Respiratory Syncytial Virus RSV Vaccine - DT-preF
"Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infections (ALRI) in infants and children across the globe. The burden is disproportionately high in low-income country settings. New estimates quantify the RSV ALRI burden at global, regional, and national scales."
PATH / CDC
Each year, RSV infects 4-5 million children in the US, and is the leading cause of infant hospitalizations (120,000). In addition, it poses a serious threat to the elderly, where it results in an additional 180,000 hospitalizations and 12,000 deaths annually, in the US alone. There are currently no frontline treatments for RSV and the only approved prophylactic for RSV is passive administration of the monoclonal antibody Synagis (Astra Zeneca), which despite only reducing severe disease by ~50% drives annual sales of ~$1 billion.
Calder’s approach in RSV is based on using DT cross-linking to lock the soluble RSV F (fusion) protein fully in its “prefusion” (preF) conformation, while also significantly thermo-stabilizing preF in order to enable its further clinical development. preF has recently been shown to account for the vast majority of protective antibodies in infected subjects, and it would therefore be an ideal vaccine immunogen – except that the molecule is still too unstable. In the absence of stabilization, soluble preF rapidly transitions, irreversibly, to its “postfusion” (postF) conformation, which is poorly protective.
Using structure-based design, our collaborators at the NIH, Barney Graham and Jason McLellan, designed a partially-stabilized variant of soluble preF called “DS-Cav1” that has already been shown to elicit ~10-fold higher anti-preF protective antibody titers in mice than any preceding postF based vaccine candidates. Since high preF titers are key to potent and sustained maternal-to-infant protection for the first 6 months of an infant’s life, DS-Cav1 served to refocus the RSV vaccine field on the dramatically improved potential of preF based vaccines. DS-Cav1 has already elicited substantial partnership interest from Pharmas to take it into clinical development. However, nothwithstanding its excellent immunogenic characteristics, and the high degree of commercial interest, DS-Cav1 quickly loses its preF conformation in storage at 4C and commercial development remains on hold.
Calder’s “DT-preF” vaccine immunogen retains the correct preF conformation and thus puts the finishing touches on this otherwise promising RSV vaccine candidate. DT-preF’s improved stability also results in several-fold higher potency, and renders feasible, for the first time, maternal-to-infant protection, for up to 6 months.
Barney Graham, M.D., Ph.D., Deputy Director of, and Chief of Viral Pathogenesis at, the Vaccine Research Center of the NIH
Jason S. McLellan, Associate Professor at the University of Texas, Austin
Kerry Empey, Pharma, Ph.D., Assistant Professor, University of Pittsburgh. This work is supported by SBIR grants R44AI112124 and R43AI140941.