Streptococcus pyogenes causes significant global morbidity and mortally through a range of pathologies. The most common sites of infection are the upper respiratory tract and the skin, resulting in pharyngitis and impetigo respectively. Non-invasive infections are usually self-limiting; however, they have the potential to progress to life threatening invasive diseases such as toxic-shock syndrome and necrotizing fasciitis with a high rate of mortality. Furthermore, S. pyogenes infections can give rise to auto-immune sequelae of ARF/RHD and ASPGN that result in approximately 500 000 deaths each year. Despite global efforts that span decades, no human vaccine is approved for use. The major hurdles in vaccine development are the broad serotypic and antigenic diversity of S. pyogenes, the risk for potential auto-immune disease due to the molecular mimicry of the S. pyogenes M-protein (a prime vaccine target) and human cardiac myosin, and the ability of S. pyogenes to infect different body sites that require different protective immune mechanisms. Previous research has shown that exposure to S. pyogenes can result in protective antibodies, though immunity is slow to develop and its role in preventing subsequent infections is poorly understood. In addition, there is a need to understand the mechanism of cross-compartment immunity to aid in guiding vaccine development to protect from multiple serotypes and also at various infection sites. To understand the mechanisms involved in site-specific and cross-compartment immunity, repeated mucosal exposures to S. pyogenes non-lethal infections in mice were performed to mimic endemic settings. Repeated homologous mucosal infections resulted in significant site-specific protection that endured for at least 9 weeks. Mice developed type-specific serum antibodies and antibody secreting cells (ASCs) that increased with increasing number of infections. These data indicate that the longevity of the antibody response is governed by the number of prior mucosal infections; however, no direct correlation with protection was established. Mucosal protection indicated a role for cell-mediated immunity. Repeated acute mucosal infections resulted in significant neutrophil recruitment to the local site of inflammation that correlated with protection. Cytokine analysis suggested a role for IL-17A in mucosal protection, particularly for enduring protection. To assess the importance of IL-17, IL-17 knockout (IL-17-/-) mice were given repeated homologous mucosal infections. Unlike wild type BALB/c mice, IL-17-/- mice failed to generate mucosal protection with repeated exposures. Furthermore, IL-17-/- mice had significantly reduced M-protein type-specific salivary IgG, IgG and IgA-secreting cells in bone marrow, and neutrophil influx to the lung, correlating with lack of protection. Mice required only one prior mucosal infection to develop significant and long-lasting protection against a homologous mucosal challenge. However, when cross-compartment protection at the skin was assessed, mice required a minimum of four repeated mucosal infections to generate significant protection. These data suggest that developing a protective immune response by repeated exposures is unlikely in a real-world setting. The literature indicates that multiple different S. pyogenes types move through communities, and people rarely encounter the same strain again within a short period of time. Realising these constraints in developing naturally acquired immunity to S. pyogenes, the next question was then asked: ‘could vaccine mediated immunity be boosted and broadened via natural exposures to S. pyogenes?’ Vaccine candidates based on the conserved C-terminal region of S. pyogenes M-protein (p145) have made considerable progress. The C-terminal region of the M protein is conserved across the majority of S. pyogenes strains, therefore forgoing the issue of serotype diversity. Two vaccine epitopes at the forefront of development, J8 and p17, when conjugated to the carrier protein, diphtheria toxoid (DT), create J8-DT and p17-DT. p17-DT delivered intramuscularly with the adjuvant, alum, (p17-DT/Alum) has shown promising immunogenicity and protection against several S. pyogenes isolates; however, it does not protect mice against intranasal challenge with a hypervirulent covR/S mutant strain. To test the hypothesis that infection will boost vaccine-mediated immunity, mice received two vaccinations with p*17-DT/Alum, followed by repeated mucosal infections every three weeks with heterologous isolates. Mice that received vaccinations followed by sequential infections showed increasing protection against NALT (nasal associated lymphoid tissue) bacterial load with each subsequent infection when compared to naïve mice. Bacterial load in the NALT was significantly reduced in these mice following a covR/S mutant challenge. Antigen-specific ASCs were assessed as a determinant of humoral immunity. Although no increase in serum antibody levels or antibody avidity were observed between mice that received vaccination alone or when followed by repeated infections, the mice that received vaccination and sequential infections had significantly increased IgG secreting cells in the spleen. The ASCs, in combination with lung specific CD4+ T-cell responses may be contributing to increased protection seen in mice that were boosted with repeated heterologous infections. Although promising, the results were scattered, which may be attributed to the differences in sequence homology of p145 as well as characteristics of different isolates. These data suggest that vaccine-mediated immunity has the potential to be boosted with repeated exposures to S. pyogenes. However, it was demonstrated that there is room for improvement in vaccination strategy and alternative approaches should be explored. Therefore, the next aim was to assess if new delivery methods could be used to increase vaccine-mediated immunogenicity and protection. Different methods of vaccine delivery can invoke varied immune responses. Skin-based immunisation routes have gained attention due to targeting of the epidermis and dermis layers rich in immune cells. Several advantages are associated with cutaneous routes, particularly when using high density/micro array patches (MAPs and HD-MAPs). These include dose sparing, enhanced thermostability, ease of administration, reduced generation of sharp-waste and risk of needle-stick injuries, good tolerability and enhanced acceptability in patients. HD-MAPs, developed by Vaxxas Pty Ltd, are at an advanced stage of development and have shown promising clinical trials results. The aim of his final study was to determine if the M-protein-based vaccine candidate J8-DT would have comparable immunogenicity and protection if delivered on the adjuvant free HD-MAP in comparison to intramuscular delivery. The effect of dose sparing and the number of vaccinations on the antibody response profile of vaccinated mice were assessed. A reduction in the number of vaccinations (from three to two) with J8-DT/HD-MAP induced comparable antibody responses to three vaccinations with intramuscular J8-DT/Alum. J8-DT/HD-MAP vaccination led to a significant reduction in the number of S. pyogenes colony forming units in skin (92.9%) and blood (100%) compared to intramuscular vaccination with unadjuvanted J8-DT when assessed following skin challenge. J8-DT/HD-MAP induced a shift in the antibody isotype profile, with a bias towards Th1-related isotypes, compared to J8-DT/Alum (Th2 bias). Based on the results of this study, the use of J8-DT/HD-MAP should be considered in future clinical development and control programs against S. pyogenes. The studies in this thesis demonstrate the constraints in developing naturally acquired immunity and highlight the importance for developing an effective vaccine against S. pyogenes.