Managing menstrual toxic shock syndrome

May 16, 2024

Sarah Anderson joined Drug Discovery News as an assistant editor in 2022. She earned her PhD in chemistry and master’s degree in science journalism from Northwestern University and served as managing editor of “Science Unsealed.”

In the summer of 1978, several teenaged girls in the Minneapolis-St. Paul area came down with what appeared to be scarlet fever — until they showed no trace of the group A Streptococci bacteria that cause the disease. Puzzled, their families and physicians enlisted the help of researchers studying scarlet fever at the University of Minnesota, including microbiologist and immunologist Patrick Schlievert. They observed that the patient samples all contained Staphylococcus aureus bacteria, which produced a distinct toxin that previously had not been identified.

Schlievert continued to study the mysterious ailment at the University of California, Los Angeles, despite encountering skepticism and resistance from other scientific and medical figures. “I was working on a disease that basically didn't exist,” Schlievert said. “It was simply not viewed as important enough, even though there were a lot of cases, and it was a brand-new disease, and it should have been investigated. ...It was absolutely clear that was because it was a woman’s issue.”

If the biomedical science community wouldn’t recognize the disease, Schlievert thought, maybe he could raise awareness among young women, their doctors, and the Los Angeles County Health Department. To spread the word, Schlievert spoke with a reporter at the Los Angeles Times who published an article outlining the features of the disease on a Saturday in June of 1980. By Monday, Schlievert was overwhelmed with reported cases and journalists clamoring to talk to him.

With the disease widely publicized, scientists gathered more information on risk factors, quickly uncovering a link with tampon use (1). Since then, tampon-associated menstrual toxic shock syndrome has been established as a real and life-threatening condition. Seeking new ways to prevent and treat the disease, a dedicated group of researchers are exploring therapeutic strategies in tampon manufacturing, toxin neutralization, and vaccination. With the conviction that each life affected or lost is one too many, they hope to close a long-standing gap in women’s health.

Later in the summer of 1980, the CDC sent Schlievert a collection of vaginal samples from women with and without menstrual toxic shock syndrome to see if he could distinguish them. When he cultured S. aureus from the samples and purified the proteins the bacteria secrete, he observed that some contained the distinct toxin and correctly classified them as the menstrual toxic shock syndrome cases. He then isolated the toxin and showed that it could induce the disease in rabbits.

The toxin, eventually named TSST-1, is produced by certain strains of S. aureus, a common infectious microbe in the human body that can colonize the vagina. TSST-1 binds to and stimulates T lymphocytes, which in turn activate macrophages to release proinflammatory cytokines. As the macrophages push against the vaginal mucosa to rush to the site of the infection, they make the barrier more permeable to TSST-1, helping it escape into the bloodstream. The toxin then prompts a systemic immune response, producing a storm of cytokines such as interleukin-1β, which elicits fever, and tumor necrosis factor α, which causes fluid to leak from the blood vessels. While it typically manifests as flu- or stomach bug-like symptoms at first, menstrual toxic shock syndrome can result in organ failure, limb necrosis requiring amputation, and even death.

Menstrual toxic shock syndrome is rare, with an estimated incidence of 0.5 to 1 per 100,000 people in the United States (2). For the families affected, however, statistics bring no comfort. In 2017, Maddy Massabni was celebrating her 19th birthday with family and friends when she started to feel unwell. “I said, ‘We're going to go to the doctor first thing in the morning. It's been 24 hours, and I want to take you in and see what's going on,’” said her mother, Dawn Massabni. The next morning, when her mother tried to wake Maddy up, “She was staring at me. And I was like, ‘Maddy, it’s Mommy, you know who I am.’ She just didn't look right,” Massabni said. Maddy then started to move in a strange way, and her mother immediately called for help. “By the time they got there, she died in my arms at home.”

Victims of menstrual toxic shock syndrome are often blamed for leaving their tampons in for too long, according to Massabni, but she has learned of cases resulting from a wide variety of tampon use lengths. Science supports her perspective: The gold standard 1982 Tri-State Toxic Shock Syndrome Study of women in Minnesota, Wisconsin, and Iowa reported no statistical significance regarding tampon wear time and menstrual toxic shock syndrome (1,3). Instead, the oxygen content of the tampon, a function of its absorbency, presented the strongest risk for the disease (1,3).

Schlievert’s team demonstrated that S. aureus possess a two-component oxygen sensing system that regulates toxin production (4). “If there's no oxygen, there is no toxin of any sort made by Staphylococcus aureus,” Schlievert said. The oxygen trapped inside a tampon is introduced into the vagina upon insertion, where it can trigger TSST-1 production and menstrual toxic shock syndrome.

