The group A Streptococcus (GAS) bacterium—is one of the top-10 infectious causes of deaths in the world [1]. According to the Global Burden of Disease 2010 study, this disease affects more than 34 million people, causing >345,000 deaths and 10 million disability-adjusted life years (DALYs) lost per year, almost all in low- and middle-income countries (LMIC) [23]. Most cases and deaths occur in children, adolescents, and young adults, depriving developing countries of many young people. In particular GAS, through the progressive cardiac condition known as rheumatic heart disease, causes substantial morbidity and mortality in pregnancy—with consequences for the expectant mother and her child.

GAS infections cause substantial worldwide morbidity and mortality—the combined mortality associated with rheumatic heart disease (RHD) and invasive GAS exceeds all other causes of infectious disease death excluding human immunodeficiency virus, tuberculosis, malaria, and S. pneumonia [34]. GAS nosology includes suppurative complications (pharyngitis, invasive GAS disease, and impetigo), non-suppurative (immune) syndromes (acute rheumatic fever [ARF], RHD, and acute post-streptococcal glomerulonephritis), and toxin-mediated diseases such as scarlet fever and streptococcal toxic shock syndrome. A consequence of ARF, RHD is responsible for progressive valvular heart disease (VHD) such as mitral stenosis and mitral regurgitation, and in resource limited settings pregnant women suffer a marked increase in maternal morbidity and unfavorable fetal outcomes, which are related to severity of disease [5]. While RHD has become relatively rare in developed countries, it remains quite common in the developing world where 90% of all heart disorders in women of childbearing age are rheumatic in origin. Although accurate statistics are lacking, the estimated incidence of rheumatic fever in sub-Saharan Africa is approximately 13 cases per 100,000 per year based on clinical screening, while estimations between 21.5 and 30.4 per 1,000 have been reported for example in Cambodia and Mozambique when using echocardiographic screening. Besides its high prevalence, RHD in developing countries is characterized by the occurrence of severe VHD at a younger age than in developed countries [67]. ARF, the condition that precedes RHD, is believed to be a form of autoimmunity mediated by the similarity between the GAS coiled M protein and GAS polysaccharides to human myosin and between GAS cell wall and carbohydrates on heart muscle [8]. An alternate explanation is an interaction between M protein and type IV valvular collagen, inducing an immune response to collagen [8910]. Antibodies found in ARF recognize valvular endothelium structural proteins such as collagen and elastin, and similarly also recognize N-acetylglucosamine and target dopamine receptors in the brain, possibly explaining the choreiform movements found in ARF [1011].

GAS is a neglected disease of poverty and social injustice [12] that can however be prevented, using one of the cheapest and oldest antibiotics known—penicillin. The urgency for disease control is yet to be recognized at the highest level as it has been largely ignored by international organizations and other key stakeholders. Few affected countries have any coordinated strategy to implement control programs [13]. A GAS vaccine represents and urgent need for this neglected disease and should therefore deserve the greatest attention of international organizations, donors and vaccine manufacturers.

GAS strains are categorized by variation in the nucleotide sequence of the emm gene that encodes the variable M protein. Limited data on emm gene sequences are available from LMIC which, as with serotypes, seem to differ from high-income countries [14]. Africa and the Pacific are characterized by a wider diversity of emm types, and many of the common emm types found in industrialized countries are far less common (emm 1, 4, 6, and 12). One explanation provided is the high prevalence of GAS impetigo accompanied by large numbers of circulating GAS of multiple emm types that are readily transmitted and found in some resource-poor settings [15].

Like pneumococcal vaccines, a GAS vaccine would need to overcome the issue of multiple strains. Recent data from both whole M protein sequencing and multivalent vaccines suggest that M protein–based vaccines may evoke cross-protective antibodies that would broaden their potential efficacy and potentially mitigate any concerns about the emergence of new non-vaccine serotypes [1617]. Some data are available for a vaccine (J8), which contains a common B-cell epitope of M protein whose structure seems highly conserved among GAS strains in a limited number of tropical settings [14]. Another 26-valent M protein-based vaccine, which contains N-terminal M peptides from 26 of the most common serotypes in North America, would likely provide good coverage in high-income countries, particularly United States, Canada, and Europe, but poor coverage in Africa and the Pacific and only intermediate coverage in Asia and the Middle East [18]. These data clearly have significant implications for multivalent M protein vaccines and are the subject of ongoing investigation.

Several arguments suggest that a GAS vaccine is feasible [1920]. GAS infection is common in childhood and uncommon in adulthood, suggesting that immunity is acquired through lifetime exposure. Longitudinal data showing the development of antibodies against common emm types in the United States support this hypothesis. Moreover, pre-clinical studies in animals show protection against challenge with GAS. Older studies of a GAS vaccine showed efficacy in a human challenge model against homologous S. pyogenes challenge [21].

