QBI presents a seminar with Raghavan Varadarajan, Professor of Molecular Biophysics at the Indian Institute of Science in Bangalore.

Professor Varadarajan's laboratory works on understanding the relationship between protein sequence, stability and structure, the application of high throughput mutagenesis to guide protein structure prediction, and on immunogen design for HIV-1, influenza, SARS-CoV-2, and other sarbecoviruses. In 2010, the laboratory in collaboration with Merck, demonstrated one of the first examples of structure guided vaccine design, to elicit antibodies that protect from heterologous influenza challenge. In 2017, Dr. Varadarajan co-founded the startup Mynvax, to take forward the influenza immunogen design work to the clinic. In early 2020, his laboratory initiated immunogen design efforts for COVID-19 and demonstrated that lyophilized derivatives of the SARS-CoV-2 RBD were highly thermotolerant and could be stored at 37°C for over a month without loss of protective efficacy. Several of the designed immunogens elicit broadly neutralizing antibodies, and protect transgenic mice and hamsters from viral challenge with diverse viral variants. A candidate vaccine formulation for influenza is currently being tested in a Phase 1 clinical trial in Australia.

Talk Title: Design of Efficacious, Thermotolerant Viral Vaccine Formulations

There have been recent, transformative advances in the area of protein structure prediction. However, reliable prediction of stabilizing mutations for complex, hetero-oligomeric proteins is still difficult. While large mutant libraries are readily screened for improved activity or ligand binding, screening for stabilized mutants is more challenging. Most current viral vaccine formulations, including for COVID-19, require low temperature storage. This is a major impediment to widespread deployment, and contributed to the highly skewed distribution of vaccines, worldwide.

In his talk, Professor Varadarajan will share his lab's development of general methodology to rapidly isolate stabilized protein variants, including identification of thermostable Receptor Binding Protein (RBD) derivatives of the Spike protein of SARS-CoV-2 and other sarbecoviruses. These display enhanced yield and immunogenicity relative to the corresponding wild-type RBD, as well as to stabilized Spike ectodomains; the COVID-19 formulations can be stored at 37°C for several weeks without loss of antigenicity or protective efficacy. He and his team are employing similar approaches to stabilize other viral vaccine antigens, to enhance protective efficacy, and to minimize cold chain requirements, thus facilitating deployment in resource limited settings.

Host: Ujjwal Rathore