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

Ade Meidian Ambari; Faqrizal Ria Qhabibi; Dwita Rian Desandri; Bambang Dwiputra; Pirel Aulia Baravia; Indira Kalyana Makes; Basuni Radi

doi:10.12688/f1000research.144903.3

Home Browse Unveiling the Group A Streptococcus Vaccine-Based L-Rhamnose from...

ALL Metrics

Views

Downloads

Get PDF

Get XML

Export

▬

✚

Review

Revised

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

[version 3; peer review: 2 approved]

Ade Meidian Ambari ^1,2, Faqrizal Ria Qhabibi³, Dwita Rian Desandri^1,2, [...] Bambang Dwiputra^1,2, Pirel Aulia Baravia⁴, Indira Kalyana Makes³, Basuni Radi^1,2

Ade Meidian Ambari ^1,2, Faqrizal Ria Qhabibi³, [...] Dwita Rian Desandri^1,2, Bambang Dwiputra^1,2, Pirel Aulia Baravia⁴, Indira Kalyana Makes³, Basuni Radi^1,2

PUBLISHED 30 Jan 2025

Author details Author details

¹ Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, Jakarta, 11420, Indonesia
² Cardiology and Vascular Department, Faculty of Medicine, University of Indonesia, Jakarta, Jakarta, 10430, Indonesia
³ Research Assistant, National Cardiovascular Center Hospital Harapan Kita, Jakarta, Jakarta, 11420, Indonesia
⁴ Cardiovascular Prevention and Rehabilitation Department, Dr. Saiful Anwar General Hospital, Malang, East Java, 65122, Indonesia

Ade Meidian Ambari
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Faqrizal Ria Qhabibi
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Dwita Rian Desandri
Roles: Data Curation, Formal Analysis, Investigation, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Bambang Dwiputra
Roles: Conceptualization, Data Curation, Investigation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation

Pirel Aulia Baravia
Roles: Data Curation, Investigation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Indira Kalyana Makes
Roles: Investigation, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Basuni Radi
Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Pathogens gateway.

Abstract

Group A Streptococcus (GAS) is a widely distributed bacterium that is Gram-positive and serves as the primary cause of acute rheumatic fever (ARF) episodes. Rheumatic heart disease (RHD) is a sequela resulting from repeated ARF attacks which are also caused by repeated GAS infections. ARF/RHD morbidity and mortality rates are incredibly high in low- and middle-income countries. This is closely related to poor levels of sanitation which causes the enhanced incidence of GAS infections. Management of carditis in RHD cases is quite challenging, particularly in developing countries, considering that medical treatment is only palliative, while definitive treatment often requires more invasive procedures with high costs. Preventive action through vaccination against GAS infection is one of the most effective steps as a solution in reducing RHD morbidity and mortality due to curative treatments are expensive. Various developments of M-protein-based GAS vaccines have been carried out over the last few decades and have recently begun to enter the clinical stage. Nevertheless, this vaccination generates cross-reactive antibodies that might trigger ARF assaults as a result of the resemblance between the M-protein structure and proteins found in many human tissues. Consequently, the development of a vaccine utilizing L-Rhamnose derived from the poly-rhamnose backbone of Group A Carbohydrate (GAC) commenced. The L-Rhamnose-based vaccine was chosen due to the absence of the Rhamnose biosynthesis pathway in mammalian cells including humans thus this molecule is not found in any body tissue. Recent pre-clinical studies reveal that L-Rhamnose-based vaccines provide a protective effect by increasing IgG antibody titers without causing cross-reactive antibodies in test animal tissue. These findings demonstrate that the L-Rhamnose-based vaccine possesses strong immunogenicity, which effectively protects against GAS infection while maintaining a significantly higher degree of safety.

Keywords

Acute rheumatic fever; Rheumatic heart disease; Group A Streptococcus; L-rhamnose; Vaccine

Corresponding author: Ade Meidian Ambari

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2025 Ambari AM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Ambari AM, Qhabibi FR, Desandri DR et al. 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 [version 3; peer review: 2 approved]. F1000Research 2025, 13:132 (https://doi.org/10.12688/f1000research.144903.3) First published: 22 Feb 2024, 13:132 (https://doi.org/10.12688/f1000research.144903.1) Latest published: 30 Jan 2025, 13:132 (https://doi.org/10.12688/f1000research.144903.3)

Revised Amendments from Version 2

The final revision of this paper incorporates multiple modifications based on feedback from the second reviewer, including the addition in the limitations section addressing techniques and a discussion on hyposensitivity and protein shielding (adjuvants) in polysaccharide-based vaccines to enhance the effectivity and immunogenicity of the proposed vaccine.

See the authors' detailed response to the review by Arif Nur Muhammad Ansori
See the authors' detailed response to the review by Mark Kaddumukasa

Introduction

Group A Streptococcus (GAS) is a cosmopolitan bacterium that has become the etiology of various human diseases, from mild illnesses such as tonsilitis and impetigo, to severe ones such as scarlet fever, toxic shock, and necrotizing fasciitis. Acute rheumatic fever (ARF) is an inflammatory reaction triggered by Group A Streptococcus infection which usually occurs approximately two to three weeks following a sore throat illness.¹^,² ARF is characterized by several clinical symptoms consisting of polyarthritis migrant (35-88%) and carditis (50-78%) which usually cause mitral or aortic valve regurgitation. Besides that, other signs that usually accompany ARF include abnormal involuntary movement or Sydenham chorea (2-19%), erythema marginatum (<6%), subcutaneous nodule (1-13%), and increased laboratory values such as erythrocyte sedimentation rate, neutrophils, and CRP.²^–⁵ These clinical symptoms are used in establishing the diagnosis of ARF which is concluded in Jones criteria which was first proposed in 1944 and has undergone several revisions until the American Heart Association (AHA) issued the latest revision in 2015 which divides these clinical syndromes into major and minor criteria and dividing the population based on where they live whether they are classified into low, medium, or high-risk areas.³^,⁶ Various clinical manifestations that appear during ARF are the result of autoantibodies against tissues found in the joints, brain, and heart due to the similarity of the molecular structure of protein found in body tissues with the molecular structure of M-protein antigen found in GAS.⁷^,⁸ The structural similarity between α-helical coiled M-protein antigens in GAS and various body proteins that cause autoantibodies is referred to as molecular mimicry ( Figure 1). Molecular mimicry between Streptococcus and the heart reveals a cross-reactive antibody that recognizes several types of epitopes found on Streptococcus M-protein and protein found on heart valves.⁸^,⁹ In the latest development, the concept of “neo-antigen” theory emerged and explains that GAS gained access to the sub-endothelial collagen matrix, where the peptide associated with rheumatic fever (PARF) M-protein domain binds to type IV in the CB3 region thereby creating a neo-antigen that can induce an autoimmune response against collagen.¹⁰^,¹¹ Both molecular mimicry and neo-antigen theories are still being further researched, however, repeated ARF will cause tissue scarring as a result of response to pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-12, and tumor necrosis factor-α (TNF-α) which increased when ARF occurs and ultimately causing tissue fibrosis.¹²^,¹³ Fibrosis in cardiac valves, notably the mitral valve, leads to valve regurgitation, which progresses to stenosis. Mitral regurgitation (MR) to mitral stenosis (MS) conversion is a pathognomonic sign of rheumatic heart disease (RHD).¹²^,¹⁴^,¹⁵

Figure 1. Pathogenesis of ARF in heart and related tissues.

MHC = Major Histocompatibility Complex, TCR = T-cell Receptor, IL = Interleukin, VCAM-1 = Vascular Cell Adhesion Molecule-1.

Rheumatic heart disease (RHD) is a myocardial pan-carditis and the cardiac sequela of ARF. Although ARF is self-limiting, inflammation in heart valves caused by a single or repeated episode of ARF can lead to scarring and chronic valve dysfunction.¹⁶^,¹⁷ Chronic rheumatic heart disease (RHD) is clinically identified by the occurrence of fibrinous pericarditis and interstitial granulomas or Aschoff’s nodules. These nodules consist of clusters of loose granulomas with necrosis of central fibrinoids, macrophages, B cells, and multinucleated giant cells in the myocardium. The myocardial damage caused by RHD can improve without leaving any lasting harm, nevertheless, if accompanied by valvulitis, it leads to permanent damage.¹⁸^,¹⁹ The diagnosis of carditis due to RHD based on the finding of diastolic murmur sound through auscultation at the apex of the heart is categorized as clinical carditis. Meanwhile, the establishment of carditis through echocardiography examination due to normal findings during physical examination is referred to as subclinical carditis.²⁰^,²¹ Heart valve-related RHD is the most serious clinical manifestation and has been the focus of numerous studies for the last several decades.⁹^,²²^–²⁴ In symptomatic severe valvular cases, ideally, treatment for RHD requires surgery or catheter-based treatment. Pharmacological therapy is typically employed solely to address heart failure or atrial fibrillation (AF), which often arises from valve regurgitation or stenosis related to rheumatic heart disease (RHD).²¹ For patients with severe symptomatic mitral stenosis, percutaneous mitral balloon commissurotomy (PBMC) is the main treatment of choice.²¹^,²⁵^,²⁶ PBMC treatment is a main option, particularly in low and middle-income countries, due to its lower cost compared to valve surgery and a success rate above 95%.²⁷ Nonetheless, there are several contraindications including left atrial clots or extensive calcium deposits, that render PBMC inadvisable; thus, the sole alternative is valve surgery, which is considerably more costly.²¹^,²⁶ The high cost of curative treatment for RHD arises from the absence of pharmacological treatment to address valve problems, rendering costly invasive procedures the sole alternative. Therefore, preventive measures have a vital role in efforts to reduce the global burden of RHD. RHD prevention and control is broadly divided into three parts, including primordial prevention, primary prevention, and secondary prevention.²¹^,²⁸^,²⁹ Vaccination serves as a preventive measure against ARF and RHD by providing targeted protection against GAS infection.³⁰ Therefore, vaccine development is very promising as a big step to diminish the incidence of ARF and RHD, particularly in low- and middle-income countries which have worse sanitation and socioeconomic levels than high-income countries, which ultimately affects the rate of GAS infection.

Discussion: Current Global Epidemiology of GAS, ARF, and RHD

GAS ranks among the top ten causes of infection-related death worldwide. GAS infections predominantly occur in low and middle-income (developing) nations, where factors such as overcrowding, inadequate nutrition, unsatisfactory sanitation, and substandard living conditions are believed to contribute to the widespread occurrence of GAS disease.³¹^,³² GAS is responsible for approximately 700 million cases of pharyngitis per year globally. An estimated minimum of 517,000 fatalities are attributed to severe GAS infections each year, with a minimum prevalence of 18.1 million cases and an annual increment of 1.78 million new cases. Meanwhile, the burden of invasive GAS (iGAS) cases is very high, with 600,000-663,000 new cases reported every year with a mortality rate of 25% or around 163,000 deaths per year.³²^–³⁵ Streptococcal pharyngitis is a very common infection in children. Streptococcus in susceptible hosts can trigger an abnormal inflammatory immune response due to the cross-reactivity of Streptococcal antibodies to myocardial, synovial, and basal ganglia tissue, thus becoming the main etiology of ARF. ARF which is a sequela of GAS infection primarily manifests in children and adolescents. The peak incidence of ARF is between 5 to 15 years, and it is exceedingly rare around 30 years of age. Epidemiologically, ARF occurs in all parts of the world.⁸^,³⁶ In every single year, approximately 500,000 new cases of ARF are reported worldwide.²^,³⁷ A study conducted by the World Health Organization (WHO) reveals that the total global burden of acute rheumatic fever (ARF) cases amounts to 471,000 cases annually. Among children aged 5 to 15 years old, the incidence of ARF is 10 cases per 100,000 in industrialized countries and 374 cases per 100,000 in Pacific countries.³² From an economic perspective, the financial burden of ARF is substantial; for instance, in the USA, it is estimated that the annual cost of ARF ranges from 224 to 539 million USD.⁴

Around 60% of individuals residing in endemic populations who have ARF will ultimately develop RHD. RHD is a serious consequence of inappropriate GAS infection management resulting in recurrent ARF attacks. According to the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease report, the global prevalence of RHD exceeds 40 million cases, primarily concentrated in low- and middle-income nations.³⁸ RHD has a substantial impact on the morbidity and mortality rates in low- and middle-income countries, resulting in over 300,000 deaths annually and more than 10 million disability-adjusted life years.³⁹ According to data released in 2013, the prevalence of RHD cases is 33 million, with an annual death rate of 275,000, dominated by low- and middle-income countries. The prevalence of RHD escalates with age, and the survival rate is determined upon access to and adherence to secondary prophylaxis to prevent ARF recurrence, the severity of valve damage, and the availability of specialists and surgical intervention.³²^,³⁹^,⁴⁰ The epidemiology of RHD varies in each region, the prevalence is quite high in the Pacific⁴¹ and Africa,⁴²^,⁴³ but high burden in Latin American country,⁴⁴ the Middle East,⁴⁵ and Asia.³² Meanwhile, in industrialized countries such as the USA, the incidence of RHD is exceedingly low (0.04 cases per 1000 children).⁴⁶ An estimate shows that 40% of people with RHD remain oblivious to an ARF episode, meaning they are unaware of having experienced an ARF attack. Consequently, RHD is only detected when individuals show cardiac symptoms that appear late in the disease.¹⁵^,⁴⁷ If we draw a common thread from the high prevalence, morbidity, and mortality rates of RHD, it cannot be separated from the presence of GAS infection as the main etiology of ARF. Worldwide, Group A Streptococcus (GAS) continues to exhibit sensitivity to penicillin, despite evidence indicating that penicillin has not been successful in completely eliminating GAS-related pharyngitis and tonsillitis. In addition, GAS remains susceptible to other beta-lactam antibiotics such as amoxicillin and cephalosporins.⁴⁸^,⁴⁹ Recent research has shown an uncommon mutation in penicillin-binding protein (PBP) 2B in two strains of GAS, which decreases their vulnerability to beta-lactam antibiotics.⁵⁰ This serves as a warning that GAS is progressing towards resistance against commonly administered antibiotics, such as penicillin and amoxicillin. Consequently, the most promising strategy for combating antibiotic resistance in GAS, the main etiology of ARF that can develop into RHD, development and implementation of a GAS vaccine.

