through an experiment in mice that when bacteria that normally reside on skin are exposed to isocyanate, a component of diisocyanates, they adapt by stopping production of the oils that skin needs to stay healthy. These findings were recently published in the journal Science Advances.

Eczema affects up to 20% of children and up to 10% of adults in high-income countries. People with eczema experience severe itching, skin redness, oozing from the skin, and scaly rashes, all of which can be painful. A particularly stressful aspect of eczema is its unpredictability, as symptoms can worsen from exposure to multiple substances or without any obvious trigger.

Prior to 1970, the prevalence of eczema in the United States was three to six times lower than it is today. While genetic risk factors are known to play a strong role in the incidence of eczema, the rapidly increasing prevalence of the disease indicates that environmental factors are also important. NIAID researchers led by Ian Myles, M.D., M.P.H, sought to identify environmental pollutants that may be contributing to this increase. Dr. Myles is chief of the Epithelial Research Unit in the NIAID Laboratory of Clinical Immunology and Microbiology.

The investigators compared a database that collates clinic visits for atopic dermatitis with two Environmental Protection Agency resources: the Toxics Release Inventory, which tracks the amounts of certain toxic chemicals that are released into the environment for each U.S. zip code; and the Risk-Screening Environmental Indicators model, which models the route of each chemical release through the environment and the potential human exposure that may result. The scientists identified emissions of diisocyanates as the strongest predictor of local eczema rates.

Diisocyanates have been used since the late 1940s to make polyurethane products, such as rigid and flexible foams, coatings, adhesives, sealants, and elastomers (rubbery materials). Exposure to these products has been shown to increase the risk of eczema, according to the NIAID researchers. The active portion of the diisocyanate molecule, the isocyanate side chain, is also a component of other known eczema triggers, such as wildfires, cigarette smoke, and automobile exhaust from catalytic converters, which became mandatory in the United States in 1975. 

The investigators conducted experiments on the skin of mice to explore how isocyanates might contribute to eczema. Previous research demonstrated that exposing mouse skin to diisocyanates could directly induce eczema, yet the mechanisms were unclear. The current study found that when bacteria that live on healthy skin are exposed to isocyanate, they must adapt to survive. When they adapt, these bacteria shift their metabolism away from making the lipids, or oils, that skin needs to stay healthy. This finding suggests that eczema may be treatable by replacing the modified skin bacteria with healthy bacteria, according to the scientists.

Further research is needed to validate the association between environmental exposure to isocyanate or diisocyanates and eczema and to determine whether the causative mechanisms identified in mice are also found in people.

Dr. Myles and colleagues previously reported the results of a small, early-phase clinical trial that found applying healthy versions of a skin bacterium called Roseomonas mucosa to the skin of people with eczema led to a significant reduction in eczema symptoms that persisted even after the medication was stopped. A subsequent, larger, placebo-controlled clinical trial of R. mucosa strains found that the data failed to meet statistical significance for the primary endpoint of EASI-50 (the proportion of patients with at least a 50% improvement in atopic dermatitis disease severity as measured by the Eczema Area and Severity Index). However, the subgroup of study participants who completed the Phase 2 trial demonstrated sustained, modest, but statistically significant clinical improvements that differed by study site diisocyanate levels.

To facilitate their availability as a potentially beneficial probiotic, NIAID is making the R. mucosa strains available for commercial, non-therapeutic development.

References:

J Zeldin et al. Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria. Science Advances DOI: 10.1126/sciadv.ade8898 (2023).

SM Langan et al. Atopic dermatitis. The Lancet DOI: 10.1016/S0140-6736(20)31286-1 (2020).

BC Martel et al. Translational animal models of atopic dermatitis for preclinical studies. Yale Journal of Biology and Medicine (2017).

IA Myles et al. Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Science Translational Medicine DOI: 10.1126/scitranslmed.aaz8631 (2020).

When healthy people in the same age range are immunized with the same vaccine, some people’s immune systems make substantially more protective antibodies than others. Scientists want to figure out why some people respond to vaccination better than others.

Investigators have identified predictors of a robust antibody response to a few specific vaccines, such as those for influenza, yellow fever, and hepatitis B. Until recently, however, scientists did not know if there was a common predictor of a potent antibody response to most vaccines. If one does exist, researchers reasoned, perhaps it could guide the development of new strategies to enhance the antibody response to vaccination. This would be especially helpful for infants, older adults, and immunosuppressed individuals, who do not always mount an effective immune response to vaccines.

