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Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Rational design of MERS-CoV RBD vaccine with enhanced efficacy.Mice were immunized with two engineered RBD fragments containing a glycan probe at residue 511 (R511N/E513T) and residue 579 (T579N), respectively. Wild type RBD and PBS buffer were used as controls. Immunized mice were challenged with MERS-CoV (EMC-2012 strain), and observed for survival rate (a) and weight changes (b).
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f5: Rational design of MERS-CoV RBD vaccine with enhanced efficacy.Mice were immunized with two engineered RBD fragments containing a glycan probe at residue 511 (R511N/E513T) and residue 579 (T579N), respectively. Wild type RBD and PBS buffer were used as controls. Immunized mice were challenged with MERS-CoV (EMC-2012 strain), and observed for survival rate (a) and weight changes (b).

Mentions: The efficacies of the RBD vaccines were evaluated based on the morbidity and mortality of the immunized and challenged mice. First, hDPP4-Tg mice immunized with the negative-epitope-masked RBD vaccine (that is, RBD containing T579N mutation) all survived MERS-CoV challenge (100% survival rate), whereas hDPP4-Tg mice immunized with the wild type RBD vaccine and with the positive-epitope-masked RBD vaccine (that is, RBD containing R511N/E513T mutations) demonstrated survival rates of 67 and 17%, respectively, after MERS-CoV challenge (Fig. 5a). Second, MERS-CoV challenge did not cause any weight loss in hDPP4-Tg mice immunized with the negative-epitope-masked RBD vaccine, but led to significant weight loss in hDPP4-Tg mice immunized with either the wild type RBD vaccine or the positive-epitope-masked RBD vaccine (Fig. 5b). The experiments were further repeated twice and similar results were obtained. These results revealed the enhanced efficacy of the negative-epitope-masked RBD vaccine and reduced efficacy of the positive-epitope-masked RBD vaccine, and demonstrated the utility of NII in developing a vaccine with increased immunogenicity in a stringent model of severe MERS.


Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines
Rational design of MERS-CoV RBD vaccine with enhanced efficacy.Mice were immunized with two engineered RBD fragments containing a glycan probe at residue 511 (R511N/E513T) and residue 579 (T579N), respectively. Wild type RBD and PBS buffer were used as controls. Immunized mice were challenged with MERS-CoV (EMC-2012 strain), and observed for survival rate (a) and weight changes (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121417&req=5

f5: Rational design of MERS-CoV RBD vaccine with enhanced efficacy.Mice were immunized with two engineered RBD fragments containing a glycan probe at residue 511 (R511N/E513T) and residue 579 (T579N), respectively. Wild type RBD and PBS buffer were used as controls. Immunized mice were challenged with MERS-CoV (EMC-2012 strain), and observed for survival rate (a) and weight changes (b).
Mentions: The efficacies of the RBD vaccines were evaluated based on the morbidity and mortality of the immunized and challenged mice. First, hDPP4-Tg mice immunized with the negative-epitope-masked RBD vaccine (that is, RBD containing T579N mutation) all survived MERS-CoV challenge (100% survival rate), whereas hDPP4-Tg mice immunized with the wild type RBD vaccine and with the positive-epitope-masked RBD vaccine (that is, RBD containing R511N/E513T mutations) demonstrated survival rates of 67 and 17%, respectively, after MERS-CoV challenge (Fig. 5a). Second, MERS-CoV challenge did not cause any weight loss in hDPP4-Tg mice immunized with the negative-epitope-masked RBD vaccine, but led to significant weight loss in hDPP4-Tg mice immunized with either the wild type RBD vaccine or the positive-epitope-masked RBD vaccine (Fig. 5b). The experiments were further repeated twice and similar results were obtained. These results revealed the enhanced efficacy of the negative-epitope-masked RBD vaccine and reduced efficacy of the positive-epitope-masked RBD vaccine, and demonstrated the utility of NII in developing a vaccine with increased immunogenicity in a stringent model of severe MERS.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus