At present, no vaccine against group A Streptococcus (GAS, S. pyogenes) exists. This Gram-positive bacterial pathogen is a leading cause of global morbidity and mortality. With an estimated >500,000 annual deaths, GAS ranks among the top 10 causes of mortality from infectious disease. The extraordinary antigenic variability of the M protein, the most abundant and antigenic protein on the GAS surface, has been a major impediment in the development of such a vaccine. Sequence variation is localized to N-terminal portions of the mature M protein, and in particular, a region denoted the hypervariable region (HVR) that distinguishes one M type from another. More than 220 distinct M HVRs have been identified. The hypervariability of this region is ascribable to immune pressure, as the HVR is a target of opsonizing antibodies. Such antibodies are generally type-specific, recognizing the immunizing M type but not other M types. A biologically inspired solution to this problem is suggested by our recent ground-breaking work (Buffalo et al., Nat Micro), which revealed the existence of functionally conserved sequence patterns that are hidden within the HVRs of a large number of M proteins. These conserved sequence patterns are required for the indispensable function of recruiting the inhibitory complement factor C4b-binding protein (C4BP) to the GAS surface. The type-promiscuity of C4BP contrasts sharply with the type-specificity displayed by antibodies. We seek in this proposal to ask the simple but critical question of whether antibodies can be generated that mimic the type-promiscuous binding mode of C4BP and thereby provide broadly neutralizing immunity. Compelling evidence exists to support the hypothesis that an M protein antigen containing just the conserved and essential C4BP- binding pattern will evoke a broadly neutralizing response.
In Aim 1, we will ?refocus? antibody recognition from antigenically variable amino acids in M protein HVRs to conserved C4BP-binding ones. We will do this by minimizing protein constructs to the short C4BP-binding sequence pattern, and verify that these constructs retain the dimeric, ?-helical coiled-coil structure and C4BP-binding of native M protein HVRs.
In Aim 2, we will ask whether these minimized M protein HVR constructs evoke broad neutralizing immunity against M proteins containing the C4BP-binding sequence patterns. These studies will be carried out through the multi-PD/PI mechanism with PIs Partho Ghosh and Victor Nizet. A uniquely synergistic and long-standing collaboration exists between the complementary efforts of the Ghosh (biochemistry and structural biology) and Nizet (bacterial pathogenesis and innate immunity) laboratories in studying GAS virulence from atoms to animals.

Public Health Relevance

The group A strep bacterium, which is responsible for strep throat, also causes serious, life-threatening diseases. No vaccine against group A strep exists, and a major problem for the development of such a vaccine is the antigenic variability of the group A strep M protein. Antibodies raised against one antigenic variant of the M protein typically do not recognize other antigenic variants of the M protein. We are pursuing a biologically inspired way to overcome this problem. Results from our study will have implications for the design of a group A strep vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Vaccines Against Microbial Diseases Study Section (VMD)
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GU, Xin-Xing
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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