In pursuit of this goal, researchers associated with the NIAID-funded Human Immunology Project Consortium (HIPC) examined immune responses from the blood of 820 healthy adults ages 18 to 55 years before and after they received a shot of one of 13 different vaccines against 11 different pathogens. These vaccines collectively used six different approaches, or platforms, to generate an immune response. The investigators looked for patterns of genes that were turned on, or expressed, in immune cells before vaccination in people who made high, medium, or low levels of antibodies after vaccination. The scientists found that people who had gene expression patterns associated with inflammation before receiving a shot made the highest level of antibodies. The findings were published in the journal Nature Immunology.

Now, researchers want to figure out how to safely induce this level of inflammation and learn if doing so on the day of immunization helps people generate a stronger antibody response to a pathogen than would be expected otherwise.

A caveat to the findings from this study is that the predictive patterns observed in younger adults did not hold up when the researchers applied them to the small number of study participants ages 50 and older. It’s unclear whether other gene expression patterns would predict the antibody response to vaccines in older adults or in children, who were not included in the study. HIPC-affiliated investigators are seeking an answer to this question.

In related research, NIAID-funded HIPC investigators examined immune responses from the same 820 adults who received one of the 13 different vaccines in the earlier study, but this time, the blood samples were drawn over a period of 21 days after vaccination. The researchers looked for a similar pattern of gene expression among all the participants after immunization that could predict the strength of the antibody response several weeks later. Initially, no common pattern appeared for all 13 vaccines. However, when the investigators adjusted the data to synchronize the timing of expression of specific genes, they did find a predictive pattern. The activation and replication of precursors of antibody-producing B cells predicted a robust antibody response to immunization. These findings, also published in Nature Immunology, indicate that after making a time adjustment, scientists can look at gene expression to accurately forecast the magnitude of an individual’s antibody response.

Notably, these two studies do not account for other aspects of the immune response that may be important for vaccine protection, such as the variety of molecules to which the antibodies bind, the strength of antibody binding, and the T-cell response. 

The published and ongoing research reported in the two studies described here is possible because data from numerous clinical trials of more than a dozen different vaccines was shared, standardized, and pooled to answer broad questions about immune responses to vaccines.

The National Institutes of Health Data Management and Sharing policy requires scientists to describe how they will plan to preserve and publicly share data from research funded by or conducted at NIH. Data from the two studies and publications described here is available at www.ImmPort.org, a NIAID-supported data repository that provides access to NIAID-funded research findings. Adherence to the NIH Data Management and Sharing policy and ease of access to shared data will accelerate the pace of biomedical research, enable the validation of research results, and ensure optimal use of high-value datasets.  

References:

S Fourati et al. Pan-vaccine analysis reveals innate immune endotypes predictive of antibody responses to vaccination. Nature Immunology DOI: 10.1038/s41590-022-01329-5 (2022).

T Hagan et al. Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses. Nature Immunology DOI: 10.1038/s41590-022-01328-6 (2022).

Research by NIAID grantees strongly suggests that immune responses to a newly discovered species of gut bacteria may cause some cases of a common autoimmune disease called rheumatoid arthritis, or RA. The findings were recently published in Science Translational Medicine.

In people with RA, their own antibodies and T cells attack their joints, especially in the hands, wrists, and knees. This leads to inflammation, pain, and swelling in the joint lining. Over time, RA progresses to irreversible joint tissue damage, chronic pain, loss of function, and deformities. Scientists do not know what causes RA despite extensive efforts to understand the earliest stages of this disease.  

Some RA research has focused on understanding what triggers the development of the antibodies and T cells that attack the joints. Several studies have suggested that the production of joint-targeting antibodies starts at mucosal surfaces, such as the lining of the mouth, airways, and gut, more than a decade before symptoms arise and might be stimulated by bacteria at these sites. Until now, however, the bacterial culprit remained unknown.

In the new study, investigators isolated antibody-secreting cells called plasmablasts from the blood of people at risk for RA and found that the antibodies produced by these cells recognized certain bacteria in the gut microbiome of these individuals. The researchers identified a previously unknown bacterial species targeted by these antibodies, which they named Subdoligranulum didolesgii. This bacterium was present in the feces of four out of 24 people who were either at risk for or diagnosed with RA but absent from the feces of 12 healthy people.

