Structural Basis of Antibody Recognition of Viruses

Citation

Esswein, Shannon Rose (2022) Structural Basis of Antibody Recognition of Viruses. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/krjp-se81. https://resolver.caltech.edu/CaltechTHESIS:05202022-005152490

Abstract

The Zika epidemic in 2015-2016 and COVID-19 pandemic in 2019-2021 are the latest reminders of the enormous impact of viruses on the world. Zika, a flavivirus transmitted by mosquitos, can cause severe neurodevelopmental abnormalities including microcephaly in the newborns of the infected mothers. Vaccine design is complicated by concern that elicited antibodies may also recognize other epidemic-causing flaviviruses that share a similar envelope protein, such as dengue virus, West Nile Virus, and yellow fever virus. This cross-reactivity, if non-neutralizing, may worsen symptoms of a subsequent infection through antibody-dependent enhancement (ADE). To better understand the neutralizing antibody response and risk of ADE, we compared germline and mature antibody binding to Zika and other flaviviruses. We showed that affinity maturation of the light chain variable domain is important for strong binding of VH3-23/VK1-5 neutralizing antibodies to Zika virus envelope domain III (EDIII) and identified interactions that contribute to weak, cross-reactive binding to West Nile Virus EDIII. These findings informed our design of EDIII-conjugated mosaic nanoparticles as a pan-flavivirus vaccine candidate. Sera from immunization trials with nanoparticles displaying EDIIIs of Zika and dengue serotypes 1-4 showed cross-reactive binding to Zika, dengue 1-4, and West Nile Virus, a promising step towards the development of safe and effective flavivirus vaccines.

Coronaviruses are another group of viruses responsible for widespread morbidity and mortality, including the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemics and current SARS-CoV-2 pandemic. Given concerns regarding new SARS-CoV-2 variants and the possibility for additional zoonotic betacoronaviruses to cause future outbreaks, we investigated how the epitopes on the SARS-CoV-2 receptor binding domain (RBD) targeted by VH3-30-derived antibodies correlate with their neutralization potency and breadth of betacoronavirus recognition. Analyses showed how variations in antibody light chains and CDRH3 lengths facilitate the diverse RBD epitopes, cross-reactivity, and neutralization profiles of VH3-30 Abs, illustrating their importance for vaccine design and therapeutic antibody development.

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