Elsevier

Vaccine

Volume 31, Supplement 2, 18 April 2013, Pages B216-B222
Vaccine

Review
Group A streptococcal vaccines: Paving a path for accelerated development

https://doi.org/10.1016/j.vaccine.2012.09.045Get rights and content

Abstract

Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. These organisms cause a wide spectrum of disease, ranging from uncomplicated sore throat to invasive, life-threatening infections, as well as immune complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and acute post-streptococcal glomerulonephritis (APSGN). Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. Several vaccine candidates against GAS infection are in various stages of pre-clinical and clinical development, including M protein-based vaccines (N-terminal vaccine candidates and M protein conserved region vaccines), and non-M protein vaccine candidates representing conserved GAS antigens. Some of the obstacles to GAS vaccine development are related to the complexity of the global epidemiology of GAS infections, the limitation in the criteria for selection of antigens to include in combination vaccines as well as the issues around autoimmunity and vaccine safety, among others. Overcoming these obstacles will require collaborative efforts to develop innovative strategies that address key steps in the pre-clinical and clinical development process, as well as clearly defining the global burden of GAS diseases and the molecular epidemiology of infections. Specific recommendations are presented for an accelerated plan leading to the introduction of a broadly protective vaccine designed for deployment in low-, middle-, and high-income countries.

Highlights

► We summarize the global burden of group A streptococcal diseases. ► We review the current status of group A streptococcal vaccines. ► We describe obstacles to streptococcal vaccine development. ► We detail a path for accelerated vaccine development. ► Cooperation and collaboration are keys to success.

Introduction

Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. Recent population-based estimates indicate that there are at least 517,000 deaths each year due to severe GAS diseases (e.g., acute rheumatic fever (ARF), rheumatic heart disease (RHD), acute post-streptococcal glomerulonephritis (APSGN), and invasive infections) [1]. The greatest burden of GAS disease is due to RHD, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. Previous estimates indicated that 6.4 million disability adjusted life years (DALYs) are attributed to RHD worldwide and almost 6 million of these are in low-income countries [2]. RHD is a disease whose manifestations peak during the child-bearing and wage-earning years and thus can have devastating effects on the well-being of entire families. The global burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths estimated each year [1], with an incidence ranging from 1.6 to 82.5 per 100,000 in difference geographic regions [3]. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis [1].

Epidemiologic data from developing countries for most GAS diseases is poor. Recent studies in developing countries indicate that there is a large burden of undiagnosed RHD, which may mean that the true mortality from RHD is several-fold higher than previous estimates [4], [5], [6]. Updated estimates are expected soon from the 2010 Global Burden of Disease (GBD) Injuries and Risk Factors Study. Note that the estimates cited here do not adequately take into account the substantial additional contribution of RHD to deaths from stroke, endocarditis, and atrial fibrillation in developing countries. There are a number of challenges to estimating GAS disease burden in low and middle income countries, including a lack of uniform methodology across studies, poor access to laboratory diagnosis, limited access to health care services for some high risk groups; inadequate medical records and unreliability or absence of vital events registration systems. In an effort to remedy some of the problems, standard protocols for GAS burden estimation were developed in 2005 [7]. Although these protocols have been used at a number of sentinel sites (Mali, Nicaragua, Fiji, and the Vanguard Community in Cape Town), there is a need to ensure that these protocols are regularly updated, implemented more widely and to establish additional sentinel research sites. Although revised consensus criteria have been published for the echocardiographic diagnosis of RHD [8], there remain key issues related to the significance of clinically silent RHD in children [9]. Longitudinal studies will be required to establish the proportion of children with subclinical findings that progress to symptomatic disease. Protocols for laboratory diagnostic and emm typing methods have been established [10]. Consensus standardized protocols and nomenclature will be crucial for global surveillance activity.

Recognizing the significant global burden of disease and the potential benefit of vaccine prevention of serious GAS disease and RHD, Hilleman Laboratories sponsored a consultation with experts from around the world in New Delhi in March, 2010 to discuss the desirability and feasibility of GAS vaccines [11]. In parallel with the Decade of Vaccines Collaboration, the World Health Organization's Initiative for Vaccine Research convened a satellite meeting of experts in June, 2011 to evaluate GAS vaccines for the developing world. The overall goal is to develop a roadmap for vaccine development, which would include additional surveillance, vaccine research, regulatory hurdles, and clinical development pathways. The proceedings of this workshop and the proposal for the development of a roadmap have informed the topics presented in this manuscript [12].

Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. Vaccine development has met several obstacles, including the theoretical risk that vaccines may induce ARF or APSGN through molecular mimicry or other autoimmune mechanisms. It is important to note that initial safety concerns have been mostly allayed by the results of subsequent studies. Since 1923 there have been 19 clinical trials of numerous GAS vaccine candidates, ranging from whole, killed bacteria to highly purified M proteins involving thousands of subjects [13]. Only one small study, which was significantly flawed in design, appeared to suggest an increased risk of ARF in subjects that were hyper-immunized with crude vaccine preparations [14], [15]. More recently, two different multivalent M protein-based vaccines have been tested in Phase 1/2 clinical studies involving 128 normal adult volunteers [16], [17]. There was no evidence of autoimmunity or clinical sequelae in any of the vaccine recipients [16], [17], [18]. Pre-clinical evaluation of a new 30-valent vaccine has also shown it to be free of human tissue cross-reactive epitopes [19].