The scientists hypothesized that a mucosal immune response to S. didolesgii in the gut might progress to a body-wide immune response. To test their hypothesis, the researchers gave mice an oral dose of the bacterium and monitored their immune and physical responses. The mice developed antibodies and T cells that attacked their joints and led to visible joint swelling. In addition, the immunologic changes that the scientists observed in the mice extended over time from the gut mucosa to sites throughout the body. 

Taken together, the findings suggest that in some people with RA, immune responses to S. didolesgii in the gut may trigger the production of antibodies and T cells that circulate throughout the body and attack the joints, leading to chronic inflammation. Thus, it appears that RA may develop because immune-system targets shared by S. didoglesgii and joint tissue have a similar structure or amino-acid sequence.

Didolesgi is the Cherokee word for arthritis or rheumatism and was proposed as the name for the newly discovered bacterium by the study’s first author, Meagan E. Chriswell, B.S., who is an enrolled member of the Cherokee Nation of Oklahoma. Ms. Chriswell, an M.D./Ph.D. candidate in immunology at the University of Colorado Anschutz Medical Campus in Aurora, and Kristine A. Kuhn, M.D., Ph.D., an associate professor of medicine at the university, led the research. 

The study was co-funded by NIAID and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, both part of the National Institutes of Health.

Reference: ME Chriswell, et al. Clonal IgA and IgG autoantibodies from individuals at risk for rheumatoid arthritis identify an arthritogenic strain of Subdoligranulum. Science Translational Medicine DOI: 10.1126/scitranslmed.abn5166 (2022).

Women are disproportionately affected by HIV, with young women in sub-Saharan Africa three times as likely to be infected than young men in the same age group. In 2015, the World Health Organization (WHO) recommended that tenofovir-based pre-exposure prophylaxis (PrEP) be offered to high-risk individuals for prevention. As a result, oral PrEP has been introduced in more than 70 countries, including sub-Saharan Africa. Despite expanded access to oral PrEP in the region, women experience challenges to daily pill-taking, including discrimination, difficulties swallowing pills, and the fear of violence from partners, family, and community members. Additionally, oral PrEP drug concentrations in vaginal tissues are lower than in rectal tissues, therefore women must take 6-7 doses per week to achieve levels associated with HIV prevention. An effective alternative to daily PrEP is critical to women’s health and ending the HIV epidemic. 

This phase 3 clinical trial compared the safety and effectiveness of two treatment options for HIV prevention in HIV-uninfected women—daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) and injectable cabotegravir given every 8 weeks. The study was conducted in 20 clinical sites in seven sub-Saharan African countries where the burden of HIV is high. High-risk women aged 18-45 years were eligible for this study if they agreed to use contraception during the study and reported two vaginal intercourse episodes 30 days prior to enrollment. Study participants were randomized to either of the treatment groups at enrollment and provided adherence counselling, HIV testing, and physical exams at every visit. The clinical trial design ensured that neither the participants nor the study staff could identify which treatment group each participant was assigned to.  

The results of this large trial showed that injectable cabotegravir was superior to daily oral TDF-FTC for the prevention of HIV in women at substantial risk in sub-Saharan Africa. Participants in the cabotegravir group had an 88% lower risk of HIV infection compared with those in the TDF-FTC group. Furthermore, there was no difference in the frequency of adverse events between the two study groups outside of injection site reactions, suggesting cabotegravir was generally safe and well-tolerated. Of particular note, cabotegravir offered an adherence advantage over the daily pills. Most of the participants that acquired a HIV infection in the daily PrEP treatment group had unquantifiable drug concentrations at the time of infection. This study provides evidence that injectable cabotegravir could be a viable alternative to daily oral PrEP for HIV prevention in women in high-incidence settings. In a related study, injectable cabotegravir was shown to be safe and effective in preventing HIV in cisgender and transgender women who have sex with men.  

Reference: Delany-Moretlwe et al. Cabotegravir for the prevention of HIV-1 in Women:  results from HPTN 084, a phase 3, randomized clinical trial, Lancet, April 1, 2022 - Volume 399 – Issue103378 - p 1779-1789.

