Structural Immunology Studies Reveal New Insights into Viral Immunity and Vaccine Design

Two recent studies from teams including IBBR researchers and collaborators, published in Nature Communications, demonstrate how structural immunology is advancing our understanding of viral immunity and guiding vaccine design.

T cells are critical to the body’s immune system and can identify and destroy infected cells by recognizing epitopes, small viral fragments presented on the surface of infected cells. In the study “Structural insights into clonal restriction and diversity in T cell recognition of two immunodominant SARS-CoV-2 nucleocapsid epitopes,” researchers examined SARS-CoV-2, the virus responsible for the global COVID-19 pandemic, to better understand how T cells recognize different viral epitopes. The researchers sought to determine why certain viral epitopes trigger varying levels of protective immune responses and how the structural features of T cell receptors influence these responses.

Using advanced structural biology tools, the researchers examined how T cell receptors bind these viral fragments at the molecular level. By determining the high-resolution molecular structures of these complexes, they gained insight into why certain viral targets produce different immune responses. The study also compared these experimentally determined structures to structural models generated by multiple versions of the deep learning method, AlphaFold, highlighting some success while showing room for improvement in current AI approaches for modeling immune interactions. Together, the findings underscore the continued importance of experimental structural biology and point to opportunities for improving computational modeling.

A second study, “Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk,” addressed vaccine design for a group of viruses that includes Zika virus and Dengue virus, among others. This group of viruses poses a unique challenge because antibodies generated against one virus can sometimes worsen illness caused by another closely related virus, a phenomenon known as antibody-dependent enhancement. To address this issue, the researchers employed a novel structure-guided engineering approach. They designed a vaccine candidate that elicited a strong immune response while masking regions associated with harmful antibody reactions, offering a promising strategy for developing safer and broadly protective vaccines. This design was validated using state-of-the-art cryoelectron microscopy (cryoEM) capabilities available in the IBBR CryoEM Center. 

These two studies are among many that highlight the strength of IBBR’s structural immunology team. By combining various techniques such as cryo-EM, crystallography, and computational modeling, they are revealing how immune molecules interact at atomic resolution and using those insights to better guide vaccine design and immune therapies. This work expands our understanding of immunity and supports the development of improved vaccines and immune therapies to benefit global health.