Table 1 provides an overview of the vaccine candidates at various pre-clinical and clinical stages. To address strain diversity, several vaccine design approaches have been proposed using M protein– and non-M protein–based vaccine antigens.

Nineteen clinical studies of GAS vaccines have been conducted involving thousands of subjects. Candidate vaccines have generally been safe and well tolerated [19]. However, one major concern was the possible induction of ARF through autoimmune mechanisms triggered by vaccine components [36]. Following some initial unfortunate experiences in humans, the U.S. Food and Drug Administration issued a regulation preventing licensure of vaccines containing GAS or its derivatives; a restriction removed in 2006. It is now believed that immunogenic regions of the M protein could be distinguished from those sections believed to be rheumatogenic. Subsequent studies of M protein vaccines that do not include M protein components cross-reacting with human tissues suggest that these vaccines are safe.

Table 2 summarizes the key scientific and strategic challenges to GAS vaccine development. The estimates of the global burden of disease, particularly the morbidity and mortality associated with ARF/RHD, acute post-streptococcal glomerulonephritis and invasive disease have been based on limited data from LMIC [37383940]. Deployment of vaccines into populations at highest risk for ARF/RHD will require additional surveillance and effectiveness studies to provide the data required to support policy decisions and effective implementation. There is also a considerable burden of GAS impetigo in tropical settings. There is a hypothetical link between GAS impetigo and ARF and RHD, although the pathogenetic link remains unknown [41]. Preventing skin infections would be highly desirable for a global GAS vaccine. However, little is known about immune protection against skin infections.

Human immune correlates of protection against GAS infection are not clearly defined. The focus for decades has been on the protective role of M protein antibodies in animal models of infection. For most of the potential GAS vaccine antigens, there are few data supporting their role in protection against natural infection in humans. The small animal models currently used to assess potential vaccine efficacy are considered to be of limited predictive value and could lead to the exclusion of potentially efficacious antigens [42]. There are limited criteria for selection of antigens to include in combination vaccines that would optimize vaccine efficacy. Vaccines containing M protein peptides evoke opsonic antibodies that promote bactericidal killing in vitro. C5a peptidase induces antibodies that neutralize the enzyme [43], thus preventing the degradation of this potent chemo-attractant. Adhesins evoke antibodies that block bacterial adherence [44]. Many of the non-M protein common antigens do not have associated functional in vitro assays that could be applied in pre-clinical or clinical studies.

The complex global epidemiology of GAS infections poses a challenge to the development of a single vaccine for the entire world [2425]. Vaccines containing amino-terminal peptides of M proteins may or may not provide sufficient serotype coverage, or durable serotype coverage, in areas of the world where ARF is highly prevalent.

World Health Organization (WHO) has made the development of GAS vaccines a priority. GAS vaccine development is mentioned in the Global Vaccine Action Plan 2010-2020, framework approved by the World Health Assembly in May 2012 to achieve the Decade of Vaccines vision by delivering universal access to immunization [45]. So far, no detailed plan has been developed with vaccine developers, researchers, vaccine manufacturers, global health policy makers, and donors. The strategic goal to accelerate the development and licensure of an effective and affordable GAS vaccine to prevent ARF and RHD as well as invasive infections in LMIC should receive utmost attention. Unfortunately, this effort seems, at least for the moment, precluded by the absence of industrial manufacturers and sufficient public/private funding. Funding for RHD prevention and GAS vaccines accounts for less than 0.1% of neglected tropical diseases global health funding [46].

The establishment of a roadmap implies an international collaborative effort, leadership, administrative and governance structures, gathering key stakeholders including public health and scientific experts on GAS disease pathogenicity and epidemiology, immunology, pre-clinical and clinical vaccinology, assay development, health policy and cost-effectiveness, vaccine manufacturers, private and public donors to secure sufficient funding for a comprehensive strategy. The WHO is positioned to provide leadership, and a funded product development partnership that is focused on the critical path to GAS vaccine development will be important to the success of this undertaking.

GAS infection and its devastating morbidity and mortality remain a 'hidden' public health disease borne disproportionately in LMIC that received little attention. The scale and impact of GAS infections and the preliminary evidence that a vaccine may be successful make cogent and compelling case for work on a GAS vaccine. Importantly, engagement of major vaccine manufacturer would facilitate the successful development of this product, and there is experience in developing vaccines for global health needs that have used product development partnerships funded by private philanthropy. To achieve these goals, a strong advocacy effort is needed by establishing and maintaining country-level dialogues to facilitate decision-making on GAS vaccine policy that would benefit to LMIC populations most at risk for GAS infection.