Just as babies are born with tiny toes and no teeth, their immune system also starts out as a work-in-progress. Immature immune systems need time to develop, which leaves young children at risk for infectious diseases such as respiratory syncytial virus (RSV). In late fall to spring, this airborne virus causes symptoms ranging from mild coughing to life-threatening respiratory issues and is responsible for the majority of infant hospitalizations. Although vaccines are available for older adults, none have been approved for children.
This is partially because infants “are immunologically immature and … less efficient at generating somatically mutated antibodies,” explains Samuel Scharffenberger, a PhD candidate in Dr. Andrew McGuire’s lab in the Vaccine and Infectious Disease Division. Scharffenberger spearheaded a project, recently published in Cell Reports, to test a new vaccination strategy to protect babies from RSV.
Typical vaccines expose the body to an antigen–often, a carefully chosen piece of the pathogen—to train B cells to produce antibodies that neutralize infection. To generate antibodies that bind the antigen snugly, B cells undergo a process called somatic hypermutation to randomly diversify their gene segments and change their binding properties. The body then tests these new products against the antigen to determine if the binding improves. These tests, called affinity maturation, allow the immune system to convert generic, ‘off-the-shelf’ antibodies to making hyper-specific, tailored defenses. Without efficient somatic hypermutation, affinity maturation is impaired; this ultimately leads to a different, and often less protective, antibody profile for babies compared to adults.
The McGuire Lab took advantage of the recent finding that many individuals have a subset of B cells already “hardwired to produce RSV-neutralizing antibodies without the need for affinity maturation”. In other words: rather than needing a bespoke suit to fit, these antibodies can neutralize RSV right off the rack. However, these exact kind of RSV-neutralizing antibodies are rare: their particular heavy chain-light chain pairing only occurs 0.2% of the time in naïve B cells.
The authors wanted to increase the production of this antibody class beyond the natural frequency of 0.2%. However, simply presenting the immune system with an antigen—in this case, the fusion protein of RSV, which has been successfully used as bait in other strategies—does not guarantee success. There are many places on antigens that antibodies can bind, and the response can sometimes be skewed towards sites that might not block infection.
To get the exact immune response they wanted, the authors needed something that they knew would bind these particular RSV antibodies with high affinity. They figured: what better way to get an extremely targeted response than with … an antibody! They focused their attention on anti-idiotypic antibodies—that is, antibodies raised against other antibodies—that could encourage production of the RSV-neutralizing antibodies with a high degree of precision. (Sound familiar? The anti-idiotypic antibody approach has also been used for HIV vaccine development efforts.)
Through collaboration with the Fred Hutch Antibody Technology Shared Resource, the authors found four anti-idiotypic antibodies (ai-mAbs) that bound either the desired heavy chain or light chain. Three of the four ai-mAbs bound the light chain while one bound the heavy chain. None bound the exact pair, so they created a hybrid ai-mAb by expressing half of each and linking the halves together. Tests of this bi-specific ai-mAb showed that it prefers antibodies with both desired heavy and light chains and is less interested in antibodies that have only one.
They sorted naïve B cells with this bi-specific ai-mAb and found that 40% of the B cells isolated with this method had the allele usage they wanted, a 200-fold jump over the natural frequency of 0.2%. Having confirmed that these are the correct type of antibodies, they expressed several of them and found that some were capable of blocking RSV infection in cell culture.
This study shows that using ai-mAbs as immunogens can guide B cells in vitro toward a desired immune response. This is especially exciting as similar experiments have been found to be representative of what happens during immunization in humans. “The next steps will be to establish the efficacy of our vaccine in vivo,” Scharffenberger says, a challenge because small animal models do not have the same heavy and light chain gene pairing found in humans that their ai-mAbs target. To overcome this, they are working with mice that are engineered to express the requisite heavy and light chain genes.
Overall ai-mAbs are an attractive strategy for vaccinating against RSV, especially in infants. Because the immunogen is not derived from the virus itself, the immune response will be laser-focused on producing ready-made RSV-neutralizing antibodies quickly and without need for further mutations. In addition, this system won’t clash with “maternal or prophylactic antibodies that may be present in the infant's system”, Scharffenberger explains. This will give infants protection during the first few months of life, and ultimately allow time to develop their immune systems to protect themselves against severe RSV.
The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Juliana McElrath, and Andrew McGuire contributed to this work.
Scharffenberger, S. C., Wan, Y. H., Homad, L. J., Kher, G., Haynes, A. M., Poudel, B., Sinha, I. R., Aldridge, N., Pai, A., Bibby, M., Chhan, C. B., Davis, A. R., Moodie, Z., Palacio, M. B., Escolano, A., McElrath, M. J., Boonyaratanakornkit, J., Pancera, M., & McGuire, A. T. (2024). Targeting RSV-neutralizing B cell receptors with anti-idiotypic antibodies. Cell Rep, 43(10), 114811.