Eczema, or atopic dermatitis, is an inflammatory, non-contagious condition that presents as dry and itchy skin that can weep clear fluid when scratched, possibly leaving the body particularly susceptible to bacterial, viral and fungal infections.

The exact cause remains unclear, but links between eczema and autoimmune diseases are being explored by National Institutes of Health scientists. The National Institute of Allergy and Infectious Diseases, a part of NIH, stands with the scientific community in recognizing October as Eczema Awareness Month and acknowledging the need for continued research into possible cures and therapeutics.

NIAID is currently supporting research into genetic determinates of eczema, the relationships between skin bacteria and eczema and other studies.

Eczema can affect anyone but largely affects children and adolescents. About 7 million children in the U.S. have eczema and an estimated one-third also suffer from food allergy, according to a collaborative paper published by NIAID scientists in the Journal of Allergy and Clinical Immunology.

In general, people with eczema are often diagnosed with allergies they may not have because allergy blood tests measure the level of a type of antibody called immunoglobulin E (IgE) which is specific to a particular food or a protein within the food. People with food allergies make more IgE than normal to that food or protein, but people with eczema are likely to have high total IgE levels in general, resulting in positive allergy test results, even though they may not actually have a food allergy.

False-positive allergy tests can lead to an unnecessarily restrictive food-elimination diet with unwanted outcomes such as malnutrition, weight loss or low weight gain.

Fernanda Young, M.D., a clinician in NIAID’s Laboratory of Allergic Diseases, is leading the Phase 2 clinical trial, Food-Specific and Component IgE Threshold Levels That Predict Food Allergy in People With Elevated Total Serum IgE Levels and Atopic Dermatitis  which aims to identify threshold IgE levels to peanut and milk or a component of these foods that predict whether a person has a food allergy.

NIAID spoke with Dr. Young to learn more about her research team’s work.

1. What new findings have researchers uncovered since this trial began in 2019?
   Since the study is ongoing, it is early to make conclusions, which is why we are thrilled to have patients that are interested in helping us learn more about food allergies and how to better diagnose them. We are particularly excited since patients will be able to undergo the gold standard test-an oral food challenge with us at their bedside-to see if they truly have an allergy to milk or peanut.
2. Why are the misdiagnoses of allergies in people with atopic dermatitis such an important area to study? How will this additional knowledge benefit the medical community and the public?
   At a community level, knowing which foods someone can safely eat or those they need to avoid is a huge plus for places like day care, school and recreational events. At an individual level, having this knowledge empowers our patients to reintroduce and enjoy foods with less anxiety. It also makes it clear in settings such as going to potlucks or ordering take-out what allergens definitely have to be avoided. We as clinicians desperately want to help and not harm our patients and having better predictive markers will help us to better counsel and treat our patients.
3. What are some of the biggest challenges faced so far with this study and in eczema research?
   The SARS-CoV-2 pandemic had a tremendous impact on the health of the nation. We paused recruitment and focused on keeping our patients safe. We are resuming enrollment with appropriate precautions to balance the safety of patients while also advancing the understanding of their eczema and food allergy. For example, we start with a telehealth visit and then group the in-person visits as much as possible. We know that eczema is a chronic disease that affects about 1 of every 10 kids. Since this is a school-age population, a major challenge is making sure that they do not miss a lot of school either because of their disease and its complications or because of medical procedures. As such, any child or teen that we can help to manage their allergic disease is a major step toward improving their life. 
4. Briefly discuss another NIAID study you are excited about.
   I mentioned the COVID-19 pandemic. We saw incredible advances in vaccine development, and we saw reactions to vaccines as well. I am very proud of the Laboratory of Allergic Diseases for quickly starting and completing a trial COVAAR (COVID Vaccine Allergy Reaction) to better understand these vaccine responses so that we could ultimately help the patients stay safe. Stay tuned for those results!
5. Why did you join the NIH?
   I am a firm believer that in service to the government, I am also in service to the nation. I joined NIAID so that I could bring my knowledge and experience in allergy, immunology, food and drug reactions, and vaccine development, to add to what we understand about allergic reactions. There is a lot we do not know and that humbles me and motivates me to find out. Not just because it is important at a fundamental understanding of our world, but more so because there are patients out there that need that information for their diagnostic and therapeutic benefit. Here at the NIH, I can focus on these questions, and I am grateful to the patients and their support systems who make this research possible.