Early-onset group B streptococcal disease in African countries and maternal vaccination strategies.

Invasive group B streptococcal (GBS) disease is the commonest perinatally-acquired bacterial infection in newborns; the burden is higher in African countries where intrapartum antibiotic prophylaxis strategies are not feasible. In sub-Saharan Africa, almost one in four newborns with GBS early-onset disease will demise, and one in ten survivors have moderate or severe neurodevelopmental impairment. A maternal GBS vaccine to prevent invasive GBS disease in infancy is a pragmatic and cost-effective preventative strategy for Africa. Hexavalent polysaccharide protein conjugate and Alpha family surface protein vaccines are undergoing phase II clinical trials. Vaccine licensure may be facilitated by demonstrating safety and immunological correlates/thresholds suggestive of protection against invasive GBS disease. This will then be followed by phase IV effectiveness studies to assess the burden of GBS vaccine preventable disease, including the effect on all-cause neonatal infections, neonatal deaths and stillbirths.

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

20 million pregnant women with group B streptococcus carriage: consequences, challenges, and opportunities for prevention.

PURPOSE OF REVIEW: Intrapartum antibiotic prophylaxis (IAP) is currently the only recommended preventive approach against clinical consequences of maternal Group B Streptococcus (GBS) colonization. In this review, we discuss new findings of total perinatal GBS burden and relative effectiveness of differing targeting of IAP, notably microbiology-based and risk factor-based screening, including potential limitations. Finally, we provide updates on maternal GBS vaccines and their potential cost-effectiveness in disease reduction. RECENT FINDINGS: Updated estimates of the burden of GBS related to pregnancy outcomes show (1) early-onset GBS disease incidence and deaths are high in some low- and middle-income countries where IAP has not been implemented and (2) late-onset GBS disease, preterm birth, and stillbirth, which are not preventable by IAP, remain a public health problem in both high and low-middle income settings. Observational evidence indicates that microbiology-based screening may be more effective than risk factor-based screening, but even in high-income countries, compliance is imperfect. To address the need for alternative prevention strategies, several maternal vaccine candidates are in clinical development, and modelling suggests these could be cost-effective in most scenarios. SUMMARY: Recent progress in GBS vaccine research holds promise of reducing the large and preventable burden of mortality and disability caused by GBS disease, especially in higher-burden settings where clinical and laboratory services may be limited. Importantly vaccines also hold potential to prevent GBS stillbirths and GBS-associated preterm births.

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.

Maternal vaccination with a type-III glycoconjugate protects mouse neonates against Group B Streptococcus intranasal infection.

Group B Streptococcus (GBS) is generally an asymptomatic colonizer of human mucosa but it occasionally infects pregnant women and neonates through vertical transmission, causing disease during the first weeks of life with frequent and severe complications. Preclinical studies have shown that maternal vaccination with polysaccharide-based vaccines protects mothers and offspring from GBS mucosal colonization and consecutive infection. In these models, bacteria were inoculated in mouse either intravaginally in the last trimester of pregnancy or systemically in pups. Here, we investigated whether maternal vaccination with glycoconjugate vaccines may also prevent GBS-mediated colonization and disease in neonates using an infection route that more closely mimics inhalation or ingestion of bacteria during human delivery. To address this point, mice aged less than two days were intranasally challenged with epidemiologically relevant GBS strains. Bacteria were found to colonize nose and intestine, reaching in some cases lungs and blood during the first days of life. Bacteria were also found in vagina of a fraction of colonized female mice within the first month of life. GBS-specific IgG induced by maternal vaccination with a glycoconjugate vaccine formulation were found in blood and mucosal tissues of newborns. Finally, when intranasally challenged with GBS serotype III strains, pups delivered by vaccinated mothers were partially protected against mucosal colonization and deeper infection.

Polyethylenimine quantity and molecular weight influence its adjuvanting properties in liposomal peptide vaccines.

We recently reported that polyethylenimine (PEI; molecular weight of 600 Da) acted as a vaccine adjuvant for liposomal group A Streptococcus (GAS) vaccines, eliciting immune responses in vivo with IgG antibodies giving opsonic activity against five Australian GAS clinical isolates. However, to date, no investigation comparing the structure-activity relationship between the molecular weight of PEI and its adjuvanting activity in vaccine development has been performed. We hypothesized that the molecular weight and quantity of PEI in a liposomal vaccine will impact its adjuvanting properties. In this study, we successfully formulated liposomes containing different molecular weights of PEI (600, 1800, 10k and 25k Da) and equivalents of PEI (0.5, 1 and 2) of branched PEI. Outbred mice were administrated the vaccine formulations intranasally, and the mice that received a high ratio of PEI 600 reported a stronger immune response than the mice that received a lower ratio of PEI 600. Interestingly, mice that received the same quantity of PEI 600, PEI 10k and PEI 25k showed similar immune responses in vivo and in vitro. This comparative study highlights the ratio of PEI present in the liposome vaccines impacts adjuvanting activity, however, PEI molecular weight did not significantly enhance its adjuvanting properties. We also report that the stability of PEI liposomes is critical for vaccines to elicit the desired immune response.

Poly(hydrophobic amino acid)-Based Self-Adjuvanting Nanoparticles for Group A Streptococcus Vaccine Delivery.

Peptide antigens have been widely used in the development of vaccines, especially for those against autoimmunity-inducing pathogens and cancers. However, peptide-based vaccines require adjuvant and/or a delivery system to stimulate desired immune responses. Here, we explored the potential of self-adjuvanting poly(hydrophobic amino acids) (pHAAs) to deliver peptide-based vaccine against Group A Streptococcus (GAS). We designed and synthesized self-assembled nanoparticles with a variety of conjugates bearing a peptide antigen (J8-PADRE) and polymerized hydrophobic amino acids to evaluate the effects of structural arrangement and pHAAs properties on a system's ability to induce humoral immune responses. Immunogenicity of the developed conjugates was also compared to commercially available human adjuvants. We found that a linear conjugate bearing J8-PADRE and 15 copies of leucine induced equally effective, or greater, immune responses than commercial adjuvants. Our fully defined, adjuvant-free, single molecule-based vaccine induced the production of antibodies capable of killing GAS bacteria.

The Italian arm of the PREPARE study: an international project to evaluate and license a maternal vaccine against group B streptococcus.

BACKGROUND: Group B streptococcus (GBS) is a leading cause of sepsis, pneumonia and meningitis in infants, with long term neurodevelopmental sequelae. GBS may be associated with poor pregnancy outcomes, including spontaneous abortion, stillbirth and preterm birth. Intrapartum antibiotic prophylaxis (IAP) is currently the only way to prevent early-onset disease (presenting at 0 to 6 days of life), although it has no impact on the disease presenting over 6 days of life and its implementation is challenging in resource poor countries. A maternal vaccine against GBS could reduce all GBS manifestations as well as improve pregnancy outcomes, even in low-income countries. MAIN BODY: The term "PREPARE" designates an international project aimed at developing a maternal vaccination platform to test vaccines against neonatal GBS infections by maternal immunization. It is a non-profit, multi-center, interventional and experimental study (promoted by the St George University of London. [UK]) with the aim of developing a maternal vaccination platform, determining pregnancy outcomes, and defining the extent of GBS infections in children and mothers in Africa. PREPARE also aims to estimate the protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa and to conduct two trials on candidate GBS vaccines. PREPARE consists of 6 work packages. In four European countries (Italy, UK, Netherlands, France) the recruitment of cases and controls will start in 2020 and will end in 2022. The Italian PREPARE network includes 41 centers. The Italian network aims to collect: GBS isolates from infants with invasive disease, maternal and neonatal sera (cases); cord sera and GBS strains from colonized mothers whose infants do not develop GBS infection (controls). SHORT CONCLUSION: PREPARE will contribute information on protective serocorrelates against the main GBS serotypes that cause diseases in Europe and Africa. The vaccine that will be tested by the PREPARE study could be an effective strategy to prevent GBS disease.

Concerns for efficacy of a 30-valent M-protein-based Streptococcus pyogenes vaccine in regions with high rates of rheumatic heart disease.

The prevalence of rheumatic heart disease (RHD) in the Aboriginal population of the Australian Northern Territory is high, and Streptococcus pyogenes skin infections likely contribute to this. A promising candidate S. pyogenes "30mer" vaccine is composed of 30 pharyngitis associated type-specific antigens from the S. pyogenes M protein. Cross opsonisation experiments suggest that 30mer vaccine protection may extend to non-cognate emm types. A new "emm cluster" scheme for classifying M protein is based on the full-length coding sequence, and correlates with functional and immunological properties, and anatomical tropism. Twenty-seven years of research in the Northern Territory has yielded 1810 S. pyogenes isolates with clinical and emm type data. The primary aim was to analyse these data with reference to the emm cluster scheme and cross opsonisation information, to inform estimation of 30mer vaccine efficacy in the Northern Territory. The isolates encompass 101 emm types. Variants of cluster A-C were enriched in throat isolates, and variants of emm cluster D enriched in skin isolates. Throat isolates were enriched for 30mer vaccine cognate emm types in comparison with skin isolates of which only 25% were vaccine emm types. While cross opsonisation data indicates potential for enhancing 30mer vaccine coverage, more than one third of skin isolates were within 38 emm types untested for cross opsonisation. Emm cluster D variants, in particular emm cluster D4, were not only all non-cognate with the vaccine, but were abundant and diverse, and less likely to be cross-opsonisation positive than other emm clusters. Long term persistence of many emm types in the study area was revealed. It was concluded that the 30mer vaccine efficacy in the Northern Territory will likely require both cross protection, and additional measures to elicit immunity against variants of emm cluster D.

Mucosal vaccine based on attenuated influenza virus and the group B Streptococcus recombinant peptides protected mice from influenza and S. pneumoniae infections.

Although many influenza-related deaths are attributable to secondary bacterial infection with S. pneumoniae, vaccines that simultaneously protect against influenza and pneumococcal infection are currently not developed. The aim of our study was to evaluate the possibility to prevent post-influenza pneumococcal infection using an associated vaccine based on live influenza vaccine (LAIV) combined with recombinant polypeptides derived from superficial factors of Group B streptococcus (GBS) determining pathogenicity. We demonstrated in a model of post-influenza pneumococcal pneumonia that intranasal pneumococcal super-infection seriously complicated the course of A/Shanghai/2/2013(H7N9) CDC-RG virus infection in mice. Associated immunization using LAIV and GBS vaccine (GBSV) prevented post-influenza pneumococcal pneumonia better than mono-LAIV or GBSV immunization. At the same time, parenteral pneumococcal post-influenza infection of immune mice was more severe in the groups immunized using recombinant GBS peptides which can be explained by antibody-dependent enhancement of infection. In this case, the introduction of blockers of histamine receptors type 1 and 2 reduced the burden of secondary pneumococcal infection.

Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Economic appraisal of vaccination against Streptoccocus agalactiae in Nile tilapia farms in Brazil.

Infection with Streptococcus agalactiae causes mortality and major economic losses in Nile tilapia (Oreochromis niloticus) farming worldwide. In Brazil, serotype strains Ia, Ib and III have been isolated in streptococcosis outbreaks, but serotype Ib is the most prevalent. Vaccination is considered an effective method to prevent economically-important diseases in aquaculture and has been associated with decreased use of antibiotics and improvements in fish survival. We developed a flexible partial-budget model to undertake an economic appraisal of vaccination against Streptococcus agalactiae in Nile tilapia farmed in net cages in large reservoirs. The model considers the benefits and costs that are likely to be associated with vaccination at the farm-level, in one production cycle. We built three epidemiological scenarios of cumulative mortality attributable to S. agalactiae (5%, 10%, and 20%, per production cycle) in a non-vaccinated farm. For each scenario, we applied a stochastic model to simulate the net return of vaccination, given a combination of values of "vaccine efficacy", "gain in feed conversion ratio", "feed price", "fish market price ", and "cost of vaccine dose". In the 20% cumulative mortality scenario, the net return would break-even (benefits ≥ costs) in at least 97.9% of interactions. Should cumulative mortality be lower than 10%, the profitability of vaccination would be more dependent on better feed conversion ratio. The inputs "feed price" and "cost of vaccine" had minor effects on the output, in all pre-vaccination mortality scenarios. Although our simulations are based on conservative values and consider uncertainty about the modeled parameters, we conclude that vaccination against S. agalactiae is likely to be profitable in Nile tilapia farms, under similar production conditions.

Maternal immunisation: What have been the gains? Where are the gaps? What does the future hold?

The vaccination of pregnant women has enormous potential to protect not only mothers from vaccine-preventable diseases but also their infants through the passive acquisition of protective antibodies before they are able to themselves acquire protection through active childhood immunisations. Maternal tetanus programmes have been in place since 1989, and as of March 2018, only 14 countries in the world were still to reach maternal neonatal tetanus elimination status. This has saved hundreds of thousands of lives. Building on this success, influenza- and pertussis-containing vaccines have been recommended for pregnant women and introduced into immunisation programmes, albeit predominantly in resource-rich settings. These have highlighted some important challenges when additional immunisations are introduced into the antenatal context. With new vaccine candidates, such as respiratory syncytial virus (RSV) and group B streptococcus (GBS), on the horizon, it is important that we learn from these experiences, identify the information gaps, and close these to ensure safe and successful implementation of maternal vaccines in the future, particularly in low- and middle-income countries with a high burden of disease.

Vaccine-induced antibody level as the parameter of the influence of environmental salinity on vaccine efficacy in Nile tilapia.

To effectively increase production and improve economic returns, the co-culture of Nile tilapia (Oreochromis niloticus) and marine shrimp has been adopted in many countries, including China. Although O. niloticus is an euryhaline fish that can tolerate elevated salinities and even full-strength seawater, fluctuations in salinity levels can undoubtedly induce stress and affect the immune response of this fish. Therefore, this study assessed the impact of salinity on vaccine efficacy in Nile tilapia, which used serum antibody level as a surrogate marker to detect vaccine efficacy. Nile tilapia were acclimatized to 0, 10, 20, or 30 ppt salinity, and then immunized with a formalin-inactivated Streptococcus agalactiae vaccine. Significantly lower levels of antibody in vaccinated fish were found at 20 and 30 ppt salinity compared to 0 and 10 ppt salinity. White blood cell counts, absolute blood lymphocyte counts, and serum bactericidal activity levels were all significantly lower in vaccinated fish at 20 and 30 ppt salinity. Elevated cortisol levels were detected in all of the fish exposure to salinity. Concentrations of serum electrolytes (Na+ and Cl-) were significantly higher in fish at 30 ppt salinity, as compared to fish at lower salinities. Furthermore, the mRNA transcription levels of three of the immune-related genes analyzed (IgM, IL-1ß, and IFN-γ, but not Hsp70) were significantly inhibited in the vaccinated fish at 20 and 30 ppt salinity. A suppressed immune response and decreased vaccine efficacy were also indicated by the lower survival rate of vaccinated fish at 20 ppt salinity when challenged with S. agalactiae. Therefore, salinities ≥20 ppt negatively affected antibody production in Nile tilapia, ultimately affecting vaccine efficacy.

Incidence of paediatric pneumococcal meningitis and emergence of new serotypes: a time-series analysis of a 16-year French national survey.

BACKGROUND: Successive implementation of seven-valent then 13-valent pneumococcal conjugate vaccines (PCVs) led to a marked decrease in pneumococcal disease burden, including pneumococcal meningitis. We assessed the long-term effect of implementation of PCVs on incidence of pneumococcal meningitis in children in France over a 16-year period. METHODS: We did a quasi-experimental, population-based interrupted time-series analysis with a nationwide prospective survey over 16 years in France, recruiting children aged younger than 15 years from 227 paediatric wards from January, 2001, to December, 2016. The main outcome by the time-series model was the estimated incidence of pneumococcal meningitis per 100 000 children (of a population of 12·6 million children in 2017) before and after PCV7 and PCV13 implementation. The time-series model was based on segmented regression with autoregressive error. FINDINGS: We enrolled 1778 children with pneumococcal meningitis. PCV13 implementation led to a significant reduction in monthly incidence of pneumococcal meningitis from 0·12 per 100 000 children before PCV13 to a nadir of 0·07 in December, 2014 (-38%, 95% CI -56·1 to -20·4; p<0·0001). A sharp increase occurred during 2015 and 2016, (+2·3% per month, incidence of 0·13 per 100 000 children at the end of the study period, p=0·0002), mainly related to an increase of serotype 24F, which was frequently penicillin resistant. INTERPRETATION: The early effect of PCV13 implementation greatly reduced the incidence of pneumococcal meningitis in children less than 15 years old. However, a sharp rebound in incidence linked to the emergence of serotype 24F compromised the long-term PCV efficacy. If confirmed in future studies and in other countries, pneumococcal meningitis incidence rebound and 24F emergence should be considered when developing next-generation PCVs. FUNDING: The French Pediatric Infectious Diseases Group, Association Clinique et Thérapeutique Infantile du Val de Marne, Pfizer, and for the National Reference Centre for Pneumococci, the French National Health Agency.