GAS Vaccine Development for ARF/RHD

A vaccine for GAS would theoretically be the most cost-effective intervention in an ARF/RHD endemic country. An economic assessment carried out in the USA showed that the implementation of the vaccination program would reduce the GAS infection rate by up to 20% in all age groups, thereby saving costs of approximately 1 billion USD.⁵¹ Furthermore, the development of an effective GAS vaccine will provide several potential benefits including protection from infection and diminishing usage of antibiotics thereby reducing the rate of microbial resistance.⁵²^,⁵³ However, nowadays there is no licensed GAS vaccine, and it remains in the developmental phase. In 2018, WHO issued a roadmap from the development of the first GAS vaccine.⁵⁴ The primary obstacle in developing a successful and secure GAS vaccine has been constant in recent decades, which is the production of universally applicable vaccine candidates capable of safeguarding against both existing and future strains of GAS.⁵⁵ The result of GAS genome sequencing shows two major issues in vaccine development, namely (i) extensive genome heterogenicity of gas isolates which is the result of frequent genetic recombination events such as gene exchange and single nucleotide polymorphism (SNP), and (ii) variations in protein sequences.⁵⁶^,⁵⁷ A recent extensive genomic study showed that there are 13 candidate antigenic proteins that are conserved in more than 99% of GAS isolates found globally.¹^,⁵⁸ Several candidates are still in the safety and immunogenicity testing stage in rodents or experimental mice and rabbits, while others are beginning to enter clinical trial development on human subjects. Antigenic protein candidates are broadly classified into two groups: (i) M-protein-based candidates and (ii) non-M-protein candidates.¹^,⁵⁹^–⁶¹

M-protein is an immunodominant GAS protein encoded by the emm gene. The M-protein structure comprises a coiled-coil structure that extends 600 nm and is anchored in the bacterial cell wall.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. Consequently, M-protein significantly contributes to virulence factors by resisting opsonophagocytosis.⁶⁵^–⁶⁷ Recent investigations have shown a potential GAS vaccine candidate resulting from the development of vaccines containing the N-terminal or C-terminal domains of the M protein, or a combination thereof, demonstrating protective effectiveness against GAS infections.¹ To date, there have been three GAS vaccine candidates recorded on globaldata.com that have been tested in the clinical trials phase or are scheduled for clinical trial phase I.¹^,³³ In 2020, a phase I clinical trial was carried out using StreptAnova targeting M-protein. StreptAnova is a 30-valent vaccine candidate designed using the N-terminal peptide from 30 M-protein.¹^,⁶⁸^,⁶⁹ Individuals who received StrepAnova developed functional (opsonophagocytic) antibodies, although protection from this vaccine has not been conclusively proven in animal challenge models.⁷⁰ Meanwhile, other M-protein based vaccines such as StrepInCor contain a peptide consisting of 55 amino acids from the C-peptide region of the M protein. This region is the most conserved part among the GAS serotypes.⁷¹ StrepInCor vaccination in phase I clinical trials will begin in late 2023.³³ One of the most promising clinical trial approaches currently is the use of a combination of two synthetic peptides, namely two M-protein epitopes (modified p*17 and J8) which have been paired with an epitope of the streptococcal anti-neutrophil factor, Spy-CEP (K4S2).¹^,³³ Test results on pre-clinical models showed no cardiac or neurological pathologies so it was initiated into clinical trials in 2022. However, the primary challenge of developing an M-protein-based GAS vaccine is the potential for cross-reactivity with human tissues, particularly the myosin protein found in cardiac 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, cross-reactivity 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.⁸^,⁷⁴^–⁷⁷

The growing interest in developing GAS vaccines based on non-M protein antigens stems from a desire to avoid GAS vaccine targets that may cause autoimmunity. The development of non-M protein vaccines began in the 1990s using C5a peptidase (Streptococcal C5a protease, SCPA).⁷⁸ Apart from SCPA, other non-M protein GAS vaccine candidates include Streptolysin O (SLO), Streptococcal Pyrogenic Exotoxins, and multi-component vaccines.³³ All of these vaccine candidates are still in the pre-clinical trial testing phase. The main challenge in developing non-M protein-based vaccines is low coverage against all GAS strains globally. In addition, to achieve optimal protection against all GAS isolates, the various protein components in the vaccine must be present in all GAS isolates or strains.

Development of GAC Vaccine based on Poly-rhamnose Backbone from Group A Carbohydrate (GAC)

Structure and Biosynthesis of Group A Carbohydrate (GAC)

The surface polysaccharide known as Group A Carbohydrate (GAC) is present in all identified serotypes and is completely conserved. It is composed of repeating trisaccharide units with the main chain formed by α-1,2- and α-1,3-linked l-rhamnose (Rha) residue and a β-1,3-linked N-acetyl-d-glucosamine (GlcNAc) residue as a side chain embedded into the 3-O-position of the latter Rhamnose residue.⁵⁶^,⁷⁹^–⁸¹ The GAC component is abundant and essential in GAS cells because it forms approximately 40-60% of the mass of the cell wall which has a function in structural support as a barrier against the environment and maintaining cell morphology.⁷⁹ GAC forms covalent bonds with N-acetylmuramic acid (MurNAc) which is the main component of peptidoglycan. As previously mentioned, the GAC component is 100% conserved because all GAS serotypes express GAC which consists of a poly-rhamnose backbone with an N-acetylglucosamine (GlcNAc) side chain with repeating trisaccharide units [3) α- l-Rhap (1➔2) [β- d-GlcpNAc(1➔3) α- l-Rhap(1➔3)]_n. The backbone of GAC consists of l -rhamnose repeat units linked by α-1,3-α-1,2 glycosidic ( Figure 2).⁸²^–⁸⁵ The reported average molecular mass of GAC is 8.9 ± 1 kDa, attributed to the 18-unit repeat.⁵⁶

Figure 2. Schematic structure of Group A Carbohydrate (GAC) which embedded into peptidoglycan with extracellular presentation.

A molecular study shows the biosynthetic mechanism of GAC where the rhamnan (Rha) polymer is arranged on the cytoplasmic side of the plasma membrane and then translocated to the cell surface by the ABC transporter protein and modified by GlcNAc on the outside of the cell membrane. A lipid carrier, namely GlcNAc-P-P-Und, acts as an acceptor for the initiation of rhamnan backbone biosynthesis.⁸⁶^,⁸⁷ Recent studies show that there are 12 gene clusters that play a role in expressing various enzymes and functional proteins that play a role in the GAC biosynthesis process. A series of steps in the rhamnan biosynthesis process involve the action of glycotransferases encoded by the GacB, GacC, GacG, and GacF genes so that the rhamnan polymer that forms the backbone will become a structure commonly known as poly-rhamnose.⁸⁷^–⁸⁹ GacA is the first gene of the GAC gene cluster, but the GacA gene encodes an essential enzyme that has a function in catalysing the last step of the four steps of the dTDP-l-Rhamnose biosynthesis pathway during the production of poly-rhamnose GAC cores. Meanwhile, the GacD and GacE genes encode transporter proteins that play a role in translocation of rhamnan polymer from the cytoplasmic side of the membrane to the outer surface of the cell membrane.⁸⁰^,⁸⁸ The biosynthesis of the rhamnan backbone, a component of GAC, is essential for the viability of GAS. Anchoring of GlcNAc to the poly-rhamnose chain to form the GAC structure involves a protein encoded by the GacL gene. GlcNAc is tethered to the 2-hydroxyl of the rhamnose residue so that GlcNAc presentation leads out of the rhamnose helix.⁵⁶ Approximately 20 – 30% of the GlcNAc residues in GAC polymers contain modified components from glycerol phosphate.⁵⁶^,⁸⁴ These modifications are mainly found in the C6-hydroxyl group. The location of the GAC polymer is located on the outer surface of the GAS cell wall and is highly conserved among GAS strains which makes GAC interesting polysaccharide component of glycoconjugate vaccines.⁷⁹^,⁸⁹

GAC Role Towards GAS Virulence

A known mutant group A streptococcus without the presence of GlcNAc has susceptibility to leukocytes, including neutrophils that show much greater binding ability to bacteria. This is caused by cathelicidin, which is a human peptide defence, which has a higher affinity for mutant polysaccharides.⁸³^,⁹⁰ Furthermore, the absence of GlcNAc has a major influence because GlcNAc has a function in reducing the binding of cationic bactericidal enzyme human Group IIA.⁸⁴^,⁸⁸^,⁹¹ Therefore, the GlcNAc side chain is the most important virulence determinant in GAS. The polysaccharide branch consisting of rhamnose and GlcNAc side chains has shown immunogenic capabilities that have been demonstrated through rabbit and human antisera, nuclear magnetic resonance (NMR) techniques demonstrating the interaction of GAC with mAb and computer simulations.⁸² The GlcNAc side chain is predicted to have a key role in the evasion of the human immune system. The GlcNAc side chain of GAC contributes to resistance to innate immunity and the virulence phenotype of globally distributed GAS strains. In GAS serotype M1, the absence of GlcNAc results in significantly reduced survival in the blood of humans and animals modelled for infection.⁹² Meanwhile, in GAS serotype M3, the GlcNAc side chain is required to enhancing survival in human blood through platelet release.⁸³ The characteristics of resistance to neutrophil killing in GAS are more conserved in GAS strains M1, M2, M3, and M4 with the GlcNAc side chain of GAC.⁴⁸^,⁸³^,⁹²

Immunogenicity of GAC

A study conducted by Sabharwal et al. demonstrated that GAC is immunogenic and protective against GAS infection. In addition, antibodies against the presence of GAC in human serum are highly opsonic against various M-protein serotypes of GAS and are not cross-reactive against human tissues.⁹³^,⁹⁴ Another study conducted by Pinto et al. also showed that the size and orientation of the antigenic epitope of GAC are crucial parameters for recognition by both monoclonal and polyclonal antibodies so that antibodies induced by GAC-based vaccines will effectively recognize epitopes on the surface of GAS cell walls.⁹⁵ Both Pinto and Kabanova et al. simultaneously demonstrated that the repeat unit of GAC is an optimum epitope when used as a vaccine component to elicit an adequate immune response against GAS infection.⁹⁵^,⁹⁶ Meanwhile, Wang and colleagues showed that three repeat units in the GAC structure conjugated to the inactive form of group A streptococcal C5a peptidase (ScpA193) showed efficient and feasible results if developed as a vaccine against GAS infection.⁹⁴ However, several studies in pre-clinical studies show evidence that antibodies formed from pure GlcNAc-based GAC vaccines have autoimmunity capabilities due to cross-reaction with cardiac myosin protein.⁹⁷^–¹⁰⁰ The study conducted by Galvin et al. found that monoclonal antibodies derived from patients with rheumatic carditis and arthritis were cross-reacted to GlcNAc from GAC residues.¹⁰¹^,¹⁰² Antibodies that recognize GlcNAc from GAC residues are the main cause of major clinical neuronal disorders from acute rheumatic fever such as Sydenham chorea. This is confirmed by an in-vivo study conducted by Brimberg et al. used a mouse model that demonstrated the presence of streptococcal antibodies deposited in the frontal cortex, striatum, and thalamus.¹⁰³ Therefore, the utilization of the GlcNAc component from GAC residues in vaccine development will face the same challenges as developing an M-protein-based GAS vaccine, namely the presence of cross-reactivity that can arise against human body tissue.

A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells.¹⁰⁴ As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory.¹⁰⁵ Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs).¹⁰⁶ An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination’s effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself.¹⁰⁶^–¹⁰⁸ The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection.¹⁰⁵ Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines.¹⁰⁹

Rhamnose-based GAS Vaccine from GAC Backbone

l-Rhamnose (Rha) is a deoxy sugar due to the hydroxyl group on one of the carbon atoms of the sugar carbon chain is replaced with a hydrogen atom.⁸¹^,¹¹⁰ Rhamnose is very common in bacteria and plants. Rhamnose is an essential monomer for pathogenic bacteria because it is the main component of cell walls and capsules which has a vital role in virulence and bacterial survival.⁸³^,¹¹¹ l-Rhamnose is synthesized by bacteria from glucose-1-phosphate (Glu-1-P) which acts as a precursor through the enzyme glucose-1-phosphate thymidylyltransferase (RmlA) which catalyses the transfer process of thymidyl monophosphate nucleotide to Glu-1-P.⁸⁶ Afterward, the enzyme dTDP-d-glucose 4,6-dehydratase (RmlB) catalyses the deoxidation process of the hydroxyl group on C4 of the sugar ring followed by dehydration (release of H₂O). The third enzyme, namely dTDP-6-deoxy- d-xylo-4-hexulose 3,5-epimerase (RmlC), catalyses the double epimerization reaction at the C3 and C3 positions of the sugar ring. Next, the final step, namely the enzyme dTDP-6-deoxy- d-xylo-4-hexulose reductase (RmlD) reduces the keto function on C4 to form the final product, namely dTDP-l-Rhamnose or what is usually called rhamnose (Rha).⁸⁷^,¹¹¹^,¹¹² Entire multiple steps of rhamnose biosynthesis are absent in mammalian cells. To date, neither rhamnose nor the genes responsible for biosynthesis have been found in mammals, especially humans.¹¹³^,¹¹⁴ Rhamnose, which is the main component forming the GAC backbone of GAS in the form of poly-rhamnose, whose absence in mammalian cells is a very attractive candidate for the development of a universal GAS vaccine. Considering that the rhamnose biosynthesis pathway is very widespread and conserved in both Gram-positive and Gram-negative bacteria, as well as its absence in mammalian cells, rhamnose or poly-rhamnose-based GAS vaccines will have high protection coverage against various GAS serotypes without causing cross-reactivity in human body tissues.

A study conducted by van Sorge et al. who injected poly-rhamnose (GlcNAc-deficient GAC) showed a significant reduction in binding to human monoclonal antibodies obtained from patients with rheumatic carditis. Furthermore, extensive pre-clinical studies by van Sorge et al. using mouse and rabbit models of GAS infection showed that poly-rhamnose backbone injection increased GAC antibodies which promoted opsonophagocytic killing in multiple GAS serotypes ( Figure 3).⁹²

Figure 3. Protective mechanism toward GAS infection by vaccine-mediated IgG by Rhamnose-based vaccine.

IgG antibodies formed against poly-rhamnose are able to provide passive protection of the murine system against various GAS strains and induce opsonophagocytic activity against the M1 strain as well as eight other strains.⁸⁰^,⁹² Recently, a glycoconjugate vaccine has been further developed which grafts synthetic tetra- and hexa-rhamnoside from the GAC backbone onto gold nanoparticles as a vaccine delivery platform.¹¹⁵ Through the vaccine delivery platform, effectiveness and efficacy will increase significantly. Therefore, the rhamnose component is very promising in the development of a safe and effective GAS vaccine. These findings align with an in-vivo investigation performed by Khatun et al., 2021, which included six groups of C57BL/6 mice. According to the immunogenicity study following the third boost, the titer level of antigen-specific IgG was markedly elevated in the intervention control compared to the group that got a phosphate-buffered saline (PBS) injection in the controlled group. Additionally, the safety assessment in this study with 1% dimethyl sulfoxide (DMSO) revealed no adverse reactions, while the application of 10% DMSO in this in-vivo experiment demonstrated it to be non-immunogenic and non-cross reactive with self-tissues.⁹⁵ An investigation conducted by Michael et al. in 2018 utilized rhamnan polysaccharide-based glycoconjugates on New Zealand white female rabbits (received 50 μg injection of conjugate with incomplete freuds adjuvant) showing a binding activity of the post-immune serum in immunofluorescence experiments, comparing pre- and post-immune serum (D70) from rabbit RRHV3. Further, the sera from serotype k conjugate-derived animals demonstrated significant killing of homologous k bacteria at elevated titers in comparison to the control sera from protein and admixed controls. The sera from serotype f conjugate-derived mice showed a rise in opsonophagocytic titer, indicating deceased of the homologous serotype strain from pre- to post-immune sera.¹¹⁶ Research conducted by Sowmya et al. used recombinant poly-rhamnose backbone (pRha) carried using a carrier in the form of outer membrane vesicles (OMVs) from Escherichia coli bacteria to investigate immunogenicity and efficacy in animal models. The results of this study showed that pRha-OMVs induced specific antibodies that could recognize GAC from Streptococcus pyogens and Streptococcus dysgalactiae subsp. Equisimilis.¹¹⁷ An increase in IgG antibody titer correlates with increased bactericidal killing in the hypervirulent GAS strain M89. Aside from that, the increase in IL-17a in the study’s results indicated that long-term memory immune cells were stimulated after administration of the pRha-OMVs vaccine.¹¹⁷ Furthermore, regarding the safety level of the vaccine, in this study, there was no mention of any cross-reactivity to animal tissue which has been a challenge in the development of GAS vaccines. Over the last few decades, several studies have been conducted to further identify the effectiveness and safety level of rhamnose or poly-rhamnose-based vaccines from GAC ( Table 1).

Table 1. Rhamnose (Rha) Based GAS Vaccine from GAC Backbone in Pre-clinical Studies.

Author(s)	Year	Subject	Duration of Treatment	Outcome(s)	Cross-reactivity/Autoimmunity	Reference(s)
Nina M. van Sorge et al.	2014	Rabbits and mice	1 week	Stimulate an immunological response that facilitates the opsonophagocytic and immune elimination of several strains of GAS. The resulting antiserum exhibited a remarkably high sensitivity towards the immunizing antigen. The IgG effectively bound to functional wild-type M1 GAS microorganisms, as well as GAS serotypes from 7 other commonly related illness serotypes, enabling neutrophils to eliminate the bacteria. In comparison to an antiserum reactive against wild type, it enhanced the process of neutrophil phagocytosis caused by opsonization and provided immunological passive protection.	None	⁹²
Farjana Khatun et al.	2021	Pathogen free C57BL/6 mice (female, 4 – 6 weeks old)	42 days	Poly-rhamnose-specific IgG antibodies protected mice from the heterologous M49 GAS serotype and elicited phagocytosis activity induced by opsonization against nine distinctive GAS strains.	None	⁹⁵
Sowmya Ajay Castro et al.	2021	Female C57BL/6J mice aged 5 – 6 weeks old.	49 days	Poly-rhamnose (pRha)-containing outer membrane vesicles have been demonstrated to stimulate IgG antibody production. Flow cytometry data revealed that antibody accumulation was significantly higher in blood samples of animals immunized with poly-Rhamnose-OMVs than in control immunized animals. ELISA tests revealed that pRha-OMVs sera recognize Group A Streptococcus strains, including the favored clade M1T1 (a new S. pyogenes emm1 lineage).	None	¹¹⁷
Olimpia Pitirollo et al.	2023	Female CD1 mice aged 5 weeks old and New Zealand White rabbits Crl:KBL, female	28 days for mice and 35 days for rabbits	The poly-Rha conjugate elicited higher anti-poly-Rha IgG responses in mice and rabbits than the GAC (contained GlcNAc) conjugate.	None	⁸²
Nina J. Gao et al.	2021	New Zealand White Rabbit and wild-type female CD-1 mice	42 days for mice and 35 days for rabbits	Immunization of New Zealand White rabbits was performed for six of eight strains, the GAS surface binding of antiserum rising towards the GAC-modified vaccine (contained poly-rhamnose only) roughly doubled the amounts of immunoglobulin G binding seen with antiserum raised towards non-modified vaccine. Flow cytometry revealed a 100-400% increase in IgG binding to eight existing wild-type GAS strains of various M protein serotypes (M1, M2, M3, M4, M5, M6, M12, M28). In mice, the triple combination vaccine of GAC-modified vaccine + C5a peptidase + SLO provided remarkable 100% protection towards the lethal challenge. In contrast, injection of GAC modified vaccine alone increases protection by 20%.	None	⁸⁰
Tania Rivera-Hernandez et al.	2016	A group of BALB/c rats and A group of transgenic humanized plasminogen rats heterozygous for the human plasminogen gene (AlbPLG1)	28 days	According to ELISA, the response to antigen (GAC lacking GlcNAc) was significantly higher in vaccinated mice than in sham-immunized control mice in both BALB/c mice and transgenic humanized plasminogen mice. Furthermore, vaccinated mice had higher IgG levels for the GAC backbone than control mice. GAS clearance by 60% executing evasive bactericidal assay in mouse skin challenge.	None	¹¹⁸
Anna Kabanova et al.	2010	A group of CD-1 rats (Female, 5 – 6 weeks old)	35 days	Mice vaccinated and challenged with the M1 serotype had significantly reduced mortality (p-value 0.05) than control mice vaccinated with alum alone, with survival rates ranging from 29% to 50%. IgG antibodies were generated and able to bind to the GAS.	None	⁹⁶

A limitation of this research is that the data presented are derived from pre-clinical trial trials. The effectiveness of the L-Rhamnose-based vaccination utilizing the GAC backbone in enhancing human antibody titers against GAS bacteria remains inconclusive. This pertains to the development of a GAS vaccine originating from a non-M protein derivative, which remains confined to pre-clinical research and has not yet undergone official testing on human beings. Moreover, the scarcity of recent data, particularly research conducted in the past two years on L-rhamnose-based vaccines, has compelled the authors to seek data spanning the last decade or more to present substantial variations in effectiveness and safety regarding the use of L-rhamnose as a vaccine against GAS infection. The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition. This is reasonable as the author(s) seeks an extensive discourse from diverse credible sources, unrestricted by publication date, to facilitate a thorough analysis. Therefore, a flexible method is able to give various data to generate a deep review discussion. This paper represents the inaugural effort to exclusively discuss and synthesize diverse research findings regarding the efficacy and safety of L-rhamnose-based vaccines, which may serve as a significantly safer vaccine for Group A Streptococcus (GAS), given the minimal cross-reactivity resulting from the absence of rhamnose components in mammalian tissues, particularly in humans. This paper can advance research to the next stage, specifically enabling the prompt consideration and implementation of clinical trials on humans.

Conclusion

The Group A Streptococcus (GAS) vaccine based on l-Rhamnose obtained from the poly-rhamnose backbone Group A Carbohydrate (GAC) has shown a protective effect against GAS infection which has been proven through pre-clinical studies which show an increase in IgG antibody titers facilitating and improving opsonophagocytic ability against various GAS strains. In addition, various recent studies have shown that the use of Rhamnose-based vaccines does not show any cross-reactivity in test animal tissue thus the vaccine is able to provide protection against GAS infection without causing ARF attacks due to the absence of cross-reactive antibodies. These findings demonstrate that the l-Rhamnose-based vaccine possesses strong immunogenicity, which effectively protects against GAS infection while maintaining a significantly higher degree of safety. Prevention of GAS infection through effective vaccination will provide protection against ARF attacks and its sequelae, namely RHD, which has become a global burden both in terms of epidemiology and management costs, especially in low- and middle-income countries.

Data availability statement

No data are associated with this article.

