What is the human antibody response to measles virus vaccination?

PROJECT SUMMARY/ABSTRACT Vaccines are the greatest bang for our public health buck, yet vaccine development is still sometimes hit or miss. Recent efforts with SARS-CoV-2 demonstrated that acceleration of vaccine programs is possible, especially when supported by prior studies characterizing successful immune responses against related prototype pathogens. The measles virus vaccination campaign is a global success story; the live-attenuated vaccine developed in the 1960's still elicits highly protective antibodies to strains circulating today. Yet Measles outbreaks persist due to obstacles in vaccination programs such as global health inequities, vaccine hesitancy, extreme weather events related to climate change, and the SARS-CoV-2 pandemic. Furthermore, a growing population with compromised immune systems cannot receive live-attenuated viral vaccines. Thus, the threat of measles remains (there are still approximately 9-10 million cases annually), and innovative solutions will be needed to achieve global measles eradication. However, very little is known about the human antibody response to measles infection or vaccination beyond neutralizing antibody titers. Importantly, there are no structures of any antibodies in complex with any measles virus antigens. As a result, we do not know which sites on measles virus are immunodominant and protective. Much of this fundamental knowledge is lacking largely because measles was effectively eradicated from developed nations before needed scientific tools had been developed. In this work, we will use state-of-the-art tools to directly visualize the structure of human antibodies from vaccinee polyclonal sera bound to measles surface glycoproteins to understand which antigenic sites dominate in the human vaccinee response. We will also use microfluidics and rapid microscale multiplexed competition analyses to rapidly discover and analyze individual human monoclonal antibodies against measles virus for the first time. This work will reveal what components of the human immune response to this prototype paramyxovirus lead to vaccine-mediated protection, and will help guide development of modern vaccines for the immunocompromised and other vaccines against paramyxoviruses yet to emerge.