A Time to Save.

Group B Streptococcus (GBS), characterized by Lancefield in 1933, was not recognized as a human pathogen until the early 1970s when it emerged and replaced Escherichia coli as the most common cause of sepsis and meningitis among neonates and young infants. This article briefly gives a personnel account of the discovery of clinical syndromes of GBS distinguished by age at onset, vertical mode of transmission for early-onset disease, meningeal tropism for GBS capsular (CPS) type III strains, and protective CPS epitopes. It also reviews the difficult evolution of the now routine program for antenatal GBS culture screening and intrapartum antibiotic prophylaxis, development of the first GBS candidate vaccines, clinical trials documenting the immunogenicity and safety of CPS tetanus toxoid conjugate vaccines, ongoing need to prevent morbidity and mortality in neonates and young infants, and critical need for commercial vaccines for routine use in pregnant women.

Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children: Why, What, and How to Undertake Estimates?

Improving maternal, newborn, and child health is central to Sustainable Development Goal targets for 2030, requiring acceleration especially to prevent 5.6 million deaths around the time of birth. Infections contribute to this burden, but etiological data are limited. Group B Streptococcus (GBS) is an important perinatal pathogen, although previously focus has been primarily on liveborn children, especially early-onset disease. In this first of an 11-article supplement, we discuss the following: (1) Why estimate the worldwide burden of GBS disease? (2) What outcomes of GBS in pregnancy should be included? (3) What data and epidemiological parameters are required? (4) What methods and models can be used to transparently estimate this burden of GBS? (5) What are the challenges with available data? and (6) How can estimates address data gaps to better inform GBS interventions including maternal immunization? We review all available GBS data worldwide, including maternal GBS colonization, risk of neonatal disease (with/without intrapartum antibiotic prophylaxis), maternal GBS disease, neonatal/infant GBS disease, and subsequent impairment, plus GBS-associated stillbirth, preterm birth, and neonatal encephalopathy. We summarize our methods for searches, meta-analyses, and modeling including a compartmental model. Our approach is consistent with the World Health Organization (WHO) Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER), published in The Lancet and the Public Library of Science (PLoS). We aim to address priority epidemiological gaps highlighted by WHO to inform potential maternal vaccination.

Bivalent mucosal peptide vaccines administered using the LCP carrier system stimulate protective immune responses against Streptococcus pyogenes infection.

Despite the broad knowledge about the pathogenicity of Streptococcus pyogenes there is still a controversy about the correlate of protection in GAS infections. We aimed in further improving the immune responses stimulated against GAS comparing different vaccine formulations including bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and BPPCysMPEG, a derivative of the macrophage-activating lipopeptide (MALP-2), as adjuvants, respectively, to be administered with and without the universal T helper cell epitope P25 along with the optimized B cell epitope J14 of the M protein and B and T cell epitopes of SfbI. Lipopeptide based nano carrier systems (LCP) were used for efficient antigen delivery across the mucosal barrier. The stimulated immune responses were efficient in protecting mice against a respiratory challenge with a lethal dose of a heterologous S. pyogenes strain. Moreover, combination of the LCP based peptide vaccine with c-di-AMP allowed reduction of antigen dose at the same time maintaining vaccine efficacy.