References

1. Ajay Castro S, Dorfmueller HC: Update on the development of Group A Streptococcus vaccines. NPJ Vaccines. 2023 Sep 14; 8(1): 135. PubMed Abstract | Publisher Full Text | Free Full Text
2. Webb RH, Grant C, Harnden A: Acute rheumatic fever. BMJ. 2015 Jul 14; 351: h3443. Publisher Full Text
3. Kumar D, Bhutia E, Kumar P: Evaluation of the American Heart Association 2015 revised Jones criteria versus existing guidelines. Heart Asia. 2016 Feb 29; 8(1): 30–35. PubMed Abstract | Publisher Full Text | Free Full Text
4. Burke RJ, Chang C: Diagnostic criteria of acute rheumatic fever. Autoimmun. Rev. 2014 Apr; 13(4-5): 503–507. Publisher Full Text
5. Zühlke LJ, Beaton A, Engel ME, et al.: Group A Streptococcus, Acute Rheumatic Fever and Rheumatic Heart Disease: Epidemiology and Clinical Considerations. Curr. Treat. Options Cardiovasc. Med. 2017 Feb 11; 19(2): 15. PubMed Abstract | Publisher Full Text | Free Full Text
6. Gewitz MH, Baltimore RS, Tani LY, et al.: Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography. Circulation. 2015 May 19; 131(20): 1806–1818. PubMed Abstract | Publisher Full Text
7. Cunningham MW: Streptococcus and rheumatic fever. Curr. Opin. Rheumatol. 2012 Jul; 24(4): 408–416. PubMed Abstract | Publisher Full Text | Free Full Text
8. Cunningham MW: Rheumatic fever, autoimmunity, and molecular mimicry: The streptococcal connection. Int. Rev. Immunol. 2014 Jul 4; 33(4): 314–329. Publisher Full Text
9. Tandon R, Sharma M, Chandrashekhar Y, et al.: Revisiting the pathogenesis of rheumatic fever and carditis. Nat. Rev. Cardiol. 2013 Mar 15; 10(3): 171–177. PubMed Abstract | Publisher Full Text
10. Watkins DA, Beaton AZ, Carapetis JR, et al.: Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel. J. Am. Coll. Cardiol. 2018 Sep 18; 72(12): 1397–1416. Publisher Full Text
11. Williamson DA, Smeesters PR, Steer AC, et al.: M-protein analysis of streptococcus pyogenes isolates associated with acute rheumatic fever in New Zealand. J. Clin. Microbiol. 2015 Nov; 53(11): 3618–3620. PubMed Abstract | Publisher Full Text | Free Full Text
12. Ambari AM, Setianto B, Santoso A, et al.: Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Front. Cardiovasc. Med. 2020 Jul 28; 7. PubMed Abstract | Publisher Full Text | Free Full Text
13. Tsatsaronis JA, Walker MJ, Sanderson-Smith ML: Host Responses to Group A Streptococcus: Cell Death and Inflammation. PLoS Pathog. 2014 Aug 28; 10(8): e1004266. PubMed Abstract | Publisher Full Text | Free Full Text
14. Wunderlich NC, Dalvi B, Ho SY, et al.: Rheumatic Mitral Valve Stenosis: Diagnosis and Treatment Options. Curr. Cardiol. Rep. 2019 Mar 28; 21(3): 14. PubMed Abstract | Publisher Full Text
15. Roberts K, Colquhoun S, Steer A, et al.: Screening for rheumatic heart disease: Current approaches and controversies. Nat. Rev. Cardiol. 2013 Jan 13; 10(1): 49–58. PubMed Abstract | Publisher Full Text
16. Dooley LM, Ahmad TB, Pandey M, et al.: Rheumatic heart disease: A review of the current status of global research activity. Autoimmun. Rev. 2021 Feb; 20(2): 102740. PubMed Abstract | Publisher Full Text
17. Woldu B, Bloomfield GS: Rheumatic Heart Disease in the Twenty-First Century. Curr. Cardiol. Rep. 2016 Oct 27; 18(10): 96. PubMed Abstract | Publisher Full Text | Free Full Text
18. Yanagawa B, Butany J, Verma S: Update on rheumatic heart disease. Curr. Opin. Cardiol. 2016 Mar; 31(2): 162–168. Publisher Full Text
19. Ali R: A Study on Rheumatic Fever. Int. J. Res. Anal. Rev. 2018; 5(4): 203–210.
20. Zühlke L, Mayosi BM: Echocardiographic screening for subclinical rheumatic heart disease remains a research tool pending studies of impact on prognosis. Curr. Cardiol. Rep. 2013 Mar 22; 15(3): 343. PubMed Abstract | Publisher Full Text
21. Dougherty S, Okello E, Mwangi J, et al.: Rheumatic Heart Disease. J. Am. Coll. Cardiol. 2023 Jan; 81(1): 81–94. Publisher Full Text
22. Van Hagen IM, Thorne SA, Taha N, et al.: Pregnancy outcomes in women with rheumatic mitral valve disease: Results from the registry of pregnancy and cardiac disease. Circulation. 2018 Feb 20; 137(8): 806–816. Publisher Full Text
23. Kumar R, Sharma YP, Thakur JS, et al.: Streptococcal pharyngitis, rheumatic fever and rheumatic heart disease: Eight-year prospective surveillance in Rupnagar district of Punjab, India. Natl. Med. J. India. 2014; 27(2): 70–75. PubMed Abstract
24. Carapetis JR: The stark reality of rheumatic heart disease. Eur. Heart J. 2015 May 2; 36(18): 1070–1073. PubMed Abstract | Publisher Full Text
25. Yingchoncharoen T: Rheumatic Mitral Valve Disease. An Atlas of Mitral Valve Imaging. London: Springer; 2015; pp. 69–87. Publisher Full Text
26. Motiwala SR, Delling FN: Assessment of Mitral Valve Disease: A Review of Imaging Modalities. Curr. Treat. Options Cardiovasc. Med. 2015 Jul 19; 17(7): 30. Publisher Full Text
27. Nunes MCP, Nascimento BR, Lodi-Junqueira L, et al.: Update on percutaneous mitral commissurotomy. Heart. 2016 Apr 1; 102(7): 500–507. PubMed Abstract | Publisher Full Text
28. Ali SKM, Engel ME, Zühlke L, et al.: Primary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease. Acute Rheumatic Fever and Rheumatic Heart Disease. Elsevier; 2021; pp. 195–206. Publisher Full Text
29. Shimanda PP, Shumba TW, Brunström M, et al.: Preventive interventions to reduce the burden of rheumatic heart disease in populations at risk: a systematic review protocol. Syst. Rev. 2021 Dec 8; 10(1): 200. PubMed Abstract | Publisher Full Text | Free Full Text
30. Guilherme L, Ferreira FM, Köhler KF, et al.: A vaccine against streptococcus pyogenes: The potential to prevent rheumatic fever and rheumatic heart disease. Am. J. Cardiovasc. Drugs. 2013 Feb; 13(1): 1–4. Publisher Full Text
31. Ralph AP, Carapetis JR: Group A Streptococcal Diseases and Their Global Burden.2012; pp. 1–27.
32. Carapetis JR, Steer AC, Mulholland EK, et al.: The global burden of group A streptococcal diseases. Lancet Infect. Dis. 2005 Nov; 5(11): 685–694. PubMed Abstract | Publisher Full Text
33. Castro SA, Dorfmueller HC: A brief review on Group A Streptococcus pathogenesis and vaccine development. R. Soc. Open Sci. 2021 Mar 10; 8(3): rsos.201991. PubMed Abstract | Publisher Full Text | Free Full Text
34. Sanyahumbi AS, Colquhoun S, Wyber R, et al.: Global disease burden of group A Streptococcus. Streptococcus pyogenes: basic biology to clinical manifestations [Internet]. 2016.
35. Barnett TC, Bowen AC, Carapetis JR: The fall and rise of Group A Streptococcus diseases. Epidemiol. Infect. 2019 Aug 15; 147: e4. PubMed Abstract | Publisher Full Text | Free Full Text
36. Lawrence JG, Carapetis JR, Griffiths K, et al.: Acute Rheumatic Fever and Rheumatic Heart Disease. Circulation. 2013 Jul 30; 128(5): 492–501. Publisher Full Text
37. Zühlke LJ, Steer AC: Estimates of the global burden of rheumatic heart disease. Glob. Heart. 2013 Sep 1; 8(3): 189. Publisher Full Text
38. Roth GA, Mensah GA, Johnson CO, et al.: Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol. 2020; 76(25): 2982–3021. PubMed Abstract | Publisher Full Text | Free Full Text
39. James SL, Abate D, Abate KH, et al.: Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov; 392(10159): 1789–1858. PubMed Abstract | Publisher Full Text | Free Full Text
40. Roth GA, Abate D, Abate KH, et al.: Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov; 392(10159): 1736–1788. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source
41. Ledos PH, Kamblock J, Bourgoin P, et al.: Prevalence of rheumatic heart disease in young adults from New Caledonia. Arch. Cardiovasc. Dis. 2015 Jan; 108(1): 16–22. PubMed Abstract | Publisher Full Text
42. Beaton A, Okello E, Lwabi P, et al.: Echocardiography screening for rheumatic heart disease in ugandan schoolchildren. Circulation. 2012 Jun 26; 125(25): 3127–3132. PubMed Abstract | Publisher Full Text
43. Zühlke LJ, Engel ME, Watkins D, et al.: Incidence, prevalence and outcome of rheumatic heart disease in South Africa: A systematic review of contemporary studies. Int. J. Cardiol. 2015 Nov; 199: 375–383. PubMed Abstract | Publisher Full Text
44. Bocchi A: Heart Failure in South America. Curr. Cardiol. Rev. 2013 May 1; 9(2): 147–156. PubMed Abstract | Publisher Full Text | Free Full Text
45. Elamrousy DM, Al-Asy H, Mawlana W: Acute Rheumatic Fever In Egyptian Children: A 30-Year Experience in a Tertiary Hospital. J. Pediatr. Sci. 2014 Jul 6; 6(0). Publisher Full Text
46. Beaudoin A, Edison L, Introcaso CE, et al.: Acute Rheumatic Fever and Rheumatic Heart Disease Among Children — American Samoa, 2011–2012. MMWR Morb. Mortal Wkly Rep. 2015; 64(20): 555–558. PubMed Abstract | Free Full Text
47. Sliwa K, Carrington M, Mayosi BM, et al.: Incidence and characteristics of newly diagnosed rheumatic heart disease in Urban African adults: Insights from the Heart of Soweto Study. Eur. Heart J. 2010 Mar 2; 31(6): 719–727. PubMed Abstract | Publisher Full Text
48. Walker MJ, Barnett TC, McArthur JD, et al.: Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin. Microbiol. Rev. 2014 Apr; 27(2): 264–301. PubMed Abstract | Publisher Full Text | Free Full Text
49. Shulman ST, Bisno AL, Clegg HW, et al.: Clinical practice guideline for the diagnosis and management of group a streptococcal pharyngitis: 2012 update by the infectious diseases society of America. Clin. Infect. Dis. 2012 Nov 15; 55(10): 1279–1282. PubMed Abstract | Publisher Full Text
50. Vannice KS, Ricaldi J, Nanduri S, et al.: Streptococcus pyogenes pbp2x mutation confers reduced susceptibility to β-lactam antibiotics. Clin. Infect. Dis. 2020 Jun 24; 71(1): 201–204. PubMed Abstract | Publisher Full Text | Free Full Text
51. Andrejko K, Whittles LK, Lewnard JA: Health-Economic Value of Vaccination Against Group A Streptococcus in the United States. Clin. Infect. Dis. 2022 Mar 23; 74(6): 983–992. PubMed Abstract | Publisher Full Text
52. Jansen KU, Knirsch C, Anderson AS: The role of vaccines in preventing bacterial antimicrobial resistance. Nat. Med. 2018 Jan 1; 24(1): 10–19. Publisher Full Text
53. Cannon JW, Jack S, Wu Y, et al.: An economic case for a vaccine to prevent group A streptococcus skin infections. Vaccine. 2018 Nov; 36(46): 6968–6978. PubMed Abstract | Publisher Full Text
54. Vekemans J, Gouvea-Reis F, Kim JH, et al.: The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics. Clin. Infect. Dis. 2019; 69(5): 877–883. PubMed Abstract | Publisher Full Text | Free Full Text
55. Henningham A, Gillen CM, Walker MJ: Group A Streptococcal Vaccine Candidates: Potential for the Development of a Human Vaccine. Curr. Top. Microbiol. Immunol. 2012 Dec 19; 368: 207–242. PubMed Abstract | Publisher Full Text
56. Burns K, Dorfmueller HC, Wren BW, et al.: Progress towards a glycoconjugate vaccine against Group A Streptococcus. NPJ Vaccines. 2023 Mar; 8(1): 48. PubMed Abstract | Publisher Full Text | Free Full Text
57. Davies MR, McIntyre L, Mutreja A, et al.: Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics. Nat. Genet. 2019 Jun 27; 51(6): 1035–1043. PubMed Abstract | Publisher Full Text | Free Full Text
58. Sharma A, Arya DK, Sagar V, et al.: Identification of potential universal vaccine candidates against group a streptococcus by using high throughput in silico and proteomics approach. J. Proteome Res. 2013 Jan 4; 12(1): 336–346. PubMed Abstract | Publisher Full Text
59. Good MF, Pandey M, Batzloff MR, et al.: Strategic development of the conserved region of the M protein and other candidates as vaccines to prevent infection with group A streptococci. Expert Rev. Vaccines. 2015 Nov 2; 14(11): 1459–1470. PubMed Abstract | Publisher Full Text
60. Dale JB, Smeesters PR, Courtney HS, et al.: Structure-based design of broadly protective group a streptococcal M protein-based vaccines. Vaccine. 2017 Jan; 35(1): 19–26.
61. Mcmillan DJ, Drèze PA, Vu T, et al.: Updated model of group A Streptococcus M proteins based on a comprehensive worldwide study. Clin. Microbiol. Infect. 2013 May; 19(5): E222–E229. PubMed Abstract | Publisher Full Text | Free Full Text
62. Tsai JYC, Loh JMS, Clow F, et al.: The Group A Streptococcus serotype M2 pilus plays a role in host cell adhesion and immune evasion. Mol. Microbiol. 2017 Jan 14; 103(2): 282–298. PubMed Abstract | Publisher Full Text
63. Brahmadathan NK: Molecular Biology of Group A Streptococcus and its Implications in Vaccine Strategies. Indian J. Med. Microbiol. 2017 Apr; 35(2): 176–183. PubMed Abstract | Publisher Full Text
64. Aranha MP, Penfound TA, Salehi S, et al.: Design of Broadly Cross-Reactive M Protein–Based Group A Streptococcal Vaccines. J. Immunol. 2021 Aug 15; 207(4): 1138–1149. PubMed Abstract | Publisher Full Text | Free Full Text
65. Mills JO, Ghosh P: Nonimmune antibody interactions of group a streptococcus M and M-like proteins. PLoS Pathog. 2021 Feb 25; 17(2): e1009248. PubMed Abstract | Publisher Full Text | Free Full Text
66. Buffalo CZ, Bahn-Suh AJ, Hirakis SP, et al.: Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein. Nat. Microbiol. 2016 Sep 5; 1(11): 16155. PubMed Abstract | Publisher Full Text | Free Full Text
67. Rivera-Hernandez T, Rhyme MS, Cork AJ, et al.: Vaccine-induced th1-type response protects against invasive group a Streptococcus infection in the absence of opsonizing antibodies. ASM Journals. 2020 Apr 28; 11(2).
68. Dai C, Khalil ZG, Hussein WM, et al.: Opsonic activity of conservative versus variable regions of the group a streptococcus M protein. Vaccines (Basel). 2020 May 7; 8(2): 210. Publisher Full Text
69. Wang J, Ma C, Li M, et al.: Streptococcus pyogenes: Pathogenesis and the Current Status of Vaccines. Vaccines (Basel). 2023 Sep 21; 11(9): 1510. PubMed Abstract | Publisher Full Text | Free Full Text
70. Guilherme L, Branco CE, De Barros SF, et al.: Rheumatic fever: From pathogenesis to vaccine perspectives. Translational Autoimmunity. Advances in Autoimmune Rheumatic Diseases. Vol. 6. Elsevier; 2023; pp. 47–59. Publisher Full Text
71. Harbison-Price N, Rivera-Hernandez T, Osowicki J, et al.: Current Approaches to Vaccine Development of Streptococcus pyogenes Introduction and Historical Perspective.2022.
72. Pastural É, McNeil SA, MacKinnon-Cameron D, et al.: Safety and immunogenicity of a 30-valent M protein-based group a streptococcal vaccine in healthy adult volunteers: A randomized, controlled phase I study. Vaccine. 2020 Feb; 38(6): 1384–1392. PubMed Abstract | Publisher Full Text
73. Spencer JA, Penfound T, Salehi S, et al.: Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes. Vaccine. 2021 Mar; 39(12): 1773–1779. PubMed Abstract | Publisher Full Text | Free Full Text
74. Carapetis JR, Beaton A, Cunningham MW, et al.: Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Prim. 2016 Jan 14; 2(1): 15084. PubMed Abstract | Publisher Full Text | Free Full Text
75. Guilherme L, Steer AC, Cunningham M: Pathogenesis of Acute Rheumatic Fever. Acute Rheumatic Fever and Rheumatic Heart Disease. Elsevier; 2021; pp. 19–30. Publisher Full Text
76. Cunningham MW: Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive Antigens of Group A Streptococci and their Sequelae. Microbiol Spectr. 2019 Jul 19; 7(4). PubMed Abstract | Publisher Full Text | Free Full Text
77. Aranha MP, Penfound TA, Spencer JA, et al.: Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M protein-derived peptides. J. Biol. Chem. 2020 Mar; 295(12): 3826–3836. PubMed Abstract | Publisher Full Text | Free Full Text
78. Brouwer S, Rivera-Hernandez T, Curren BF, et al.: Pathogenesis, epidemiology and control of Group A Streptococcus infection. Nat. Rev. Microbiol. 2023 Jul 9; 21(7): 431–447. Publisher Full Text
79. Rush JS, Edgar RJ, Deng P, et al.: The molecular mechanism of N-acetylglucosamine side-chain attachment to the Lancefield group A carbohydrate in Streptococcus pyogenes. J. Biol. Chem. 2017 Nov; 292(47): 19441–19457. PubMed Abstract | Publisher Full Text | Free Full Text
80. Gao NJ, Uchiyama S, Pill L, et al.: Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine. Infect. Microbes Dis. 2021 Jun; 3(2): 87–100. Publisher Full Text
81. Kampff Z, van Sinderen D, Mahony J: Cell wall polysaccharides of streptococci: A genetic and structural perspective. Biotechnol. Adv. 2023 Dec; 69: 108279. PubMed Abstract | Publisher Full Text
82. Pitirollo O, Di Benedetto R, Henriques P, et al.: Elucidating the role of N-acetylglucosamine in Group A Carbohydrate for the development of an effective glycoconjugate vaccine against Group A Streptococcus. Carbohydr. Polym. 2023 Jul; 311: 120736. Publisher Full Text
83. Henningham A, Davies MR, Uchiyama S, et al.: Virulence role of the glcnac side chain of the lancefield cell wall carbohydrate antigen in non-m1-serotype group a streptococcus. mBio. 2018 Jan 30; 9(1). PubMed Abstract | Publisher Full Text | Free Full Text
84. Edgar RJ, van Hensbergen VP , Ruda A, et al.: Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nat. Chem. Biol. 2019 May 1; 15(5): 463–471. PubMed Abstract | Publisher Full Text | Free Full Text
85. Rohokale R, Guo Z: Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines. ACS Infect. Dis. 2023 Feb 10; 9(2): 178–212. PubMed Abstract | Publisher Full Text | Free Full Text
86. Zorzoli A, Meyer BH, Adair E, et al.: Group A, B, C, and G Streptococcus Lancefield antigen biosynthesis is initiated by a conserved α-D-GlcNAc-β-1,4-L-rhamnosyltransferase. J. Biol. Chem. 2019 Oct; 294(42): 15237–15256. PubMed Abstract | Publisher Full Text | Free Full Text
87. Mistou MY, Sutcliffe IC, Van Sorge NM: Bacterial glycobiology: Rhamnose-containing cell wall polysaccharides in gram-positive bacteria. FEMS Microbiol. Rev. 2016 Jul; 40(4): 464–479. PubMed Abstract | Publisher Full Text | Free Full Text
88. Gao NJ, Lima ER, Nizet V: Immunobiology of the Classical Lancefield Group A Streptococcal Carbohydrate Antigen. Infect. Immun. 2021 Nov 16; 89(12). Reference Source
89. Rush JS, Zamakhaeva S, Murner NR, et al.: Structure and mechanism of biosynthesis of Streptococcus mutans cell wall polysaccharide. bioRxiv. 2024 May 9.
90. Shelburne SA, Keith D, Horstmann N, et al.: A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus. Proc. Natl. Acad. Sci. 2008 Feb 5; 105(5): 1698–1703.
91. van Hensbergen VP , Movert E, de Maat V , et al.: Streptococcal Lancefield polysaccharides are critical cell wall determinants for human Group IIA secreted phospholipase A2 to exert its bactericidal effects. PLoS Pathog. 2018 Oct 15; 14(10): e1007348. Publisher Full Text
92. Van Sorge NM, Cole JN, Kuipers K, et al.: The classical lancefield antigen of group A Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe. 2014 Jun; 15(6): 729–740. PubMed Abstract | Publisher Full Text
93. Sabharwal H, Michon F, Nelson D, et al.: Group A Streptococcus (GAS) Carbohydrate as an Immunogen for Protection against GAS Infection. J. Infect. Dis. 2006 Jan; 193(1): 129–135. Publisher Full Text https://academic.oup.com/jid/article/193/1/129/863942
94. Wang S, Zhao Y, Wang G, et al.: Group A Streptococcus Cell Wall Oligosaccharide-Streptococcal C5a Peptidase Conjugates as Effective Antibacterial Vaccines. ACS Infect. Dis. 2020 Feb 14; 6(2): 281–290. PubMed Abstract | Publisher Full Text
95. Khatun F, Dai CC, Rivera-Hernandez T, et al.: Immunogenicity Assessment of Cell Wall Carbohydrates of Group A Streptococcus via Self-Adjuvanted Glyco-lipopeptides. ACS Infect. Dis. 2021 Feb 12; 7(2): 390–405. PubMed Abstract | Publisher Full Text
96. Kabanova A, Margarit I, Berti F, et al.: Evaluation of a group a streptococcus synthetic oligosaccharide as vaccine candidate. Vaccine. 2010 Dec; 29(1): 104–114. PubMed Abstract | Publisher Full Text
97. Lumngwena EN, Parker I, Mokaila D, et al.: The pathophysiology of RHD and outstanding gaps. SA Heart. 2022; 19(1): 38–48.
98. Root-Bernstein R, Fairweather DL: Unresolved issues in theories of autoimmune disease using myocarditis as a framework. J. Theor. Biol. 2015 Jun; 375: 101–123. PubMed Abstract | Publisher Full Text | Free Full Text
99. Nitsche-Schmitz D, Sharma A: Challenges to developing effective streptococcal vaccines to prevent rheumatic fever and rheumatic heart disease. Vaccine: Development and Therapy. 2014 May; 39. Publisher Full Text
100. Malkiel S, Liao LI, Cunningham MW, et al.: T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide, N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin. Infect. Immun. 2000 Oct; 68(10): 5803–5808. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source
101. Galvin JE, Hemric ME, Kosanke SD, et al.: Induction of Myocarditis and Valvulitis in Lewis Rats by Different Epitopes of Cardiac Myosin and Its Implications in Rheumatic Carditis. Am. J. Pathol. 2002 Jan; 160(1): 297–306. PubMed Abstract | Publisher Full Text | Free Full Text
102. Galvin JE, Hemric ME, Ward K, et al.: Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J. Clin. Invest. 2000 Jul 15; 106(2): 217–224. PubMed Abstract | Publisher Full Text | Free Full Text
103. Diamond B, Honig G, Mader S, et al.: Brain-reactive antibodies and disease. Annu. Rev. Immunol. 2013 Mar 21; 31(1): 345–385. PubMed Abstract | Publisher Full Text | Free Full Text
104. Mitchell R, Kelly DF, Pollard AJ, et al.: Polysaccharide-specific B cell responses to vaccination in humans. Hum. Vaccin. Immunother. 2014 Jun 4; 10(6): 1661–1668. PubMed Abstract | Publisher Full Text | Free Full Text
105. Anish C, Beurret M, Poolman J: Combined effects of glycan chain length and linkage type on the immunogenicity of glycoconjugate vaccines. NPJ Vaccines. 2021 Dec 10; 6(1): 150. PubMed Abstract | Publisher Full Text | Free Full Text
106. Díaz-Dinamarca DA, Salazar ML, Castillo BN, et al.: Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities. Pharmaceutics. 2022 Aug 11; 14(8): 1671. PubMed Abstract | Publisher Full Text | Free Full Text
107. Da Silva FT, Di Pasquale A, Yarzabal JP, et al.: Safety assessment of adjuvanted vaccines: Methodological considerations. Hum. Vaccin. Immunother. 2015 Jul 3; 11(7): 1814–1824. PubMed Abstract | Publisher Full Text | Free Full Text
108. Pulendran B, Arunachalam PS, O’Hagan DT: Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 2021 Jun 6; 20(6): 454–475. PubMed Abstract | Publisher Full Text | Free Full Text
109. Stefanetti G, Borriello F, Richichi B, et al.: Immunobiology of Carbohydrates: Implications for Novel Vaccine and Adjuvant Design Against Infectious Diseases. Front. Cell Infect. Microbiol. 2022 Jan 18; 11: 11. Publisher Full Text
110. de Lederkremer RM , Marino C: Deoxy Sugars: Occurrence and Synthesis. Adv. Carbohydr. Chem. Biochem. 2007; 61: 143–216. Publisher Full Text
111. van der Beek SL , Le Breton Y, Ferenbach AT, et al.: GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol.Microbiol. 2015 Dec 1; 98(5): 946–962. PubMed Abstract | Publisher Full Text | Free Full Text
112. van der Beek SL , Zorzoli A, Çanak E, et al.: Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification. Mol. Microbiol. 2019 Apr 31; 111(4): 951–964. PubMed Abstract | Publisher Full Text | Free Full Text
113. Li S, Chen F, Li Y, et al.: Rhamnose-Containing Compounds: Biosynthesis and Applications. Molecules. 2022 Aug 20; 27(16): 5315. Publisher Full Text
114. Bischer AP, Kovacs CJ, Faustoferri RC, et al.: Disruption of L-rhamnose biosynthesis results in severe growth defects in streptococcus mutans. J. Bacteriol. 2020 Feb 25; 202(6). PubMed Abstract | Publisher Full Text | Free Full Text
115. Pitirollo O, Micoli F, Necchi F, et al.: Gold nanoparticles morphology does not affect the multivalent presentation and antibody recognition of Group A Streptococcus synthetic oligorhamnans. Bioorg. Chem. 2020 Jun; 99: 103815. Publisher Full Text
116. St. Michael F , Yang Q, Cairns C, et al.: Investigating the candidacy of the serotype specific rhamnan polysaccharide based glycoconjugates to prevent disease caused by the dental pathogen Streptococcus mutans. Glycoconj J. 2018 Feb 2; 35(1): 53–64. PubMed Abstract | Publisher Full Text
117. Castro SA, Thomson S, Zorzoli A, et al.: Recombinant Group A Carbohydrate backbone embedded 1 into Outer Membrane 2 Vesicles is a potent vaccine candidate targeting Group A Streptococcus from 3 Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. bioRxiv. 2021 Nov 13.
118. Rivera-Hernandez T, Pandey M, Henningham A, et al.: Differing efficacies of lead group A streptococcal vaccine candidates and full-length M protein in cutaneous and invasive disease models. MBio. 2016 Jul 6; 7(3). PubMed Abstract | Publisher Full Text | Free Full Text

