US-12616743-B2 - Streptococcal GlcNAc-lacking glycopolypeptides, cell wall carbohydrates, streptococcus vaccines, and methods for making and using them

Abstract

In alternative embodiments, the invention provides vaccines, pharmaceutical compounds and formulations for diagnosing, preventing, treating or ameliorating Group A Streptococcus (GAS), Group C Streptococcus (GCS), or Group A Streptococcus (GGS), infections, or other pathogenic Streptococcus infections. In alternative embodiments, the invention provides compositions such as diagnostic tests, assays, immunoassays and test strips, and methods, for detecting or diagnosing the presence of a Streptococcal infection, e.g., Group A Streptococcus (GAS), Group C Streptococcus (GCS), or Group A Streptococcus (GGS), infections, or other pathogenic Streptococcus infections.

Inventors

• Victor Nizet
• Nina van Sorge

Assignees

• THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Dates

Publication Date

20260505

Application Date

20230816

Claims (12)

1. 1 . A glycoconjugate composition comprising an isolated Group A Streptococcus (GAS) cell wall carbohydrate conjugated to a GAS protein, wherein the GAS cell wall carbohydrate comprises a polyrhamnose backbone completely lacking its N-acetyl-D-glucosamine side chain.
2. 2 . The glycoconjugate composition of claim 1 further comprising an adjuvant.
3. 3 . The glycoconjugate composition of claim 2 , wherein the adjuvant is selected from the group consisting of Freund's adjuvant, aluminum phosphate, aluminum hydroxide, squalene, and levamisole.
4. 4 . The glycoconjugate composition of claim 1 , wherein the GAS cell wall carbohydrate is purified.
5. 5 . The glycoconjugate composition of claim 1 further comprising a pharmaceutical carrier.
6. 6 . The glycoconjugate composition of claim 5 , wherein the pharmaceutical carrier is a liposome.
7. 7 . An immunogenic composition comprising an effective amount of the glycoconjugate composition of claim 1 .
8. 8 . The immunogenic composition of claim 7 , wherein the GAS cell wall carbohydrate is purified.
9. 9 . The immunogenic composition of claim 7 further comprising an adjuvant.
10. 10 . The immunogenic composition of claim 9 , wherein the adjuvant is selected from the group consisting of Freund's adjuvant, aluminum phosphate, aluminum hydroxide, squalene, and levamisole.
11. 11 . The immunogenic composition of claim 7 further comprising a pharmaceutical carrier.
12. 12 . The immunogenic composition of claim 11 , wherein the pharmaceutical carrier is a liposome.

Description

RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser. No. 17/002,337, filed Aug. 25, 2020 (now U.S. Pat. No. 11,771,751), which application is a continuation of U.S. patent application Ser. No. 15/265,800 (now U.S. Pat. No. 10,780,155), filed Sep. 14, 2016, which is a divisional of U.S. patent application Ser. No. 14/237,120, filed Jun. 9, 2014 (now abandoned), which application was a national phase application claiming benefit of priority under 35 U.S.C. § 371 to Patent Convention Treaty International Application Serial No: PCT/US2012/049604, filed Aug. 3, 2012, which claims benefit of priority to U.S. Provisional Patent Application Ser. No. 61/515,287, filed Aug. 4, 2011. The aforementioned applications are expressly incorporated herein by reference in their entirety and for all purposes. GOVERNMENT RIGHTS This invention was made with government support under grants A1077780 and AI060536, awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. TECHNICAL FIELD This invention generally relates to medicine, vaccines and microbiology. In particular, in alternative embodiments, the invention provides vaccines, pharmaceutical compounds and formulations for diagnosing, preventing, treating or ameliorating Group A Streptococcus (GAS), Group C Streptococcus (GCS), or related pathogenic streptococcal, infections. In alternative embodiments, the invention provides compositions such as diagnostic tests, assays, immunoassays and test strips, and methods, for detecting or diagnosing the presence of a Streptococcal infection, e.g., Group A Streptococcus (GAS), Group C Streptococcus (GCS), or Group A Streptococcus (GGS), infections, or other pathogenic Streptococcus infections. BACKGROUND Group A Streptococcus (GAS), also known as S. pyogenes, is a preeminent human pathogen ranking among the top 10 infection-related causes of mortality worldwide. GAS causes a wide spectrum of disease, ranging from pharyngitis (“strep throat”), to severe invasive infections including necrotizing fasciitis and toxic shock syndrome, to the autoimmune disorder acute rheumatic fever (ARF). No effective GAS vaccine has been developed, a goal made more challenging by the greater than 150 different serotypes produced by the immunovariable surface M protein. Group C Streptococcus (GCS), although less extensively studied that GAS, can produce human infections quite similar to those caused by GAS, although these are more often opportunistic infections or nosocomial infections. For example, GCS can cause epidemic pharyngitis and cellulitis clinically indistinguishable from GAS disease, and can cause septicemia, endocarditis, septic arthritis and necrotizing infections in patients with predisposing conditions such as diabetes, cancer or advanced aged. GCS is also the cause of the highly contagious and serious upper respiratory tract infection of horses and other equines known as strangles, which is enzootic in a worldwide distribution. GAS is classically defined by expression of a unique carbohydrate structure called the group A carbohydrate (GAC). Comprising approximately 50% of the dry weight of the bacterial cell wall, GAC consists of a rhamnose backbone and an immunodominant N-acetylglucosamine (GlcNAc) side chain. GAC is the basis for all contemporary rapid diagnostic testing for GAS pharyngitis. GAC has shown potential as a universal GAS vaccine in animal studies, but serious safety concerns were raised since the antibodies against the GlcNAc side chain have been implicated in the immunopathogenesis of rheumatic fever (RF), a poststreptococcal inflammatory disorder of global health importance. In particular, evidence of anti-GlcNAc antibodies have been associated with two cardinal manifestations of RF: rheumatic carditis and Sydenham's chorea. Group A Streptococcus (GAS) mutants with variant group A carbohydrate (GAC), so-called A-variants, have been observed to originate upon serial passage in mice, however the molecular basis for this spontaneous variation has never been documented. In addition, such variants have never been isolated from humans, possibly indicating the GlcNAc side chain is plays an essential role in human colonization, infection or transmission. Human serum contains antibodies against GAC that are predominantly directed against the GlcNAc side chain and promote phagocytosis of GAS. However, anti-GlcNAc antibodies have also been observed to crossreact with human cardiac myosin and lysoganglioside on neuronal cells, associating them to rheumatic carditis and Sydenham chorea, respectively. Anti-GAC antibodies that recognize the rhamnose backbone have also been described to be present in human serum, however, their protective effect against streptococcal infection is currently unknown. Importantly, the identical GAC rhamnose backbone is shared by the group carbohydrate antigens of other medically important pathogens including GCS. GCS are distinguish