Sean Diehl, Ph.D., associate professor of microbiology and molecular genetics

Larner Researcher’s Collaborative Efforts Propel RSV Vaccine Development and Offer Hope for Infant Health

In 2022, about one in every 500 babies ages six months and younger was hospitalized due to respiratory syncytial virus (RSV), the second leading cause of infant mortality. But, thanks to the contributions of University of Vermont Larner College of Medicine researcher Sean Diehl, Ph.D., associate professor of microbiology and molecular genetics, and colleagues, this may soon no longer be the case.

In 2010, Diehl, alongside researchers at Amsterdam University Medical Centers (UMC), made a breakthrough — they found an antibody that offers protection against this life-threatening virus for newborns. After over a decade of tinkering and testing, the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC), alongside the Advisory Committee on Immunization Practices (ACIP), just unanimously approved to recommend that this antibody drug, known as Beyfortus (nirsevimab) and dispensed through Sanofi and AstraZeneca, be incorporated into the vaccination schedule for infants under eight months of age.

Understanding RSV and Its Impact on Children

RSV is a virus that can cause acute respiratory infections in people of all ages. While the majority of infants and young children may exhibit minor cold-like symptoms, certain babies, particularly during their initial infection, could encounter more severe lower respiratory tract ailments, such as pneumonia and bronchiolitis. These conditions involve inflammation of the small airway passages in the lungs and may necessitate visits to the emergency department or a medical practitioner’s office. Premature infants and those with chronic lung conditions or notable congenital heart problems are at the greatest susceptibility to severe RSV disease. According to the American Academy of Pediatrics, approximately 1 to 3 percent of children under 12 months of age in the United States are hospitalized each year due to RSV. Though usually seasonal in the U.S., starting during the fall and peaking in the winter, RSV is transmitted from person to person through close contact with someone who is infected.

From Antibodies to Protection

The journey to create a therapy to combat RSV began with the groundbreaking discovery of an antibody known as D-25, later licensed to MedImmune, now an independent biotech company called Viela Bio. Initially potent, D-25’s true potential was unveiled when the MedImmune team extended its half-life to address the three-month RSV season. Through strategic modifications to D-25’s constant (or fragment crystallizable [Fc]) region, MED18899, now known as nirsevimab, was born.

Nirsevimab stands apart as a passive immunization, delivering a single dose of a long-acting monoclonal antibody that blocks RSV’s ability to infect cells. This unique approach offers timely and direct protection against disease without requiring the activation of the immune system in the ways that traditional active immunizations/vaccines do. Importantly, research has also shown that nirsevimab still allows the baby’s immune system to generate its own protective responses to RSV.

In contrast, most vaccines recommended for children, such as the MMR (measles, mumps, rubella) vaccine, are active vaccines. They work by introducing harmless parts of infections to trigger the body’s immune response. Developing an active vaccine for RSV has been particularly challenging, however, due to historical failures and ethical concerns. MedImmune previously brought an anti-RSV antibody called Synagis to market, but it was only indicated for about 0.1 percent of newborns who met specific medical criteria. These limitations inspired the team at Amsterdam UMC to leverage their knowledge of how human immune B cells generate antibodies to explore alternative methods of RSV prevention.

Nirsevimab was a culmination of two decades of work that began in 2003 in Amsterdam while Diehl was a postdoctoral fellow at Amsterdam UMC. Working with immunologist and professor of cell biology Hergen Spits, Ph.D., Diehl, who was supported by a Kirchstein F32 postdoctoral fellowship from the National Institutes of Health, invented a technique — one that involved mimicking the B cell activation process while lengthening its lifespan — that was later applied to the RSV prevention efforts.

B cells serve as formidable defenders, producing antibodies that shield individuals from infections like RSV; however, unleashing their full potential for potent RSV antibodies has proven to be a challenging task. More than two decades ago, scientists Diehl, Spits, and graduate student Ferenc Scheeren embarked on a groundbreaking journey to comprehend the intricate workings of B cells, allowing them to replicate the activation process in the lab. Yet, a significant hurdle emerged: the B cells had a short half-life and rapidly perished upon removal from the bone marrow. To effectively study RSV antibodies, the team extended the activation time, leading to a transformative discovery of four potent RSV antibodies. These antibodies held the promise of revolutionizing prevention and treatment strategies for this respiratory virus.

The process involved screening immortalized cells from a volunteer who had regular contact with children. Other contributing scientists included Tim Beaumont, Ph.D., Etsuko Yasuda, Ph.D., and Mark Kwakkenbos, Ph.D., who tested these cells to identify the ones producing antibodies against RSV, leading to the discovery of four main antibodies, two of which were exceptionally potent.

Preventing RSV and Creating a Lasting Impact

Discovery of potent RSV antibodies marked a pivotal advancement in the fight against RSV, offering hope for improved protection and care for vulnerable populations, such as newborns and infants. Nirsevimab, the new RSV antibody treatment, has now received FDA and CDC approval.

The impact of this research extends beyond RSV, as antibodies against infectious diseases, including monoclonal antibody therapies for dengue, zika, and norovirus. Monoclonal therapies for COVID-19 also gained momentum during the pandemic. Importantly, Beyfortus is approved for all infants at an estimated cost of $600 for the single long-acting dose and will be included in the CDC’s Vaccines for Children program for the winter 2023 RSV season.

Diehl’s contributions to this exciting narrative have paved the way for a brighter future in the fight against RSV and infectious diseases, due to his novel insights into the transformative power of the human B cell.