Comments on this article Comments (0)

Version 3

VERSION 3 PUBLISHED 22 Feb 2024

Author details Author details

Dwita Rian Desandri
Roles: Data Curation, Formal Analysis, Investigation, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Bambang Dwiputra
Roles: Conceptualization, Data Curation, Investigation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation

Pirel Aulia Baravia
Roles: Data Curation, Investigation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Indira Kalyana Makes
Roles: Investigation, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Basuni Radi
Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (3)

version 3

Revised

Published: 30 Jan 2025, 13:132

https://doi.org/10.12688/f1000research.144903.3

version 2

Revised

Published: 28 Oct 2024, 13:132

https://doi.org/10.12688/f1000research.144903.2

version 1

Published: 22 Feb 2024, 13:132

https://doi.org/10.12688/f1000research.144903.1

© 2025 Ambari AM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download

Export To

metrics

	Views	Downloads
F1000Research	-	-
PubMed Central Data from PMC are received and updated monthly.	-	-

Citations

SEE MORE DETAILS

CITE

how to cite this article

Ambari AM, Qhabibi FR, Desandri DR et al. 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 [version 3; peer review: 2 approved]. F1000Research 2025, 13:132 (https://doi.org/10.12688/f1000research.144903.3)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

track

receive updates on this article

Track an article to receive email alerts on any updates to this article.

Open Peer Review

Version 3

VERSION 3

PUBLISHED 30 Jan 2025

Revised

Views

Reviewer Report 10 Mar 2025

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

Approved

https://doi.org/10.5256/f1000research.177425.r363558

CITE

Report a concern

Respond or Comment

Views

Reviewer Report 14 Feb 2025

Mark Kaddumukasa, Makerere University, Kampala, Central Region, Uganda

Approved

https://doi.org/10.5256/f1000research.177425.r363559

The revised manuscript and the authors responses addressed the issues that were ... Continue reading

CITE

Report a concern

Respond or Comment

Version 2

VERSION 2

PUBLISHED 28 Oct 2024

Revised

Views

Reviewer Report 10 Jan 2025

Mark Kaddumukasa, Makerere University, Kampala, Central Region, Uganda

Approved with Reservations

https://doi.org/10.5256/f1000research.173666.r343519

The manuscript covers an important topic that requires re-inventing the prevention and control of RHD in LMICs. However, some clarifications are needed to improve the article.

Please include a section on limitations pertaining to the techniques

The manuscript covers an important topic that requires re-inventing the prevention and control of RHD in LMICs. However, some clarifications are needed to improve the article.

Please include a section on limitations pertaining to the techniques and proposed.
It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests: No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 30 Jan 2025

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

30 Jan 2025

Author Response

The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the ... Continue reading The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the question.

1. Please include a section on limitations pertaining to the techniques and proposed.
Answer:
Thank you for the constructive feedback, here we have added the limitation pertaining the techniques to our revised paper.
"The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition."

2. It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.
Answer:
"A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells. As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory. Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs). An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination's effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself. The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection. Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines."

Further, the content above has been added by the authors to the revised paper in the discussion section.
The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the question.

1. Please include a section on limitations pertaining to the techniques and proposed.
Answer:
Thank you for the constructive feedback, here we have added the limitation pertaining the techniques to our revised paper.
"The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition."

2. It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.
Answer:
"A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells. As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory. Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs). An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination's effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself. The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection. Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines."

Further, the content above has been added by the authors to the revised paper in the discussion section.
Competing Interests: The authors declare have no competing of interest toward the reviewer Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 30 Jan 2025

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

30 Jan 2025

Author Response

The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the ... Continue reading The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the question.

1. Please include a section on limitations pertaining to the techniques and proposed.
Answer:
Thank you for the constructive feedback, here we have added the limitation pertaining the techniques to our revised paper.
"The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition."

2. It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.
Answer:
"A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells. As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory. Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs). An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination's effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself. The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection. Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines."

