Design of Broadly Cross-Reactive M Protein-Based Group A Streptococcal Vaccines

Copyright © 2021 by The American Association of Immunologists, Inc..

Group A streptococcal infections are a significant cause of global morbidity and mortality. A leading vaccine candidate is the surface M protein, a major virulence determinant and protective Ag. One obstacle to the development of M protein-based vaccines is the >200 different M types defined by the N-terminal sequences that contain protective epitopes. Despite sequence variability, M proteins share coiled-coil structural motifs that bind host proteins required for virulence. In this study, we exploit this potential Achilles heel of conserved structure to predict cross-reactive M peptides that could serve as broadly protective vaccine Ags. Combining sequences with structural predictions, six heterologous M peptides in a sequence-related cluster were predicted to elicit cross-reactive Abs with the remaining five nonvaccine M types in the cluster. The six-valent vaccine elicited Abs in rabbits that reacted with all 11 M peptides in the cluster and functional opsonic Abs against vaccine and nonvaccine M types in the cluster. We next immunized mice with four sequence-unrelated M peptides predicted to contain different coiled-coil propensities and tested the antisera for cross-reactivity against 41 heterologous M peptides. Based on these results, we developed an improved algorithm to select cross-reactive peptide pairs using additional parameters of coiled-coil length and propensity. The revised algorithm accurately predicted cross-reactive Ab binding, improving the Matthews correlation coefficient from 0.42 to 0.74. These results form the basis for selecting the minimum number of N-terminal M peptides to include in potentially broadly efficacious multivalent vaccines that could impact the overall global burden of group A streptococcal diseases.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:207

Enthalten in:

Journal of immunology (Baltimore, Md. : 1950) - 207(2021), 4 vom: 15. Aug., Seite 1138-1149

Sprache:

Englisch

Beteiligte Personen:

Aranha, Michelle P [VerfasserIn]
Penfound, Thomas A [VerfasserIn]
Salehi, Sanaz [VerfasserIn]
Botteaux, Anne [VerfasserIn]
Smeesters, Pierre [VerfasserIn]
Dale, James B [VerfasserIn]
Smith, Jeremy C [VerfasserIn]

Links:

Volltext

Themen:

Antibodies, Bacterial
Antigens, Bacterial
Bacterial Outer Membrane Proteins
Bacterial Proteins
Carrier Proteins
Epitopes
Journal Article
Peptides
Research Support, N.I.H., Extramural
Streptococcal M protein
Streptococcal Vaccines
Vaccines, Synthetic

Anmerkungen:

Date Completed 20.08.2021

Date Revised 16.08.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.4049/jimmunol.2100286

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM32885672X