The pediatric adjuvant formulation provides protection against RSV in neonates

Respiratory syncytial virus (RSV) is the leading cause of death in children under the age of 5 worldwide, and an effective vaccine is lacking. In a study of Precision Vaccines Program at Boston Children’s Hospital, a new vaccine formulation protected newborn mice from infection and elicited strong responses in immune cells of human newborns in the laboratory. The results were reported on August 2nd nature communication.

RSV is a leading cause of hospitalizations in US infants and also poses a threat to older adults. While several potential RSV vaccines are in late-stage clinical trials in adults, none have existed since the dramatic failure of a vaccine candidate in 1966 vaccines for children. The antibodies induced by this vaccine failed to neutralize the virus; Instead, the vaccine caused an allergy-like (“Th2”) reaction in the white blood cells in the infants’ airways. This led to shortness of breath when vaccinated infants became infected with RSV -; makes them sicker and leads to some deaths.

As a result, development of pediatric vaccines has been halted, recognizing that children’s immune systems differ from those of adults.”

Simon van Haren PhD, first author of the study and immunologist, Precision Vaccines Program, Boston Children’s Hospital

Van Haren, Ofer Levy, MD, PhD, who directs the Precision Vaccine Program, and her collaborators decided to reopen the case and investigate other ways that vaccination could stimulate the newborn’s immune system without causing harm. They looked at different receptors on immune cells and different combinations of vaccine adjuvants (ingredients added to boost the immune response) that could stimulate these receptors and make the vaccine more effective.

In 2016 they reported in the Journal of Immunology that a combination of two potential adjuvants stimulating the TLR7/8 and Mincle receptors elicited robust responses in the antigen-presenting cells of newborns, which are crucial for boosting cellular immunity. They saw strong activation of type 1 T helper (“Th1”) responses. These Th1 responses are difficult to stimulate in newborns but are required for strong defenses against viral pathogens; the unsuccessful RSV vaccine did not induce a Th1 response.)

For the new work, van Haren and Levy collaborated with Dennis Christensen, PhD, and Gabriel Pedersen, PhD at Statens Serum Institut in Copenhagen, Denmark, to formulate a new protein-based RSV vaccine. This vaccine used the same adjuvant combination reported in 2016, which they called CAF-08, coupled with a protein from RSV and packaged in fat particles called liposomes.

The team first administered the CAF-08/RSV vaccine to cultured antigen-presenting cells obtained from donated human neonatal cord blood. Led by Hanno Steen, PhD, of Boston Children’s, the researchers used phosphoproteomics to create a comprehensive profile of the cellular responses. This showed increased production of cytokines (signaling molecules) by Th1 cells and other indicators of a robust immune response.

“The group of Dr. Steen was instrumental in helping us define the mechanism of action of our adjuvant combination and why it works so well in children and less well in adults,” says van Haren. “It sets out the molecular requirements for an adjuvanted vaccine to be effective in early life.”

Next, they tested CAF-08/RSV in newborn mice and found that it protected against direct challenge with RSV, with no evidence of harm to the animals. Further studies showed that it induced Th1 cells and CD8+ T cells (also important for inducing cellular immune responses) that specifically recognized RSV, as well as neutralizing antibodies.

“The undesired components of the immune response didn’t come into play,” notes van Haren.

Notably, this vaccine formulation did not induce the same protective Th1 immune responses in either adult human or adult mouse blood cells.

“The combination is most active in early life,” says Levy, the study’s lead investigator. “We hope that this adjuvant combination, tailored to be effective early in life, will eventually enable vaccination of infants not only against RSV but also against influenza, coronaviruses and other serious infections.”

Levy and van Haren now plan to refine the RSV vaccine formulation and test it in larger animal models, with the goal of eventually moving it into clinical trials.

The study was supported by the National Institute of Allergy and Infectious Diseases (U01AI124284-01, U19AI118608, HHSN272201400052C), National Institute of Child Health and Human Development (5T32HD055148-10), Boston Children’s Hospital Department of Pediatrics, Bill and Melinda Gates Foundation (INV-004886),

Van Haren, Levy and co-author Francesco Borriello the Precision Vaccines Program are named as inventors of patents describing adjuvant compositions for early life vaccines. Co-author Barney S. Graham (NIAID) is credited as an inventor describing prefusion F as a candidate RSV vaccine. Borriello has consulting agreements with Merck Sharp & Dohme Corp., Sana Biotechnology, Inc. and F. Hoffmann-La Roche Ltd. signed. These business relationships are not related to the current study.