Further, the content above has been added by the authors to the revised paper in the discussion section.
The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the question.

1. Please include a section on limitations pertaining to the techniques and proposed.
Answer:
Thank you for the constructive feedback, here we have added the limitation pertaining the techniques to our revised paper.
"The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition."

2. It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.
Answer:
"A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells. As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory. Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs). An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination's effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself. The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection. Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines."

Further, the content above has been added by the authors to the revised paper in the discussion section.
Competing Interests: The authors declare have no competing of interest toward the reviewer Close
Report a concern

Views

Reviewer Report 29 Oct 2024

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

Approved

https://doi.org/10.5256/f1000research.173666.r335591

This revised article provides a valuable and comprehensive overview of the potential of an L-Rhamnose-based vaccine to prevent Group A Streptococcus (GAS) infections, aiming to reduce acute rheumatic fever (ARF) and the global burden of rheumatic heart disease (RHD). The authors effectively contextualize the issue, emphasizing the challenges of current management strategies, particularly in resource-limited settings, and underline the promise of preventive vaccination approaches.

The focus on the L-Rhamnose-based vaccine as an alternative to M-protein-based vaccines is scientifically sound, and the article explains well why L-Rhamnose presents a lower risk of triggering cross-reactive antibodies. This perspective is crucial, as it addresses the potential adverse effects associated with M-protein cross-reactivity—a notable concern in previous GAS vaccine developments.

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Molecular Biology and Bioinformatics

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

CITE

Report a concern

Respond or Comment

Version 1

VERSION 1

PUBLISHED 22 Feb 2024

Views

Reviewer Report 10 Oct 2024

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

Approved with Reservations

https://doi.org/10.5256/f1000research.158764.r330060

First of all, this manuscript is good and well-written. However, I may require some comments on the following issues. Basically, this manuscript is acceptable.
However, in order to improve the readability of the paper by an English editing service as various sentences are mistyped.
Title: The title is easy to follow and no mistakes.
Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Conclusion: In this part of the paper, the authors have established the conclusion of this study.
References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

No
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Molecular Biology and Bioinformatics

CITE

Report a concern

Author Response 28 Oct 2024

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

28 Oct 2024

Author Response

The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the ... Continue reading The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability.

Title: The title is easy to follow and no mistakes.
Response: Thank you for the provided assessment.

Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study.

Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade.

Conclusion: In this part of the paper, the authors have established the conclusion of this study.
Response: Thank you for the provided assessment.

References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.
Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023.
The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability.

Title: The title is easy to follow and no mistakes.
Response: Thank you for the provided assessment.

Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study.

Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade.

Conclusion: In this part of the paper, the authors have established the conclusion of this study.
Response: Thank you for the provided assessment.

References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.
Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023.
Competing Interests: The author(s) declare no competing interests Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 28 Oct 2024

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

28 Oct 2024

Author Response

The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the ... Continue reading The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability.

Title: The title is easy to follow and no mistakes.
Response: Thank you for the provided assessment.

Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study.

Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade.

Conclusion: In this part of the paper, the authors have established the conclusion of this study.
Response: Thank you for the provided assessment.

References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.
Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023.
The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability.

Title: The title is easy to follow and no mistakes.
Response: Thank you for the provided assessment.

Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study.

Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade.

Conclusion: In this part of the paper, the authors have established the conclusion of this study.
Response: Thank you for the provided assessment.

References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.
Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023.
Competing Interests: The author(s) declare no competing interests Close
Report a concern

Comments on this article Comments (0)

Version 3

VERSION 3 PUBLISHED 22 Feb 2024

Open Peer Review

Reviewer Status

Reviewer Reports

	Invited Reviewers
	1	2
Version 3 (revision) 30 Jan 25	read	read
Version 2 (revision) 28 Oct 24	read	read
Version 1 22 Feb 24	read

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, Indonesia
Mark Kaddumukasa, Makerere University, Kampala, Uganda

Comments on this article

All Comments(0)

Add a comment

Browse by related subjects

Back to all reports

Reviewer Report

2 Views

10 Mar 2025 | for Version 3

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

2 Views Cite this report Responses(0)

Approved

Approved.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Biology and Bioinformatics

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

2 Views

14 Feb 2025 | for Version 3

Mark Kaddumukasa, Makerere University, Kampala, Central Region, Uganda

2 Views Cite this report Responses(0)

Approved

The revised manuscript and the authors responses addressed the issues that were raised and was given an approval for acceptance. I have no further concerns.

Competing Interests

No competing interests were disclosed.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

14 Views

10 Jan 2025 | for Version 2

Mark Kaddumukasa, Makerere University, Kampala, Central Region, Uganda

14 Views Cite this report Responses(1)

Approved With Reservations

The manuscript covers an important topic that requires re-inventing the prevention and control of RHD in LMICs. However, some clarifications are needed to improve the article.

Please include a section on limitations pertaining to the techniques and proposed.
It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests

No competing interests were disclosed.

Respond to this report

Responses (1)

Author Response

30 Jan 2025

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

The author(s) express gratitude and appreciation for the valuable suggestions and constructive feedback. Consequently, the author(s) will return the amended manuscript addressing the prior review comments and respond to the question.

1. Please include a section on limitations pertaining to the techniques and proposed.
Answer:
Thank you for the constructive feedback, here we have added the limitation pertaining the techniques to our revised paper.
"The paper is a comprehensive narrative review; thus, the limitations related to the techniques include a lack of standardized procedures and reproducibility caused by a lack of a defined methodology for searching, selecting, and analyzing literature. Nonetheless, the authors remain to strictly check and scrutinize the articles as sources to ensure high-quality data acquisition."

2. It would be better to include within the discussion the issue of hypo responsiveness, shielding of protein immune epitopes associated with carbohydrate epitopes and how the best antigens for the proposed vaccines can be selected.
Answer:
"A further obstacle in advancing polysaccharide-based vaccines and their derivatives is the immunogenicity elicited by polysaccharides. Bacterial polysaccharides typically elicit short-lived T cell-independent responses and largely do not facilitate the development of memory B cells or the generation of long-lived plasma cells. As a result, polysaccharide-based vaccinations and their derivatives typically elicit low-affinity antibody responses and are ineffective in generating long-term, boostable immunological memory. Further, in adults, the administration of polysaccharide vaccines is suboptimal since it fails to elicit immunological memory, avidity maturation, and isotype switching. The majority of antibodies generated are IgM and IgG2, which are ineffective complement activators, therefore diminishing their capacity to defend against infections. As discussed above, a significant issue with polysaccharide vaccines is their inadequate immunogenicity. Based on the limitation, glycoconjugate vaccines were created to enhance the inadequate protection offered by polysaccharide vaccinations. Adjuvants can be categorized into many classes according to their physicochemical features, including protein-based adjuvants (PBAs). An adjuvant is a compound or combination of substances incorporated into a vaccine to augment immunogenicity and elicit an initial innate immune response by stimulating an inflammatory reaction at the injection site. Consequently, an adjuvant amplifies the intensity and longevity of the vaccination's effects while modifying the nature of particular adaptive downstream immune responses to vaccine antigens, without eliciting a specific antigenic response against itself. The covalent attachment of bacterial glycans to carrier proteins in these vaccines enhances the immunogenicity of saccharide antigens by stimulating T cell-dependent B cell responses, resulting in high-affinity antibodies and long-lasting protection. Glycoconjugate antigens may induce a T cell-dependent response, leading to the synthesis of high-affinity antibodies and the formation of carbohydrate-specific memory B cells (MBCs). Consequently, glycoconjugate vaccinations provide protection for young infants (under 2 years of age) and are generally more potent than pure polysaccharide vaccines."

Further, the content above has been added by the authors to the revised paper in the discussion section.

View more View less

Competing Interests

The authors declare have no competing of interest toward the reviewer

Back to all reports

Reviewer Report

8 Views

29 Oct 2024 | for Version 2

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

8 Views Cite this report Responses(0)

Approved

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Biology and Bioinformatics

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

28 Views

10 Oct 2024 | for Version 1

Arif Nur Muhammad Ansori, Universitas Airlangga, Surabaya, East Java, Indonesia

28 Views Cite this report Responses(1)

Approved With Reservations

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

No
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Molecular Biology and Bioinformatics

Respond to this report

Responses (1)

Author Response

28 Oct 2024

Ade Meidian Ambari, Cardiovascular Prevention and Rehabilitation Department, National Cardiovascular Center Hospital Harapan Kita, Jakarta, 11420, Indonesia

The authors convey their appreciation and gratitude to the reviewers for their constructive assessments and evaluations. The reviewers' suggestion has been optimally implemented, and these enhancements are evident in the latest version of this paper. Furthermore, we have enhanced the quality of grammar and English use by using editing services and utilizing grammar and paraphrasing tools to augment the paper's readability.

Title: The title is easy to follow and no mistakes.
Response: Thank you for the provided assessment.

Abstract: This section was well-written and easy to understand. In addition, the study's objective and the state of the art of the study is clear. Furthermore, the keywords should represent the study.
Response: Thank you for your insightful evaluation and feedback. The author modified the keywords to more accurately reflect the study.

Discussion: The discussion of the study is lack of information about the important topics. To develop a systematic discussion, the authors should mention the limitation(s) of the study.
Response: Thank you for the feedback. The authors enhance the quality of the Discussion section by including and expanding on different prior research findings, particularly those concerning the efficacy and safety of the Rhamnose-based GAS Vaccine, which is key to this study topic. In addition, the authors have included the study's limitations in the final paragraph of the discussion section. The authors faced challenges in incorporating relevant research data published in the past two years, which pertains to the study's shortcomings. The search was extended to encompass a minimum of the past decade.

Conclusion: In this part of the paper, the authors have established the conclusion of this study.
Response: Thank you for the provided assessment.

References: Many references are out of guidelines. Please kindly check the references again, do not include the old references, and check the abbreviation of the journals/proceedings. Please mention many high-quality related publications in 2023-2024.
Response: I appreciate your constructive criticism. The authors have assessed and amended all references cited in the manuscript according to metadata from the reference management software (Mendeley). Furthermore, we have eliminated several outdated references deemed non-essential (material remains accessible in other publications) (e.g., Giraud MF, Naismith JH. The rhamnose pathway. Curr Opin Struct Biol. 2000 Dec;10(6):687–96.), and the authors have incorporated recent studies published in 2023.

View more View less

Competing Interests

The author(s) declare no competing interests

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Ajay Castro S, Dorfmueller HC: Update on the development of Group A Streptococcus vaccines. NPJ Vaccines. 2023 Sep 14; 8(1): 135. PubMed Abstract | Publisher Full Text | Free Full Text

[2] 2. Webb RH, Grant C, Harnden A: Acute rheumatic fever. BMJ. 2015 Jul 14; 351: h3443. Publisher Full Text

[3] 3. Kumar D, Bhutia E, Kumar P: Evaluation of the American Heart Association 2015 revised Jones criteria versus existing guidelines. Heart Asia. 2016 Feb 29; 8(1): 30–35. PubMed Abstract | Publisher Full Text | Free Full Text

[4] 4. Burke RJ, Chang C: Diagnostic criteria of acute rheumatic fever. Autoimmun. Rev. 2014 Apr; 13(4-5): 503–507. Publisher Full Text

[5] 5. Zühlke LJ, Beaton A, Engel ME, et al.: Group A Streptococcus, Acute Rheumatic Fever and Rheumatic Heart Disease: Epidemiology and Clinical Considerations. Curr. Treat. Options Cardiovasc. Med. 2017 Feb 11; 19(2): 15. PubMed Abstract | Publisher Full Text | Free Full Text

[6] 6. Gewitz MH, Baltimore RS, Tani LY, et al.: Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography. Circulation. 2015 May 19; 131(20): 1806–1818. PubMed Abstract | Publisher Full Text

[7] 7. Cunningham MW: Streptococcus and rheumatic fever. Curr. Opin. Rheumatol. 2012 Jul; 24(4): 408–416. PubMed Abstract | Publisher Full Text | Free Full Text

[8] 8. Cunningham MW: Rheumatic fever, autoimmunity, and molecular mimicry: The streptococcal connection. Int. Rev. Immunol. 2014 Jul 4; 33(4): 314–329. Publisher Full Text

[9] 9. Tandon R, Sharma M, Chandrashekhar Y, et al.: Revisiting the pathogenesis of rheumatic fever and carditis. Nat. Rev. Cardiol. 2013 Mar 15; 10(3): 171–177. PubMed Abstract | Publisher Full Text

[10] 10. Watkins DA, Beaton AZ, Carapetis JR, et al.: Rheumatic Heart Disease Worldwide: JACC Scientific Expert Panel. J. Am. Coll. Cardiol. 2018 Sep 18; 72(12): 1397–1416. Publisher Full Text

[11] 11. Williamson DA, Smeesters PR, Steer AC, et al.: M-protein analysis of streptococcus pyogenes isolates associated with acute rheumatic fever in New Zealand. J. Clin. Microbiol. 2015 Nov; 53(11): 3618–3620. PubMed Abstract | Publisher Full Text | Free Full Text

[12] 12. Ambari AM, Setianto B, Santoso A, et al.: Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Front. Cardiovasc. Med. 2020 Jul 28; 7. PubMed Abstract | Publisher Full Text | Free Full Text

[13] 13. Tsatsaronis JA, Walker MJ, Sanderson-Smith ML: Host Responses to Group A Streptococcus: Cell Death and Inflammation. PLoS Pathog. 2014 Aug 28; 10(8): e1004266. PubMed Abstract | Publisher Full Text | Free Full Text

[14] 14. Wunderlich NC, Dalvi B, Ho SY, et al.: Rheumatic Mitral Valve Stenosis: Diagnosis and Treatment Options. Curr. Cardiol. Rep. 2019 Mar 28; 21(3): 14. PubMed Abstract | Publisher Full Text

[15] 15. Roberts K, Colquhoun S, Steer A, et al.: Screening for rheumatic heart disease: Current approaches and controversies. Nat. Rev. Cardiol. 2013 Jan 13; 10(1): 49–58. PubMed Abstract | Publisher Full Text

[16] 16. Dooley LM, Ahmad TB, Pandey M, et al.: Rheumatic heart disease: A review of the current status of global research activity. Autoimmun. Rev. 2021 Feb; 20(2): 102740. PubMed Abstract | Publisher Full Text

[17] 17. Woldu B, Bloomfield GS: Rheumatic Heart Disease in the Twenty-First Century. Curr. Cardiol. Rep. 2016 Oct 27; 18(10): 96. PubMed Abstract | Publisher Full Text | Free Full Text

[18] 18. Yanagawa B, Butany J, Verma S: Update on rheumatic heart disease. Curr. Opin. Cardiol. 2016 Mar; 31(2): 162–168. Publisher Full Text

[19] 19. Ali R: A Study on Rheumatic Fever. Int. J. Res. Anal. Rev. 2018; 5(4): 203–210.