Following this discovery, Schlievert advocated for uniform absorbency labeling of tampons, since higher absorbency products contain more oxygen and therefore pose a greater risk. He also worked to revert a misguided recommendation to change one’s tampon every two hours, which is dangerously frequent because each time someone inserts a tampon, they introduce more oxygen into the vagina.

In addition to these public health measures, researchers wondered whether they could incorporate a solution to menstrual toxic shock syndrome directly within the tampon itself. “Somebody asked me, ‘Well, why don't you put in something that scavenges oxygen?’” Schlievert said. “Well, that would be nice. We could do that. But every single molecule that scavenges oxygen is tremendously toxic to people, so you can't use them.”

Instead, Schlievert’s team set out in search of a substance that could shut off toxin production even in the presence of oxygen. They identified glycerol monolaurate, a molecule that inserts itself into the membrane of S. aureus and prevents it from making TSST-1. The researchers applied the molecule to tampons and tested them in a pilot trial in healthy menstruating women (5). They found that women who used the glycerol monolaurate-treated tampons showed reduced levels of S. aureus and TSST-1 compared to those who wore standard tampons. Glycerol monolaurate, which has been safely used in food and cosmetic products, did not disrupt the healthy vaginal microbiome and in fact promoted the growth of beneficial lactobacilli bacteria. Additionally, S. aureus did not develop resistance to glycerol monolaurate because the molecule targets the bacteria through multiple mechanisms. While disputes over the official claim associated with the glycerol monolaurate-treated tampons hampered FDA approval in the United States, these treated o.b.® tampons are available in areas including Europe, Australia, and New Zealand.

While safer tampons may reduce the risk of menstrual toxic shock syndrome, researchers are also seeking new ways to fight an active infection. Doctors administer antibiotics to clear the bacteria, but they may also need to stop the circulating toxin in its tracks. Thanks to less serious brushes with TSST-1-producing strains of S. aureus, approximately 80 percent of people already have antibodies against the toxin. These antibodies latch onto TSST-1, preventing activation of T lymphocytes and macrophages and initiation of the harmful immune response. Intravenous immunoglobulin therapy entails collecting these neutralizing antibodies from donors and infusing them into patients with toxic shock syndrome. This treatment has protected rabbits exposed to TSST-1 from its lethal effects and served as a life-saving intervention in dire cases of toxic shock syndrome caused by TSST-1 (6).

Intravenous immunoglobulin therapy, however, may not always be an option due to its high cost and dependence on large quantities of donor antibodies. To overcome these limitations, Schlievert’s team engineered a molecule that is smaller and more active than the immunoglobulins, allowing less material to be used, and expressed it in a bacterial system (7).

Starting with the variable domain of the β chain of the T lymphocyte receptor, the researchers introduced mutations that increase its affinity for TSST-1, allowing it to bind the toxin approximately 1,000 times more strongly than the native receptor. “If you inject that, the toxin is going to preferentially bind to that [molecule] rather than to the low affinity T cell receptor,” Schlievert said. “We actually showed that it has the ability to pull toxin off any T cell receptor that it’s already bound to, so you can basically abort the process.” The team has demonstrated that their TSST-1-neutralizing molecule can block the stimulation of T lymphocytes in vitro and prevent fever and mortality in rabbits challenged with the toxin.

Young women, and in particular, their mothers, would like to know whether their daughters are susceptible. ...I provide this as a free service to physicians who draw blood from their patients or from people who want to know the answer to that. - Patrick Schlievert, University of Iowa

Schlievert, now a professor emeritus at the University of Iowa, has also developed a diagnostic test to determine if a woman has enough antibodies against TSST-1 to protect her from menstrual toxic shock syndrome. “Young women, and in particular, their mothers, would like to know whether their daughters are susceptible,” Schlievert said. “I provide this as a free service to physicians who draw blood from their patients or from people who want to know the answer to that.” To arm more women with this information, companies could analyze menstrual blood from a used pad or tampon during the first menstrual period. “Menstrual blood is a reflection of what's going on in the bloodstream,” Schlievert said.

Schlievert and others have found that approximately 20 percent of people cannot produce antibodies against TSST-1 due to an abnormal immune response (1,8). While scientists knew that women in this category were susceptible to menstrual toxic shock syndrome, they questioned whether these women would be able to respond to a vaccine for the disease. Researchers have developed vaccines using TSST-1 toxoids, modified versions of the toxin that feature mutations of critical residues to abolish toxicity, but remain structurally similar enough to prompt antibody formation. Schlievert’s team tested their toxoid vaccine in rabbits, 50 percent of which had the same inability to develop antibodies against TSST-1 seen in humans. They observed that 100 percent of these rabbits produced antibodies in response to the toxoid, suggesting that the failure to develop antibodies is limited to the natural TSST-1 toxin (8).

