As cold and flu season ramps up, the most vulnerable among us need extra protection. Infants are among the most susceptible to respiratory complications from respiratory syncytial virus, or RSV. While they can receive passive protection from maternal antibodies or from prophylactic monoclonal antibodies given after birth, babies are not eligible for a vaccine that will build their own immunity.
But a new proof-of-concept study from Fred Hutch Cancer Center scientists, published in September in Cell Reports, suggests a different vaccine strategy that could potentially shore up infant immunity while sidestepping the problems encountered by prior investigational childhood RSV vaccines.
In an approach that has not yet been tested against RSV infection, the researchers engineered a special type of antibody that can directly activate immune cells that are “pre-programmed” to ward off RSV.
“The idea is that this vaccine could be given close to birth and even in the context of prophylactic treatments,” said first author Sam Scharffenberger, a graduate student in the laboratory of Fred Hutch cellular biologist and senior author Andrew McGuire, PhD. “It would be able to activate the infant's immune system while they’re still afforded protection from the mother or from the passive transfer of monoclonal antibodies.”
RSV is one of the many viruses that causes the common cold — at least in healthy adults. Nearly everyone contracts it for the first time by age two, but RSV poses a particular threat to the very young and the very old. In 2023 the U.S. Food and Drug Administration approved vaccines based on RSV proteins for pregnant people and for people over 60. In October of 2024, the FDA approved the Pfizer RSV vaccine for adults age 18-59 who are at heightened risk for RSV infection, such as immunocompromised individuals.
A vaccinated pregnant mother can pass protective antibodies to her infant in utero or through breastmilk after birth. Infants at particularly high risk of RSV complications can also receive monoclonal antibodies against RSV. But these don’t help a baby produce its own protective — and longer-lasting — antibodies. Studies in animals also suggest that maternal antibodies may hobble an infant’s immune system as it attempts to formulate its own response to RSV.
“We have good prophylaxis, but there's still kind of this break in protection [for infants],” Scharffenberger said. “It’s when they’re losing maternal antibodies … but before the infant’s immune system has matured enough to respond when it sees the virus for the first time.”
Scientists have tried to seal this immunological break before. In the 1960s, researchers inactivated RSV and tested it as a vaccine in young children.
“It actually led to an enhanced disease because of the proteins that were displayed on the surface [of the virus particle],” Scharffenberger said. “It led to a non-neutralizing antibody response.”
This meant that while immunized children produced antibodies against RSV, these antibodies didn’t block or “neutralize” RSV infection.
And while recently approved RSV vaccines “have been engineered to be stabilized and avoid the protein conformation [shape] that they think may have led to this enhanced disease, there's still a lot of caution about giving any RSV vaccine — particularly subunit vaccines — to infants,” McGuire said.
He and Scharffenberger are exploring a different strategy, one that might bypass the problems posed by RSV protein-based subunit vaccines and also bolster infant immunity even in the face of maternal or monoclonal antibodies. Rather than creating a vaccine that mimics the RSV virus, they’re going straight to the source of protection: the immune cells that produce neutralizing antibodies.
Antibodies start out as molecular “sensors” on the surface of immune cells called B cells. To deal with the extraordinary variety of microbial threats we may encounter over our lives, these B-cell receptors, or BCRs, come in an almost infinite variety. Each new B cell undergoes a process, stitching together a handful of BCR gene segments taken from a much larger grab-bag of genetic possibilities.
Another group found that BCRs that contain two particular genetic pairings form a template for antibodies that neutralize RSV. Moreover, these pairings are very common and the antibodies neutralize from the get-go. They don’t need to undergo further genetic tweaking (a process called affinity maturation) to build neutralization capacity.
This is key because infant B cells aren’t as adept at affinity maturation as adult B cells. The B cells with this genetic signature also offered a target for Scharffenberger and McGuire.
“We're trying to target this pre-programmed subset of B cells,” Scharffenberger said. “If you're able to target them specifically, you might be able to raise this protective response that kind of circumvents infants’ immunological immaturity.”
He set out to home in on these B cells using an antibody that targets another antibody. These are called anti-idiotype antibodies, and McGuire previously explored their use in vaccines for HIV.
“You need unique situations to be able to use anti-idiotypic antibodies as a vaccine,” McGuire said.
To work, the antibodies need a common pre-existing set of B cells with a shared genetic heritage whose BCRs inherently bind their target, no tweaking needed. The anti-RSV B cells fit that bill, so Scharffenberger set out to create an anti-idiotype antibody with the potential to become an RSV vaccine.
Photo courtesy of Sam Scharffenberger; Image adapted from Scharffenberger et al., Cell Reports 2024
The first step to developing an antibody against a target is to use an immune system to do the heavy lifting. Scharffenberger immunized mice with anti-RSV antibodies containing the correct genetic stitch-up and isolated antibodies the mice generated against the target.
But an idiosyncrasy in antibody structure meant this was just the first step. Antibodies are Y-shaped proteins and each arm of the Y (the part that connects with its target) is formed by two separate molecules. These are each encoded by a different gene (which are stitched together independently), which means that a given B cell may carry only half the key anti-RSV genetic signature.
This also meant that the antibodies Scharffenberger generated only targeted one genetic pairing at a time. To create an anti-idiotype antibody most likely to recognize the full combination, Scharffenberger melded two antibodies together. He engineered a new antibody in which each arm of the Y recognized one half of the anti-RSV signature.
Scharffenberger then tested whether his dual-tipped, or “bispecific,” antibody could engage B cells with the correct genetic signature (and only the correct signature). Using human donated blood samples, he found that his bispecific anti-idiotype antibody primarily bound to B cells with the characteristic genetic pairing. About 5% of the B cells produced antibodies that can neutralize the two main strains of RSV. (Given the variability of BCRs, even those that share a couple gene units, this is a large percentage, McGuire noted.)
When Scharffenberger tested the ability of his engineered antibody to activate B cells, he found that only B cells with the correct BCR signature produced antibodies. Those with only half the signature (or none of it) remained inert to his antibody’s effects.
This suggests that his antibody would primarily stimulate neutralizing antibodies. But a test of a neutralizing antibody’s capabilities showed the neutralizing antibodies prompted by Scharffenberger’s anti-idiotype antibody can still block RSV even in the face of less effective antibodies (at least in lab dishes).
“The idea is that you’d still get protection, even if not all the antibodies are going to be neutralizing,” Scharffenberger said.
Scharffenberger will next test his anti-idiotype antibody in animal models of RSV infection, to see if it stimulates an immune response that protects against the virus in its native habitat. But because the key pairing is only found in humans, they’ll need to develop mice that carry the correct (originally human) antibody gene pieces. Mouse B cells use the same mix-and-match build-a-BCR process as human B cells, so a portion of the B cells produced by the genetically engineered mice will carry the correct pairing.
Ideally, the engineered antibody will protect against infection even in the presence of maternal or monoclonal antibodies.
McGuire and Scharffenberger don’t envision their approach as a replacement for current vaccines, but potentially as “another horse in the race,” McGuire said.
“There’s no doubt been tremendous success in RSV-prevention strategies, but there’s still a need for infant immunization,” he said. “Right now, we don’t know if adult vaccines work in kids, and this could be an alternative.”
This work was funded by the National Institutes of Health, the National Institute of Allergy & Infectious Diseases, the National Institute of General Medical Sciences, The Bill and Melinda Gates Foundation and the J. B. Pendelton Charitable Trust.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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