Pediatric adjuvant formulation offers protection against RSV in neonates

Respiratory syncytial virus (RSV) is the world’s leading cause of death in children under 5 years of age and there is no effective vaccine. In a study of Precision Vaccine Program at Boston Children’s Hospital, a new vaccine formulation protected newborn mice against infection and elicited strong responses in the immune cells of human newborns in the laboratory. The results were reported on August 2 in nature communications.

RSV is one of the leading causes of childhood hospitalizations in the US and is also a threat in older adults. While several potential RSV vaccines are in late-stage clinical trials in adults, there have been no such vaccines for children since the dramatic failure of a vaccine candidate in 1966. The antibodies induced by that vaccine were unable to neutralize the virus. ; instead, the vaccine elicited an allergic-type (“Th2”) white blood cell response in the infants’ airways. This resulted in respiratory distress when the vaccinated infants became infected with RSV -; making them sicker and causing some deaths.

Consequently, the development of pediatric vaccines was halted, recognizing that the immune system of children is different from that of adults.”

Simon van Haren PhD, Study First Author and Immunologist, Precision Vaccine Program, Boston Children’s Hospital

Van Haren, Ofer Levy, MD, PhD, who heads the Precision Vaccine Program, and his collaborators decided to reopen the case and explore other ways that vaccination could boost the newborn’s immune system without causing harm. They examined different receptors on immune cells and different combinations of vaccine adjuvants (ingredients added to strengthen the immune response) that might stimulate these receptors, making vaccination more effective.

In 2016, they reported in the journal of immunology that a combination of two potential adjuvants, which stimulate TLR7/8 and Mincle receptors, elicited robust responses in newborn antigen-presenting cells, critical for boosting cellular immune defenses. They saw strong activation of type 1 T-helper (“Th1”) responses. These Th1 responses are difficult to stimulate in neonates, but are necessary for a strong defense against viral pathogens; the failed RSV vaccine did not induce a Th1 response).

For the new work, van Haren and Levy teamed up with Dennis Christensen, PhD, and Gabriel Pedersen, PhD of the Statens Serum Institut in Copenhagen, Denmark, to formulate a new protein-based RSV vaccine. This vaccine used the same combination of adjuvants reported in 2016, which they called CAF-08, along with an RSV protein and packaged inside fatty particles called liposomes.

The team first administered the CAF-08/RSV vaccine to cultured antigen-presenting cells obtained from donated umbilical cord blood from human newborns. Led by Hanno Steen, PhD, at Boston Children’s, the researchers extensively profiled cell responses with phosphoproteomics. This revealed increased production of cytokines (signaling molecules) by Th1 cells and other indicators of a robust immune response.

“Dr. Steen’s group was instrumental in helping us define the mechanism of action of our adjuvant combination and why it works so well in children and less so in adults,” says van Haren. “It establishes the molecular requirements for an adjuvanted vaccine to work in the first years of life.”

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

“Undesirable components of the immune response did not come into play,” van Haren notes.

Notably, this vaccine formulation did not induce the same protective Th1 immune responses in blood cells from adult humans or adult mice.

“The combination is more active in the first years of life,” says Levy, principal investigator of the study. “We hope that this combination of adjuvants, designed to be effective in the first years of life, will eventually enable the 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 ultimate goal of bringing it into clinical trials.

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

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

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Magazine Reference:

Van Haren, South Dakota, et al. (2022) The adjuvant CAF08 enables single-dose protection against respiratory syncytial virus infection in murine neonates. nature communications. doi.org/10.1038/s41467-022-31709-2.

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