Abstract
Viral subunit vaccines often contain immunodominant non-neutralizing epitopes that divert host immune responses. These epitopes should be eliminated in vaccine design, but there is no reliable method for evaluating an epitope's capacity to elicit neutralizing immune responses. Here we introduce a new concept ‘neutralizing immunogenicity index' (NII) to evaluate an epitope's neutralizing immunogenicity. To determine the NII, we mask the epitope with a glycan probe and then assess the epitope's contribution to the vaccine's overall neutralizing immunogenicity. As proof-of-concept, we measure the NII for different epitopes on an immunogen comprised of the receptor-binding domain from MERS coronavirus (MERS-CoV). Further, we design a variant form of this vaccine by masking an epitope that has a negative NII score. This engineered vaccine demonstrates significantly enhanced efficacy in protecting transgenic mice from lethal MERS-CoV challenge. Our study may guide the rational design of highly effective subunit vaccines to combat MERS-CoV and other life-threatening viruses.
Highlights
Viral subunit vaccines often contain immunodominant non-neutralizing epitopes that divert host immune responses
Alanine scanning of vaccine-surface residues likely leads to changes in the vaccine’s overall immunogenicity that are too subtle to be measurable using currently available experimental methods, while deletion of a whole epitope may disturb the tertiary structure of the viral receptorbinding domains (RBDs)
To understand the correlation between the epitopes’ role in receptor binding and their potential to be recognized by immune responses, we examined whether these engineered glycan probes on MERS-CoV RBD interfered with receptor binding
Summary
Viral subunit vaccines often contain immunodominant non-neutralizing epitopes that divert host immune responses. These epitopes should be eliminated in vaccine design, but there is no reliable method for evaluating an epitope’s capacity to elicit neutralizing immune responses. Correspondence and requests for materials should be addressed to S.J. A major goal of viral subunit vaccine development is to rationally design immunogens that can elicit strong neutralizing immune responses in hosts[1,2,3,4]. Rational design of viral subunit vaccines aims to focus the immune responses on neutralizing epitopes through masking or deletion of immunodominant non-neutralizing epitopes[11,12,13]. Finding a way to measure the neutralizing immunogenicity of different conformational epitopes on viral RBDs will tremendously help rational design of viral subunit vaccines
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