PIPELINE & PROGRAMS
Engineered Stabilized Protein Vaccine Programs:
RSV DT-PreF Vaccine
Universal Influenza Conformationally Locked Headless HA
Epstein-Barr Combination Vaccine
RSV DT-PreF Vaccines for Respiratory Syncytial Virus
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.
Calder’s approach in RSV is to apply our 3D-Vaxlock™ technology to lock the soluble RSV F (fusion) protein fully in its “prefusion” (preF) conformation to improve its clinical performance as a vaccine. Our collaborators at the NIH, Barney Graham and Jason McLellan (now at Univ. of Texas, Austin), designed a partially-stabilized variant of soluble preF called “DS-Cav1”. However, nothwithstanding its excellent immunogenic characteristics, DS-Cav1 quickly loses its prefusion conformation and has suboptimal potency. Therefore, several 1st generation vaccine developers have further modified this variant to improve its conformational stability and potency.
Of all of the programs in development, Calder’s “DT-preF” vaccine immunogen best holds the prefusion conformation. DT-preF’s improved stability results in an order of magnitude higher neutralizing antibody titers = best-in-class protection.
Calder will formulate its vaccine for the elderly to fully overcome immunosenescence and protect the very old and frail. Calder will formulate its maternal vaccine to induce high neutralizing Ab titers during pregnancy to provide newborn children effective protection for as long as possible.
On its RSV program, Calder has collaborated with Barney Graham, M.D., Ph.D., Deputy Director of, and Chief of Viral Pathogenesis at, the Vaccine Research Center of the NIH; with Jason S. McLellan Ph.D., Associate Professor at the University of Texas, Austin; and with Kerry Empey, Pharma, Ph.D., Assistant Professor, University of Pittsburgh. This work was supported by SBIR grants R44AI112124 and R43AI140941 and R44AG064107
Universal Influenza DT-Headless HA Vaccines
Hemagglutinin (HA) is the primary protein on the surface of the Influenza virus that the immune system mounts antibodies against. The “stalk” domain of HA is highly conserved across Influenza strains and antibodies generated against the stalk of HA protect very well against many strains. However, the head domain acts as a decoy and distracts the immune system from reacting to the stalk; and as a result very few stalk antibodies are elicited in infected patients. A conformationally locked Headless HA (DT-Headless HA) will focus immune responses on only the highly conserved stalk domain and thus elicit broad protection not just against multiple strains of seasonal influenza, but also against the risk of future pandemic influenza strains.
By introducing dityrosine crosslinks into the stalk of a complete, correctly folded HA molecule, Calder first locks the stalk of HA in its native, trimeric, prefusion conformation. Then, once the stalk is locked, we remove the head domain with a protease, using engineered cleavage sites. We aim to demonstrate that DT-Headless HA elicits broad protection against multiple influenza strains. Favorable thermostability will enable stockpiling for pandemic preparedness. We estimate a $12+ billion market opportunity between seasonal and pandemic influenza.
Calder has collaborated with James Crowe, M.D., Director, Vanderbilt Vaccine Center. This work is funded by SBIR grant R44AG059371.
Epstein-Barr Prefusion gB + gH/gL Locked DT-EBVcom
EBV is one of the most common human viruses – a herpes family virus that spreads primarily via saliva. It is the primary cause of infectious mononucleosis and is associated with several malignancies, including stomach and nasopharyngeal cancers and Hodgkin and Burkitt lymphomas; EBV infection is also associated with autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. An EBV vaccine could prevent or reduce the severity of infectious mononucleosis from EBV infection and may also contribute to the prevention of EBV-associated malignancies and autoimmune diseases.
There are roughly 125,000 cases of infectious mononucleosis each year in the US, of which approximately 10% develop fatigue that lasts >six months. About 1% of all EBV-infected individuals develop hepatitis, neurologic problems, severe blood abnormalities, or other serious complications.
Calder will apply its 3D-Vaxlock™ technology to (i) the EBV gp350, which is a conformational EBV surface protein and the primary target for neutralizing antibodies in people infected with EBV, and (ii) the EBV gB+gH/gL envelope glycoprotein (Env) trimeric complex. Our goal is to generate improved Epstein-Barr vaccine immunogens that are stabilized in their functionally relevant conformations and elicit potent neutralizing antibody responses.
Immunofluorescence of single human cell stained grown in tissue culture, stained with multiple antibodies and visualized via confocal microscopy.