[20] 20. Zühlke L, Mayosi BM: Echocardiographic screening for subclinical rheumatic heart disease remains a research tool pending studies of impact on prognosis. Curr. Cardiol. Rep. 2013 Mar 22; 15(3): 343. PubMed Abstract | Publisher Full Text

[21] 21. Dougherty S, Okello E, Mwangi J, et al.: Rheumatic Heart Disease. J. Am. Coll. Cardiol. 2023 Jan; 81(1): 81–94. Publisher Full Text

[22] 22. Van Hagen IM, Thorne SA, Taha N, et al.: Pregnancy outcomes in women with rheumatic mitral valve disease: Results from the registry of pregnancy and cardiac disease. Circulation. 2018 Feb 20; 137(8): 806–816. Publisher Full Text

[23] 23. Kumar R, Sharma YP, Thakur JS, et al.: Streptococcal pharyngitis, rheumatic fever and rheumatic heart disease: Eight-year prospective surveillance in Rupnagar district of Punjab, India. Natl. Med. J. India. 2014; 27(2): 70–75. PubMed Abstract

[24] 24. Carapetis JR: The stark reality of rheumatic heart disease. Eur. Heart J. 2015 May 2; 36(18): 1070–1073. PubMed Abstract | Publisher Full Text

[25] 25. Yingchoncharoen T: Rheumatic Mitral Valve Disease. An Atlas of Mitral Valve Imaging. London: Springer; 2015; pp. 69–87. Publisher Full Text

[26] 26. Motiwala SR, Delling FN: Assessment of Mitral Valve Disease: A Review of Imaging Modalities. Curr. Treat. Options Cardiovasc. Med. 2015 Jul 19; 17(7): 30. Publisher Full Text

[27] 27. Nunes MCP, Nascimento BR, Lodi-Junqueira L, et al.: Update on percutaneous mitral commissurotomy. Heart. 2016 Apr 1; 102(7): 500–507. PubMed Abstract | Publisher Full Text

[28] 28. Ali SKM, Engel ME, Zühlke L, et al.: Primary Prevention of Acute Rheumatic Fever and Rheumatic Heart Disease. Acute Rheumatic Fever and Rheumatic Heart Disease. Elsevier; 2021; pp. 195–206. Publisher Full Text

[29] 29. Shimanda PP, Shumba TW, Brunström M, et al.: Preventive interventions to reduce the burden of rheumatic heart disease in populations at risk: a systematic review protocol. Syst. Rev. 2021 Dec 8; 10(1): 200. PubMed Abstract | Publisher Full Text | Free Full Text

[30] 30. Guilherme L, Ferreira FM, Köhler KF, et al.: A vaccine against streptococcus pyogenes: The potential to prevent rheumatic fever and rheumatic heart disease. Am. J. Cardiovasc. Drugs. 2013 Feb; 13(1): 1–4. Publisher Full Text

[31] 31. Ralph AP, Carapetis JR: Group A Streptococcal Diseases and Their Global Burden.2012; pp. 1–27.

[32] 32. Carapetis JR, Steer AC, Mulholland EK, et al.: The global burden of group A streptococcal diseases. Lancet Infect. Dis. 2005 Nov; 5(11): 685–694. PubMed Abstract | Publisher Full Text

[33] 33. Castro SA, Dorfmueller HC: A brief review on Group A Streptococcus pathogenesis and vaccine development. R. Soc. Open Sci. 2021 Mar 10; 8(3): rsos.201991. PubMed Abstract | Publisher Full Text | Free Full Text

[34] 34. Sanyahumbi AS, Colquhoun S, Wyber R, et al.: Global disease burden of group A Streptococcus. Streptococcus pyogenes: basic biology to clinical manifestations [Internet]. 2016.

[35] 35. Barnett TC, Bowen AC, Carapetis JR: The fall and rise of Group A Streptococcus diseases. Epidemiol. Infect. 2019 Aug 15; 147: e4. PubMed Abstract | Publisher Full Text | Free Full Text

[36] 36. Lawrence JG, Carapetis JR, Griffiths K, et al.: Acute Rheumatic Fever and Rheumatic Heart Disease. Circulation. 2013 Jul 30; 128(5): 492–501. Publisher Full Text

[37] 37. Zühlke LJ, Steer AC: Estimates of the global burden of rheumatic heart disease. Glob. Heart. 2013 Sep 1; 8(3): 189. Publisher Full Text

[38] 38. Roth GA, Mensah GA, Johnson CO, et al.: Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study. J. Am. Coll. Cardiol. 2020; 76(25): 2982–3021. PubMed Abstract | Publisher Full Text | Free Full Text

[39] 39. James SL, Abate D, Abate KH, et al.: Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov; 392(10159): 1789–1858. PubMed Abstract | Publisher Full Text | Free Full Text

[40] 40. Roth GA, Abate D, Abate KH, et al.: Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov; 392(10159): 1736–1788. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source

[41] 41. Ledos PH, Kamblock J, Bourgoin P, et al.: Prevalence of rheumatic heart disease in young adults from New Caledonia. Arch. Cardiovasc. Dis. 2015 Jan; 108(1): 16–22. PubMed Abstract | Publisher Full Text

[42] 42. Beaton A, Okello E, Lwabi P, et al.: Echocardiography screening for rheumatic heart disease in ugandan schoolchildren. Circulation. 2012 Jun 26; 125(25): 3127–3132. PubMed Abstract | Publisher Full Text

[43] 43. Zühlke LJ, Engel ME, Watkins D, et al.: Incidence, prevalence and outcome of rheumatic heart disease in South Africa: A systematic review of contemporary studies. Int. J. Cardiol. 2015 Nov; 199: 375–383. PubMed Abstract | Publisher Full Text

[44] 44. Bocchi A: Heart Failure in South America. Curr. Cardiol. Rev. 2013 May 1; 9(2): 147–156. PubMed Abstract | Publisher Full Text | Free Full Text

[45] 45. Elamrousy DM, Al-Asy H, Mawlana W: Acute Rheumatic Fever In Egyptian Children: A 30-Year Experience in a Tertiary Hospital. J. Pediatr. Sci. 2014 Jul 6; 6(0). Publisher Full Text

[46] 46. Beaudoin A, Edison L, Introcaso CE, et al.: Acute Rheumatic Fever and Rheumatic Heart Disease Among Children — American Samoa, 2011–2012. MMWR Morb. Mortal Wkly Rep. 2015; 64(20): 555–558. PubMed Abstract | Free Full Text

[47] 47. Sliwa K, Carrington M, Mayosi BM, et al.: Incidence and characteristics of newly diagnosed rheumatic heart disease in Urban African adults: Insights from the Heart of Soweto Study. Eur. Heart J. 2010 Mar 2; 31(6): 719–727. PubMed Abstract | Publisher Full Text

[48] 48. Walker MJ, Barnett TC, McArthur JD, et al.: Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin. Microbiol. Rev. 2014 Apr; 27(2): 264–301. PubMed Abstract | Publisher Full Text | Free Full Text

[49] 49. Shulman ST, Bisno AL, Clegg HW, et al.: Clinical practice guideline for the diagnosis and management of group a streptococcal pharyngitis: 2012 update by the infectious diseases society of America. Clin. Infect. Dis. 2012 Nov 15; 55(10): 1279–1282. PubMed Abstract | Publisher Full Text

[50] 50. Vannice KS, Ricaldi J, Nanduri S, et al.: Streptococcus pyogenes pbp2x mutation confers reduced susceptibility to β-lactam antibiotics. Clin. Infect. Dis. 2020 Jun 24; 71(1): 201–204. PubMed Abstract | Publisher Full Text | Free Full Text

[51] 51. Andrejko K, Whittles LK, Lewnard JA: Health-Economic Value of Vaccination Against Group A Streptococcus in the United States. Clin. Infect. Dis. 2022 Mar 23; 74(6): 983–992. PubMed Abstract | Publisher Full Text

[52] 52. Jansen KU, Knirsch C, Anderson AS: The role of vaccines in preventing bacterial antimicrobial resistance. Nat. Med. 2018 Jan 1; 24(1): 10–19. Publisher Full Text

[53] 53. Cannon JW, Jack S, Wu Y, et al.: An economic case for a vaccine to prevent group A streptococcus skin infections. Vaccine. 2018 Nov; 36(46): 6968–6978. PubMed Abstract | Publisher Full Text

[54] 54. Vekemans J, Gouvea-Reis F, Kim JH, et al.: The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics. Clin. Infect. Dis. 2019; 69(5): 877–883. PubMed Abstract | Publisher Full Text | Free Full Text

[55] 55. Henningham A, Gillen CM, Walker MJ: Group A Streptococcal Vaccine Candidates: Potential for the Development of a Human Vaccine. Curr. Top. Microbiol. Immunol. 2012 Dec 19; 368: 207–242. PubMed Abstract | Publisher Full Text

[56] 56. Burns K, Dorfmueller HC, Wren BW, et al.: Progress towards a glycoconjugate vaccine against Group A Streptococcus. NPJ Vaccines. 2023 Mar; 8(1): 48. PubMed Abstract | Publisher Full Text | Free Full Text

[57] 57. Davies MR, McIntyre L, Mutreja A, et al.: Atlas of group A streptococcal vaccine candidates compiled using large-scale comparative genomics. Nat. Genet. 2019 Jun 27; 51(6): 1035–1043. PubMed Abstract | Publisher Full Text | Free Full Text

[58] 58. Sharma A, Arya DK, Sagar V, et al.: Identification of potential universal vaccine candidates against group a streptococcus by using high throughput in silico and proteomics approach. J. Proteome Res. 2013 Jan 4; 12(1): 336–346. PubMed Abstract | Publisher Full Text

[59] 59. Good MF, Pandey M, Batzloff MR, et al.: Strategic development of the conserved region of the M protein and other candidates as vaccines to prevent infection with group A streptococci. Expert Rev. Vaccines. 2015 Nov 2; 14(11): 1459–1470. PubMed Abstract | Publisher Full Text

[60] 60. Dale JB, Smeesters PR, Courtney HS, et al.: Structure-based design of broadly protective group a streptococcal M protein-based vaccines. Vaccine. 2017 Jan; 35(1): 19–26.

[61] 61. Mcmillan DJ, Drèze PA, Vu T, et al.: Updated model of group A Streptococcus M proteins based on a comprehensive worldwide study. Clin. Microbiol. Infect. 2013 May; 19(5): E222–E229. PubMed Abstract | Publisher Full Text | Free Full Text

[62] 62. Tsai JYC, Loh JMS, Clow F, et al.: The Group A Streptococcus serotype M2 pilus plays a role in host cell adhesion and immune evasion. Mol. Microbiol. 2017 Jan 14; 103(2): 282–298. PubMed Abstract | Publisher Full Text

[63] 63. Brahmadathan NK: Molecular Biology of Group A Streptococcus and its Implications in Vaccine Strategies. Indian J. Med. Microbiol. 2017 Apr; 35(2): 176–183. PubMed Abstract | Publisher Full Text

[64] 64. Aranha MP, Penfound TA, Salehi S, et al.: Design of Broadly Cross-Reactive M Protein–Based Group A Streptococcal Vaccines. J. Immunol. 2021 Aug 15; 207(4): 1138–1149. PubMed Abstract | Publisher Full Text | Free Full Text

[65] 65. Mills JO, Ghosh P: Nonimmune antibody interactions of group a streptococcus M and M-like proteins. PLoS Pathog. 2021 Feb 25; 17(2): e1009248. PubMed Abstract | Publisher Full Text | Free Full Text

[66] 66. Buffalo CZ, Bahn-Suh AJ, Hirakis SP, et al.: Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein. Nat. Microbiol. 2016 Sep 5; 1(11): 16155. PubMed Abstract | Publisher Full Text | Free Full Text

[67] 67. Rivera-Hernandez T, Rhyme MS, Cork AJ, et al.: Vaccine-induced th1-type response protects against invasive group a Streptococcus infection in the absence of opsonizing antibodies. ASM Journals. 2020 Apr 28; 11(2).

[68] 68. Dai C, Khalil ZG, Hussein WM, et al.: Opsonic activity of conservative versus variable regions of the group a streptococcus M protein. Vaccines (Basel). 2020 May 7; 8(2): 210. Publisher Full Text

[69] 69. Wang J, Ma C, Li M, et al.: Streptococcus pyogenes: Pathogenesis and the Current Status of Vaccines. Vaccines (Basel). 2023 Sep 21; 11(9): 1510. PubMed Abstract | Publisher Full Text | Free Full Text

[70] 70. Guilherme L, Branco CE, De Barros SF, et al.: Rheumatic fever: From pathogenesis to vaccine perspectives. Translational Autoimmunity. Advances in Autoimmune Rheumatic Diseases. Vol. 6. Elsevier; 2023; pp. 47–59. Publisher Full Text

[71] 71. Harbison-Price N, Rivera-Hernandez T, Osowicki J, et al.: Current Approaches to Vaccine Development of Streptococcus pyogenes Introduction and Historical Perspective.2022.

