Respiratory syncytial virus (RSV) is the leading global cause of death in children under age five years, and lacks an effective vaccine. A study by researchers for Precision Vaccines Program at Boston Children’s Hospital has shown that a new adjuvanted liposomal vaccine formulation protected newborn mice against infection and induced strong responses in immune cells from human newborns in the laboratory.
The study, led by Simon van Haren, PhD, an immunologist in the Precision Vaccines Program and Ofer Levy, MD, PhD, who directs the Precision Vaccine Program, is reported in Nature Communications, in a paper titled “CAF08 adjuvant enables single dose protection against respiratory syncytial virus infection in murine newborns.” Levy and van Haren plan to refine the RSV vaccine formulation and test it in larger animal models, with the eventual goal of bringing it into clinical trials. In their paper, researchers suggest the technology could also potentially be harnessed to develop pediatric vaccines against other pathogens. “Overall, this synergistic combination adjuvant has great potential for future development of precision adjuvanted pediatric vaccines to protect against RSV, influenza, coronaviruses, and other intracellular pathogens.”
RSV is estimated to cause 3.2 million hospitalizations and at least 59,000 deaths worldwide, predominantly in children under the age of 6 months, and the virus is the second most likely single pathogen to cause death in children under one year of age, the authors noted. 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 candidate vaccine in 1966. The antibodies induced by that vaccine could not neutralize the virus; instead, the vaccine caused an allergic-like, type 2 T helper (Th2) white blood cell response in the infants’ airways. This resulted in respiratory distress when vaccinated infants became infected with RSV—making them sicker and leading to some deaths. “Consequently, pediatric vaccine development was halted, recognizing that the immune system in kids is different from that in adults,” said first author van Haren.
Van Haren, Levy and collaborators were interested in exploring other ways that vaccination could stimulate the newborn 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 had reported in the Journal of Immunology that a combination of two potential adjuvants, stimulating the TLR7/8 and Mincle receptors, provoked robust responses in newborns’ antigen-presenting cells, which are critical for kickstarting cellular immune defenses. “We have previously conducted a screen of TLR and CLR adjuvant combinations that demonstrated that newborn DCs [dendritic cells] can be activated to instruct a Th1 response by combined stimulation through TLR7/8 and the C-type Lectin Receptor (CLR) Mincle using R848 and trehalose-6,6-dibehenate (TDB), respectively…” they wrote. Using this approach resulted in strong activation of type 1 T-helper (Th1) responses, which are typically hard to stimulate in newborns, but are needed for a strong defense against viral pathogens. The failed RSV vaccine did not induce a Th1 response.
For the newly reported work, van Haren and Levy partnered with Dennis Christensen, PhD, and Gabriel Pedersen, PhD at the 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 named CAF-08, coupled with a protein from RSV and packaged inside liposomes. “Herein, we evaluated the ability of liposomal formulations containing the lipidated TLR7/8 agonist 3M-052, a Mincle agonist and the RSV pre-F antigen, to induce a potent and balanced Th1/Th2 immune response in newborn mice.”
The team first administered the CAF-08/RSV vaccine to cultured antigen-presenting cells obtained from donated cord blood from human newborns. Led by Hanno Steen, PhD, at Boston Children’s, the researchers comprehensively profiled the cells’ responses with phosphoproteomics. This revealed enhanced 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 lays out the molecular requirements for an adjuvanted vaccine to work in early life.”
They next tested CAF-08/RSV in newborn mice and found that it protected against a direct challenge with RSV, with no evidence of any harm to the animals. Further studies showed that it induced Th1 cells and CD8+ T cells (also important in inducing cellular immune responses) that specifically recognized RSV, as well as neutralizing antibodies. “The undesirable components of the immune response did not come into play,” commented van Haren.
Notably, the vaccine formulation did not induce the same protective Th1 immune responses in blood cells from either human adults or adult mice. “The combination is most active in early life,” said Levy, the study’s senior investigator. “We hope this adjuvant combination, tailored to be effective in early life, will eventually enable the vaccination of infants against not only RSV, but also influenza, coronaviruses, and other serious infections.”
The authors further wrote, “In conclusion, our study describes an adjuvanted vaccine formulation that overcomes the neonatal bias towards Th2-mediated immunity and provide robust Th1 and CD8-mediated protective immunity against RSV … The CAF08-adjuvanted pre-F vaccine induced an RSV-specific, Th1-polarized immune response in newborn animals. “This adjuvant platform for neonatal vaccines represents a promising approach to enhance the efficacy of a future vaccine against RSV and other pediatric pathogens against whom robust Th1 immunity is required for protection.”
Levy and van Haren now plan to refine the RSV vaccine formulation and test it in larger animal models, with the eventual goal of bringing it into clinical trials.
