New research could help improve future whooping cough vaccines

Researchers at the University of Texas at Austin have discovered critical insights into improving whooping cough vaccines. Their groundbreaking study identifies two powerful antibodies that could neutralize the dangerous pertussis toxin. The research comes at a crucial time when whooping cough outbreaks are increasing globally, particularly threatening infants. These findings offer promising potential for developing more effective, longer-lasting vaccines to combat this potentially deadly respiratory disease.

"\"Training the immune system to target the most vulnerable sites on the toxin is expected to create more effective vaccines\" - Jennifer Maynard, Professor

Whooping cough, also known as pertussis, was formerly a leading cause of death in children in the United States and around the world before vaccines were introduced in the 1940s.

Key Points

1 New antibodies identified to neutralize pertussis toxin

2 Vaccine effectiveness declining post-pandemic

3 Research aims to protect vulnerable infants

4 Breakthrough could revolutionize vaccine design

In the decades since, the bacterial disease has been practically eradicated in the United States, with annual fatalities falling into the double digits.

Now, new research from The University of Texas at Austin could aid in improving whooping cough vaccines to once again push this disease toward eradication by targeting two key weaknesses in the infection.

But the disease has made a troubling comeback in recent years as vaccine coverage declined after the Covid-19 pandemic. In 2024, several outbreaks left public health officials and hospitals scrambling to accommodate a sudden influx of patients, primarily infants, who are often too young to be vaccinated and suffer the most severe symptoms.

Against this backdrop, a team of researchers, including members of UT's McKetta Department of Chemical Engineering and Department of Molecular Biosciences, has made significant strides in understanding and enhancing pertussis immunity. One of the things that makes pertussis infections dangerous is pertussis toxin (PT), a chemical weapon produced by the bacteria that weakens a patient's immune response and causes many of the severe symptoms associated with whooping cough.

The new research, described in a new study published in the Proceedings of the National Academy of Sciences, focuses on two powerful antibodies, hu11E6 and hu1B7, which neutralize the PT in different ways.

Using cutting-edge cryo-electron microscopy approaches, the researchers identified the specific epitopes on PT where these antibodies bind. Epitopes are chemical targets the immune system can zero in on to fight pathogens. Hu11E6 blocks the toxin from attaching to human cells by interfering with sugar-binding sites, while hu1B7 prevents the toxin from entering cells and causing harm. These findings are the first to precisely map these critical regions, providing a blueprint to improve vaccines.

"There are currently several promising new pertussis vaccines in the research and clinical trial phases," said Jennifer Maynard, professor of chemical engineering at the Cockrell School of Engineering and corresponding author of the new study. "Our findings could be incorporated into future versions quite easily, improving overall effectiveness and longevity of protection."

She pointed to innovations like mRNA technology used in the Covid-19 vaccine, as well as breakthroughs in using genetic engineering on pertussis toxin (PTgen) to generate safer and more potent new recombinant acellular pertussis vaccines as technologies preserving neutralizing epitopes that can combine with her team's new findings.

"Training the immune system to target the most vulnerable sites on the toxin is expected to create more effective vaccines," Maynard said. "And the more effective and longer-lasting a vaccine is, hopefully, the more people will take it."

In addition to helping guide future vaccine designs, the hu1B7 and hu11E6 antibodies themselves hold promise as therapeutic medicines for infected and high-risk infants. Previous work by Maynard and colleagues show that they can prevent the lethal aspects of pertussis infection. UT researchers are actively seeking partnerships to develop ways to prevent lung damage and death in newborns exposed to the disease.

Caused by the bacterium Bordetella pertussis, whooping cough is infamous for its violent coughing fits, which can lead to complications like pneumonia, seizures, and even death, particularly in infants.

One nickname for the disease is the 100-days cough because the painful coughing fits can linger for months, even in mild or moderate cases. The disease kills an estimated 200,000 people each year worldwide, most of them infants and children, and survivors of severe illness can be left with brain damage and lung scarring.

While modern vaccines have reduced the toll, their effectiveness wanes over time, with protection only lasting two to five years. Modern pertussis vaccines are acellular, which means they contain portions of the bacteria that train the immune system to recognize the pathogen, including PT.

Recent outbreaks of whooping cough around the world have stunned public health officials. This fall, New York City saw a 169% increase in whooping cough cases since 2023. Cases have increased 500% since 2019. Australia is currently suffering through the largest outbreak of whooping cough since the introduction of the vaccine in the 1940s, with an estimated 41,000 cases reported this year.

Health officials point to missed initial and booster vaccinations as major contributors to the outbreaks.

While advances in fighting pertussis are exciting, they face a dual challenge: overcoming the biological complexity of pertussis and the societal hurdles of vaccine hesitancy. The most effective way to prevent pertussis in vulnerable newborns is for mothers to be vaccinated during pregnancy, which confers protection to the newborn until it is old enough to be vaccinated.

According to the CDC, the full vaccination rate against pertussis in kindergarteners is typically over 90 per cent in the US, but under 60 per cent of mothers receive the vaccine during pregnancy.

Skepticism about vaccine safety and slow normalization of routine vaccination after the Covid-19 pandemic has led to pockets of under-vaccinated communities and overall low protection of newborns, providing fertile ground for deadly outbreaks. This environment, coupled with the limitations of current vaccines, makes innovation essential.

Co-author Annalee W. Nguyen, a research professor in chemical engineering, emphasized the importance of prevention over treatment. "It's always easier to prevent disease in a high-risk person," she said. "Once someone is extremely ill, their immune system isn't functioning well, and it's harder to help them recover.

Mothers have an incredible opportunity to shield their babies after they are born by getting a pertussis booster vaccination during pregnancy, and parents can continue to protect their families by working with their pediatrician to ensure children and teens are up-to-date on vaccinations."

By focusing on neutralizing epitopes--areas where antibodies can effectively block the toxin--new vaccines can potentially provide stronger, longer-lasting immunity. This could help bolster public confidence in pertussis vaccines and curb the disease's resurgence.

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