[72] 72. Pastural É, McNeil SA, MacKinnon-Cameron D, et al.: Safety and immunogenicity of a 30-valent M protein-based group a streptococcal vaccine in healthy adult volunteers: A randomized, controlled phase I study. Vaccine. 2020 Feb; 38(6): 1384–1392. PubMed Abstract | Publisher Full Text

[73] 73. Spencer JA, Penfound T, Salehi S, et al.: Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes. Vaccine. 2021 Mar; 39(12): 1773–1779. PubMed Abstract | Publisher Full Text | Free Full Text

[74] 74. Carapetis JR, Beaton A, Cunningham MW, et al.: Acute rheumatic fever and rheumatic heart disease. Nat. Rev. Dis. Prim. 2016 Jan 14; 2(1): 15084. PubMed Abstract | Publisher Full Text | Free Full Text

[75] 75. Guilherme L, Steer AC, Cunningham M: Pathogenesis of Acute Rheumatic Fever. Acute Rheumatic Fever and Rheumatic Heart Disease. Elsevier; 2021; pp. 19–30. Publisher Full Text

[76] 76. Cunningham MW: Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive Antigens of Group A Streptococci and their Sequelae. Microbiol Spectr. 2019 Jul 19; 7(4). PubMed Abstract | Publisher Full Text | Free Full Text

[77] 77. Aranha MP, Penfound TA, Spencer JA, et al.: Structure-based group A streptococcal vaccine design: Helical wheel homology predicts antibody cross-reactivity among streptococcal M protein-derived peptides. J. Biol. Chem. 2020 Mar; 295(12): 3826–3836. PubMed Abstract | Publisher Full Text | Free Full Text

[78] 78. Brouwer S, Rivera-Hernandez T, Curren BF, et al.: Pathogenesis, epidemiology and control of Group A Streptococcus infection. Nat. Rev. Microbiol. 2023 Jul 9; 21(7): 431–447. Publisher Full Text

[79] 79. Rush JS, Edgar RJ, Deng P, et al.: The molecular mechanism of N-acetylglucosamine side-chain attachment to the Lancefield group A carbohydrate in Streptococcus pyogenes. J. Biol. Chem. 2017 Nov; 292(47): 19441–19457. PubMed Abstract | Publisher Full Text | Free Full Text

[80] 80. Gao NJ, Uchiyama S, Pill L, et al.: Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine. Infect. Microbes Dis. 2021 Jun; 3(2): 87–100. Publisher Full Text

[81] 81. Kampff Z, van Sinderen D, Mahony J: Cell wall polysaccharides of streptococci: A genetic and structural perspective. Biotechnol. Adv. 2023 Dec; 69: 108279. PubMed Abstract | Publisher Full Text

[82] 82. Pitirollo O, Di Benedetto R, Henriques P, et al.: Elucidating the role of N-acetylglucosamine in Group A Carbohydrate for the development of an effective glycoconjugate vaccine against Group A Streptococcus. Carbohydr. Polym. 2023 Jul; 311: 120736. Publisher Full Text

[83] 83. Henningham A, Davies MR, Uchiyama S, et al.: Virulence role of the glcnac side chain of the lancefield cell wall carbohydrate antigen in non-m1-serotype group a streptococcus. mBio. 2018 Jan 30; 9(1). PubMed Abstract | Publisher Full Text | Free Full Text

[84] 84. Edgar RJ, van Hensbergen VP , Ruda A, et al.: Discovery of glycerol phosphate modification on streptococcal rhamnose polysaccharides. Nat. Chem. Biol. 2019 May 1; 15(5): 463–471. PubMed Abstract | Publisher Full Text | Free Full Text

[85] 85. Rohokale R, Guo Z: Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines. ACS Infect. Dis. 2023 Feb 10; 9(2): 178–212. PubMed Abstract | Publisher Full Text | Free Full Text

[86] 86. Zorzoli A, Meyer BH, Adair E, et al.: Group A, B, C, and G Streptococcus Lancefield antigen biosynthesis is initiated by a conserved α-D-GlcNAc-β-1,4-L-rhamnosyltransferase. J. Biol. Chem. 2019 Oct; 294(42): 15237–15256. PubMed Abstract | Publisher Full Text | Free Full Text

[87] 87. Mistou MY, Sutcliffe IC, Van Sorge NM: Bacterial glycobiology: Rhamnose-containing cell wall polysaccharides in gram-positive bacteria. FEMS Microbiol. Rev. 2016 Jul; 40(4): 464–479. PubMed Abstract | Publisher Full Text | Free Full Text

[88] 88. Gao NJ, Lima ER, Nizet V: Immunobiology of the Classical Lancefield Group A Streptococcal Carbohydrate Antigen. Infect. Immun. 2021 Nov 16; 89(12). Reference Source

[89] 89. Rush JS, Zamakhaeva S, Murner NR, et al.: Structure and mechanism of biosynthesis of Streptococcus mutans cell wall polysaccharide. bioRxiv. 2024 May 9.

[90] 90. Shelburne SA, Keith D, Horstmann N, et al.: A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus. Proc. Natl. Acad. Sci. 2008 Feb 5; 105(5): 1698–1703.

[91] 91. van Hensbergen VP , Movert E, de Maat V , et al.: Streptococcal Lancefield polysaccharides are critical cell wall determinants for human Group IIA secreted phospholipase A2 to exert its bactericidal effects. PLoS Pathog. 2018 Oct 15; 14(10): e1007348. Publisher Full Text

[92] 92. Van Sorge NM, Cole JN, Kuipers K, et al.: The classical lancefield antigen of group A Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe. 2014 Jun; 15(6): 729–740. PubMed Abstract | Publisher Full Text

[93] 93. Sabharwal H, Michon F, Nelson D, et al.: Group A Streptococcus (GAS) Carbohydrate as an Immunogen for Protection against GAS Infection. J. Infect. Dis. 2006 Jan; 193(1): 129–135. Publisher Full Text https://academic.oup.com/jid/article/193/1/129/863942

[94] 94. Wang S, Zhao Y, Wang G, et al.: Group A Streptococcus Cell Wall Oligosaccharide-Streptococcal C5a Peptidase Conjugates as Effective Antibacterial Vaccines. ACS Infect. Dis. 2020 Feb 14; 6(2): 281–290. PubMed Abstract | Publisher Full Text

[95] 95. Khatun F, Dai CC, Rivera-Hernandez T, et al.: Immunogenicity Assessment of Cell Wall Carbohydrates of Group A Streptococcus via Self-Adjuvanted Glyco-lipopeptides. ACS Infect. Dis. 2021 Feb 12; 7(2): 390–405. PubMed Abstract | Publisher Full Text

[96] 96. Kabanova A, Margarit I, Berti F, et al.: Evaluation of a group a streptococcus synthetic oligosaccharide as vaccine candidate. Vaccine. 2010 Dec; 29(1): 104–114. PubMed Abstract | Publisher Full Text

[97] 97. Lumngwena EN, Parker I, Mokaila D, et al.: The pathophysiology of RHD and outstanding gaps. SA Heart. 2022; 19(1): 38–48.

[98] 98. Root-Bernstein R, Fairweather DL: Unresolved issues in theories of autoimmune disease using myocarditis as a framework. J. Theor. Biol. 2015 Jun; 375: 101–123. PubMed Abstract | Publisher Full Text | Free Full Text

[99] 99. Nitsche-Schmitz D, Sharma A: Challenges to developing effective streptococcal vaccines to prevent rheumatic fever and rheumatic heart disease. Vaccine: Development and Therapy. 2014 May; 39. Publisher Full Text

[100] 100. Malkiel S, Liao LI, Cunningham MW, et al.: T-Cell-Dependent Antibody Response to the Dominant Epitope of Streptococcal Polysaccharide, N-Acetyl-Glucosamine, Is Cross-Reactive with Cardiac Myosin. Infect. Immun. 2000 Oct; 68(10): 5803–5808. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source

[101] 101. Galvin JE, Hemric ME, Kosanke SD, et al.: Induction of Myocarditis and Valvulitis in Lewis Rats by Different Epitopes of Cardiac Myosin and Its Implications in Rheumatic Carditis. Am. J. Pathol. 2002 Jan; 160(1): 297–306. PubMed Abstract | Publisher Full Text | Free Full Text

[102] 102. Galvin JE, Hemric ME, Ward K, et al.: Cytotoxic mAb from rheumatic carditis recognizes heart valves and laminin. J. Clin. Invest. 2000 Jul 15; 106(2): 217–224. PubMed Abstract | Publisher Full Text | Free Full Text

[103] 103. Diamond B, Honig G, Mader S, et al.: Brain-reactive antibodies and disease. Annu. Rev. Immunol. 2013 Mar 21; 31(1): 345–385. PubMed Abstract | Publisher Full Text | Free Full Text

[104] 104. Mitchell R, Kelly DF, Pollard AJ, et al.: Polysaccharide-specific B cell responses to vaccination in humans. Hum. Vaccin. Immunother. 2014 Jun 4; 10(6): 1661–1668. PubMed Abstract | Publisher Full Text | Free Full Text

[105] 105. Anish C, Beurret M, Poolman J: Combined effects of glycan chain length and linkage type on the immunogenicity of glycoconjugate vaccines. NPJ Vaccines. 2021 Dec 10; 6(1): 150. PubMed Abstract | Publisher Full Text | Free Full Text

[106] 106. Díaz-Dinamarca DA, Salazar ML, Castillo BN, et al.: Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities. Pharmaceutics. 2022 Aug 11; 14(8): 1671. PubMed Abstract | Publisher Full Text | Free Full Text

[107] 107. Da Silva FT, Di Pasquale A, Yarzabal JP, et al.: Safety assessment of adjuvanted vaccines: Methodological considerations. Hum. Vaccin. Immunother. 2015 Jul 3; 11(7): 1814–1824. PubMed Abstract | Publisher Full Text | Free Full Text

[108] 108. Pulendran B, Arunachalam PS, O’Hagan DT: Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. 2021 Jun 6; 20(6): 454–475. PubMed Abstract | Publisher Full Text | Free Full Text

[109] 109. Stefanetti G, Borriello F, Richichi B, et al.: Immunobiology of Carbohydrates: Implications for Novel Vaccine and Adjuvant Design Against Infectious Diseases. Front. Cell Infect. Microbiol. 2022 Jan 18; 11: 11. Publisher Full Text

[110] 110. de Lederkremer RM , Marino C: Deoxy Sugars: Occurrence and Synthesis. Adv. Carbohydr. Chem. Biochem. 2007; 61: 143–216. Publisher Full Text

[111] 111. van der Beek SL , Le Breton Y, Ferenbach AT, et al.: GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol.Microbiol. 2015 Dec 1; 98(5): 946–962. PubMed Abstract | Publisher Full Text | Free Full Text

[112] 112. van der Beek SL , Zorzoli A, Çanak E, et al.: Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification. Mol. Microbiol. 2019 Apr 31; 111(4): 951–964. PubMed Abstract | Publisher Full Text | Free Full Text

[113] 113. Li S, Chen F, Li Y, et al.: Rhamnose-Containing Compounds: Biosynthesis and Applications. Molecules. 2022 Aug 20; 27(16): 5315. Publisher Full Text

[114] 114. Bischer AP, Kovacs CJ, Faustoferri RC, et al.: Disruption of L-rhamnose biosynthesis results in severe growth defects in streptococcus mutans. J. Bacteriol. 2020 Feb 25; 202(6). PubMed Abstract | Publisher Full Text | Free Full Text

[115] 115. Pitirollo O, Micoli F, Necchi F, et al.: Gold nanoparticles morphology does not affect the multivalent presentation and antibody recognition of Group A Streptococcus synthetic oligorhamnans. Bioorg. Chem. 2020 Jun; 99: 103815. Publisher Full Text

[116] 116. St. Michael F , Yang Q, Cairns C, et al.: Investigating the candidacy of the serotype specific rhamnan polysaccharide based glycoconjugates to prevent disease caused by the dental pathogen Streptococcus mutans. Glycoconj J. 2018 Feb 2; 35(1): 53–64. PubMed Abstract | Publisher Full Text

[117] 117. Castro SA, Thomson S, Zorzoli A, et al.: Recombinant Group A Carbohydrate backbone embedded 1 into Outer Membrane 2 Vesicles is a potent vaccine candidate targeting Group A Streptococcus from 3 Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. bioRxiv. 2021 Nov 13.

[118] 118. Rivera-Hernandez T, Pandey M, Henningham A, et al.: Differing efficacies of lead group A streptococcal vaccine candidates and full-length M protein in cutaneous and invasive disease models. MBio. 2016 Jul 6; 7(3). PubMed Abstract | Publisher Full Text | Free Full Text

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

Abstract

Keywords

Revised Amendments from Version 2

Introduction

Figure 1. Pathogenesis of ARF in heart and related tissues.

Discussion: Current Global Epidemiology of GAS, ARF, and RHD

GAS Vaccine Development for ARF/RHD

Development of GAC Vaccine based on Poly-rhamnose Backbone from Group A Carbohydrate (GAC)

Structure and Biosynthesis of Group A Carbohydrate (GAC)

Figure 2. Schematic structure of Group A Carbohydrate (GAC) which embedded into peptidoglycan with extracellular presentation.

GAC Role Towards GAS Virulence

Immunogenicity of GAC

Rhamnose-based GAS Vaccine from GAC Backbone

Figure 3. Protective mechanism toward GAS infection by vaccine-mediated IgG by Rhamnose-based vaccine.

Table 1. Rhamnose (Rha) Based GAS Vaccine from GAC Backbone in Pre-clinical Studies.

Conclusion

Data availability statement

References

Comments on this article Comments (0)

Open Peer Review

Comments on this article Comments (0)

Open Peer Review

Reviewer Status

Reviewer Reports

Comments on this article

Browse by related subjects

Competing Interests Policy

Stay Updated