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

Abstract

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.

Incidence and clinical and microbiological features of invasive and probable invasive streptococcal group A infections in children and adults in the Brussels-Capital Region, 2005–2020

“…In the present study, 63.9% of iGAS and piGAS infections would be covered by this vaccine. Cross-reactions have been demonstrated in vitro [ 42 ] and suggest a broader cross-reaction coverage of the 30-valent vaccine in humans. However, in vivo studies are needed to confirm this.…”

Unveiling the Group A Streptococcus Vaccine-Based L-Rhamnose from Backbone of Group A Carbohydrate: Current Insight Against Acute Rheumatic Fever to Reduce the Global Burden of Rheumatic Heart Disease

“…59,60,62,63 M-protein has been widely studied and is believed to have a role in adhering to host cells and blocking phagocytosis thereby helping GAS colonization. 63,64 M-protein is a versatile protein in terms of both structure and function. M-protein can bind to fibrinogen, fibronectin, and host plasminogen, apart from that it also plays a role in interfering with complement protein deposits through binding to the Fc domain with IgG and complement regulators namely C4BP protein and factor H so that M-protein has a big role in virulence factors because can resist opsonophagocytosis.…”

“…However, the main problem in developing an M-protein-based GAS vaccine is cross-reactivity with human organs, especially the myosin protein in heart muscle cells. 64,72,73 The first evidence showing the existence of cross-reactivity between anti-streptococcal antibodies and human heart tissue was found in experimental mice that had been immunized with GAS components. In fact, crossreactivity has become one of the main hypothesized mechanisms causing the emergence of ARF attacks several weeks after the onset of manifestations of GAS infection such as sore throat infection or impetigo due to autoimmunity which recognizes the M-protein GAS along with the proteins found in the heart valves, synovial tissue, and basal ganglia due to the similarity of protein structures which is referred to as molecular mimicry.…”

Design of aStreptococcus pyogenesM protein immunogen to elicit M type cross-reactivity

“…Notably, 15 of the 30 M protein HVRs in StreptAnova TM have the C4BP-binding 3D pattern, and correspondingly 20 of the ~50 cross-reactive M protein types elicited by StreptAnova TM have the 3D pattern (26,27), suggesting that at least some of the cross-reactivity of StreptAnova TM is due to recognition of the 3D pattern. Likewise, M type crossreactivity observed for three other multi-HVR immunogens may be explained by recognition of the 3D pattern (39)(40)(41). The composition of these three immunogens, which are pentavalent or hexavalent and mostly contain HVRs that are also in StreptAnova TM , is based on physicochemical properties rather than M type prevalence in North America and Europe as it is for StreptAnova TM (26).…”