It’s shaping up to be a severe season for respiratory syncytial virus infections – one of the worst some doctors say they can remember. But even as babies struggling to breathe fill hospital beds across the United States, there may be a light ahead: After decades of disappointment, four new RSV vaccines may be nearing review by the US Food and Drug Administration, and more than a dozen others are in testing.
There’s also hope around a promising long-acting injection designed to be given right after birth to protect infants from the virus for as long as six months. In a recent clinical trial, the antibody shot was 75% effective at heading off RSV infections that required medical attention.
Experts say the therapies look so promising, they could end bad RSV seasons as we know them.
And the relief could come soon: Dr. Ashish Jha, who leads the White House Covid-19 Response Task Force, told CNN that he’s “hopeful” there will be an RSV vaccine by next fall.
Charlotte Brown jumped at the chance to enroll her own son, a squawky, active 10-month-old named James, in one of the vaccine trials this summer.
“As soon as he qualified, we were like ‘absolutely, we are in,’ ” Brown said.
Babies have to be at least 6 months old to enter the trial, which is testing a vaccine developed at the National Institutes of Health – the result of decades of scientific research.
Brown is a pediatrician who cares for hospitalized children at Vanderbilt University Medical Center in Nashville, and she sees the ravages of RSV firsthand. A recent patient was in the back of her mind when she was signing up James for the study.
“I took care of a baby who was only a few months older than him and had had nine days of fever and was just absolutely pitiful and puny,” she said. Brown said his family felt helpless. “And I was like, ‘this is why we’re doing it. This single patient is why we’re doing this.’ “
Even before this year’s surge, RSV was the leading cause of infant hospitalizations in the US. The virus infects the lower lungs, where it causes a hacking cough and may lead to severe complications like pneumonia and inflammation of the tiny airways in the lungs called bronchiolitis.
Worldwide, RSV causes about 33 million infections in children under the age of 5 and hospitalizes 3.6 million annually. Nearly a quarter-million young children die each year from complications of their infections.
RSV also preys on seniors, leading to an estimated 159,000 hospitalizations and about 10,000 deaths a year in adults 65 and over, a burden roughly on par with influenza.
Despite this heavy toll, doctors haven’t had any new tools to head off RSV for more than two decades. The last therapy approved was in 1998. The monoclonal antibody, Synagis, is given monthly during RSV season to protect preemies and other high-risk babies.
Lessons learned after grave setback
The hunt for an effective way to protect against RSV stalled for decades after two children died in a disastrous vaccine trial in the 1960s.
That study tested a vaccine made with an RSV virus that had been chemically treated to render it inert and mixed with an ingredient called alum, to wake up the immune system and help it respond.
It was tested at clinical trial sites in the US between 1966 and 1968.
At first, everything looked good. The vaccine was tested in animals, who tolerated it well, and then given to children, who also appeared to respond well.
“Unfortunately, that fall, when RSV season started, many of the children that were vaccinated required hospitalization and got more severe RSV disease than what would have normally occurred,” said Steven Varga, a professor of microbiology and immunology at the University of Iowa, who has been studying RSV for more than 20 years and is developing a nanoparticle vaccine against the virus.
A study published on the trial found that 80% of the vaccinated children who caught RSV later required hospitalization, compared with only 5% of the children who got a placebo. Two of the babies who had participated in the trial died.
The outcomes of the trial were a seismic shock to vaccine science. Efforts to develop new vaccines and treatments against RSV halted as researchers tried to untangle what went so wrong.
“The original vaccine studies were so devastatingly bad. They didn’t understand immunology well in those days, so everybody said ‘oh no, this ain’t gonna work.’ And it really was like it stopped things cold for 30, 40 years,” said Dr. Aaron Glatt, an infectious disease specialist at Mount Sinai South Nassau in New York.
Regulators re-evaluated the guardrails around clinical trials, putting new safety measures into place.
“It is in fact, in many ways, why we have some of the things that we have in place today to monitor vaccine safety,” Varga said.
Researchers at the clinical trial sites didn’t communicate with each other, Varga said, and so the US Food and Drug Administration put the publicly accessible Vaccine Adverse Events Reporting System into place. Now, when an adverse event is reported at one clinical trial site, other sites are notified.
Another problem turned out to be how the vaccine was made.
Proteins are three-dimensional structures. They are made of chains of building blocks called amino acids that fold into complex shapes, and their shapes determine how they work.
In the failed RSV vaccine trial, the chemical the researchers used to deactivate the virus denatured its proteins – essentially flattening them.
“Now you have a long sheet of acids but no more beautiful shapes,” said Ulla Buchholz, chief of the RNA Viruses Section at the National Institutes of Allergy and Infectious Diseases.
“Everything that the immune system needs to form neutralizing antibodies that can block and block attachment and entry of this virus to the cell had been destroyed in that vaccine,” said Buchholz, who designed the RSV vaccine for toddlers that’s being tested at Vanderbilt and other US sites.
In the 1960s trial, the kids still made antibodies to the flattened viral proteins, but they were distorted. When the actual virus came along, these antibodies didn’t work as intended. Not only did they fail to recognize or block the virus, they triggered a powerful misdirected immune response that made the children much sicker, a phenomenon called