Engineering protein antigens to refocus the immune response

Abstract

Infectious diseases continue to be a threat to millions globally – largely because of highly effective immune evasion mechanisms evolved in pathogens. Our work focuses on engineering proteins to shield selected epitopes thereby refocusing the immune response to other regions on the protein antigen. In the context of vaccine design, nanopatterning can help preferentially elicit broadly neutralizing antibodies while suppressing the response to epitopes that serve as immunological decoys. We have developed two approaches to achieve this shielding and refocusing – one referred to as “Nanopatterning” that uses site-specifically conjugated polymeric shields and a second approach that uses engineered antibody fragments (Fabs) as shielding agents. Using these tools, we have demonstrated the ability to refocus the immune response to broadly neutralizing epitopes of medically relevant antigens from diseases including Malaria, Influenza and Zika. In summary, this work explores two new approaches to achieve immunofocusing – allowing refocusing of the immune response to broadly neutralizing epitopes of protein antigens. These tools should be broadly applicable for the design of broadly protective vaccines against pathogens such as malarial parasites, influenza, flaviviruses and HIV.