To prevent toxic shock syndrome in people with no TSST-1 antibodies or levels that are too low to be protective, researchers at the company Biomedical Research & Bio-Products AG and the Medical University of Vienna have brought a TSST-1 toxoid vaccine to clinical trials. To design their toxoid, they mutated a glycine residue to arginine, disrupting its interaction with the antigen-presenting molecules that present the toxin to T lymphocytes, and swapped out a histidine residue for alanine, preventing the toxin from binding to the T cell receptor. Preclinical studies in rabbits and mice demonstrated that the vaccine initially induces nonspecific binding antibodies, the immune system’s first line of defense against a foreign substance, and eventually selects for TSST-1-neutralizing antibodies. The team found that none of the vaccinated animals developed toxic shock syndrome when exposed to TSST-1, while all of the unvaccinated animals died from the disease.

In their phase 1 trial, the researchers administered the vaccine to healthy subjects, collected blood samples, and quantified their antibody levels (9). To assess antibody function, they combined blood serum with human T lymphocytes and the TSST-1 toxin and measured T cell proliferation. They observed that the antibodies effectively neutralized TSST-1, preventing it from binding to the T lymphocytes and therefore blocking T cell activation and proliferation. The team found that the vaccine was safe and well-tolerated, and that approximately 90 percent of the vaccinated participants showed seroconversion, or a four-fold increase in antibody levels. While there was a small group of nonresponders, whether or not a subject had antibodies against TSST-1 prior to vaccination did not correlate with their response to the vaccine.

In a larger phase 2 trial, the researchers validated their positive results and found that more than 80 percent of subjects developed a protective immune response that has lasted two years after receiving one, two, or three vaccinations (10). “We are confident that when you have one shot and a booster shot, maybe after six months or so, that we can achieve lifelong protection,” said Andreas Roetzer, a microbiologist and head of vaccine research and development at Biomedical Research & Bio-Products AG. The team also compared groups treated with a high dose and a low dose of the vaccine in the phase II study and found that while seroconversion rates increased with the higher dose, there remained a minor portion of nonresponders in both groups, which will be a subject of further study.

The researchers plan to progress their vaccine to a phase 3 trial and hope to bring the first vaccine for Staphylococcus-mediated toxic shock syndrome to market. They are interested in incorporating the vaccine into a broad spectrum, multicomponent vaccine consisting of toxoids of multiple toxins. “This would cover most likely 99 percent of all Staphylococcal toxic shock syndrome cases, both menstrual and nonmenstrual,” Roetzer said. The team is also exploring the possibility of a program to incentivize vaccinated people with high levels of TSST-1-neutralizing antibodies to donate their blood, increasing the quantity available for intravenous immunoglobulin therapy in toxic shock syndrome patients.

Bernd Jilma, a clinical pharmacologist at the Medical University of Vienna involved in clinical development of the vaccine, hopes to eliminate the need for these after-the-fact interventions altogether. “You may be out of the hospital in three weeks, and hopefully you will have your limbs — I think this is not a good option,” he said. To save lives in terms of both quantity and quality, the only guarantee is prevention. “[The vaccine] would be something which will hopefully help many women in the end,” Jilma said.

After losing her daughter to menstrual toxic shock syndrome, Massabni took on the same goal. “We decided that we were going to honor her and not let her die in vain and make sure no one else died from this,” Massabni said. As founder of Don’t Shock Me: The Maddy Massabni Foundation for Toxic Shock Awareness, she has carried out this mission through public speaking engagements, articles and documentaries, and legislative advocacy. She is fighting to pass Madalyn’s Law, which would require education on menstrual toxic shock syndrome in 4th through 12th grade health classes as well as warning posters in public restrooms, doctors’ offices, schools, and menstrual product dispensers. She is also working to pass the Medical Questions Act, which would require medical professionals to ask about the timing of tampon use and symptom onset when treating patients capable of menstruation who present with a flu- or stomach bug-like illness. “I am grateful that something extremely positive is coming out of this,” Massabni said. “I feel like my daughter gave her life for all these other people to live.”

Sarah Anderson joined Drug Discovery News as an assistant editor in 2022. She earned her PhD in chemistry and master’s degree in science journalism from Northwestern University and served as managing editor of “Science Unsealed.”

July/August 2023 Issue