An ideal GAS vaccine would prevent pharyngeal colonization, carriage, symptomatic and asymptomatic infection, as well as impetigo, invasive disease, toxin mediated complications, ARF, RHD and APSGN. The disease burden, public demand, public health and economic priorities for a GAS vaccine differ in various parts of the world. In industrialized countries, the factors driving the development and deployment of GAS vaccines are a reduction in the number of cases of GAS pharyngitis and prevention of invasive GAS disease [20], [21], [22]. Prevention of GAS pharyngitis may translate into a marked reduction in the number of antimicrobial prescriptions for sore throat symptoms and time spent away from school/work. In the USA, it has been estimated that prevention of invasive GAS cases would translate into reductions in severe morbidity and mortality [20]. In the developing world, the drivers are broader and include the high burden of ARF/RHD, invasive disease, and APSGN with its potential for contributing to chronic renal disease in adulthood [23], [24]. Prevention of ARF/RHD would translate into a significant reduction in global mortality and morbidity as well as a considerable socio-economic impact with reductions in RHD-related health care costs associated with chronic cardiac failure and expensive cardiac surgery, and improvements in economic productivity given that RHD affects children, adolescents and young adults.

Section snippets

Molecular epidemiology of GAS infections and implications for vaccine development

emm sequence typing is the most widely used method for defining GAS strains. Most of the available data are from high-income countries (84%), with limited data from low-income countries [25]. Limited data indicate that the epidemiology of GAS disease in low- and middle-income countries in Africa, Asia and the Pacific region appears to differ from that in other parts of the world, especially when compared to high-income countries. In Africa and the Pacific, there appear to be no dominant emm

Current status of GAS vaccine development

Several vaccine candidates against GAS infection are in various stages of pre-clinical and clinical development (Table 1).

Type specific M protein-based vaccines. These vaccines consist of short peptides from the N-terminal region of M proteins from multiple different GAS emm types fused together in tandem to form larger vaccine polypeptides. A 26-valent vaccine has been constructed that includes 80–90% of serotypes that historically caused invasive infections or pharyngitis, as demonstrated by

The barriers to vaccine development

  • (1)

    The global epidemiology of GAS infections is complex, posing a challenge to the development of a single vaccine for the entire world. 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. Although many experts agree that we have knowledge sufficient to construct combination vaccines that could elicit broadly protective immune responses, there has been

Recommendations to accelerate GAS vaccine development

The working groups that participated in the World Health Organization's Initiative for Vaccine Research satellite meeting and the Decade of Vaccines Collaboration have developed the following recommendations aimed at accelerating the development of GAS vaccines. The recommendations are consistent with the Draft Global Vaccine Action Plan that was presented to the 65th World Health Assembly on May 11, 2012 [46], which, in part, calls for the development, licensure and introduction of new

Priority areas of work and key activities

To achieve the goals of this plan, development of a roadmap is critical. This will be a collaborative effort to identify and address challenges as well as make recommendations about which activities could serve as areas of investment to accelerate the development of a group A streptococcal vaccine. A number of key activities need to be undertaken in the pre-clinical and clinical development and evaluation of GAS vaccines as outlined below.

Develop a roadmap

(1) Develop a roadmap/pathway for the proposed work through WHO-led international effort. The Roadmap will include the administrative and governance structure of the program, details of the work proposed, the desired target product profile, as well as the development of an overall short- and long-range vaccine clinical development plan and initial vaccine introduction considerations.

  • A core group of experts will serve as the catalyst for development of a roadmap.

  • International meetings will be

Pre-clinical development and evaluation

(4) Develop consensus on an accelerated pathway for non-clinical evaluation of candidate GAS vaccines.

(5) Establish the optimal GAS candidate vaccine that evokes broadly protective immune responses in animals. Formulate and test combinations of GAS antigens in pre-clinical studies to identify those that provide broadly protective immunity. Based on the current status of research and clinical development of potential vaccine candidates, the proposed approach will assess the breadth of the

Clinical development and evaluation

(8) Develop protocols for the testing of GAS vaccines to accelerate a pre-clinical and clinical development plan and regulatory requirements. These would include the development of improved standardized tools for clinical testing of vaccine candidates including a high throughput bactericidal assay, multiplex ELISA or luminex for multiple antigens and automated assays for tissue cross-reactive antibodies. These protocols would be applicable to both current vaccines and to future combination

Clinical trials

(12) Evaluate the candidate vaccine expected to evoke broadly protective immune responses in phase 1, 2 and 3 clinical trials. It is likely that efficacy can be established in an expanded phase 2 study to be followed by a phase 3 study to establish safety that will be needed for licensure. Initial studies would be conducted in industrialized countries with subsequent studies in developing countries.

Policy and commercialization

(13) Establish and maintain country-level dialogues to facilitate decision-making on GAS vaccine policy. This is necessary to anticipate challenges with formulation of immunization policy for GAS vaccines to ensure that people in high endemic areas/low and middle income countries have reliable access to the vaccine in an optimal and timely manner once licensure has been achieved. Contact with national stakeholders in countries with high burden of GAS disease needs to be established. To date

Conclusions

The global burden of disease caused by GAS infections and their complications is significant. Safe, effective and affordable vaccines designed to prevent GAS infections could have a major impact on the health of millions of people. Research over a period of several decades has yielded a number of different candidate vaccines in various stages of pre-clinical and clinical development. Vaccine development efforts have been hampered by several obstacles which can be overcome through global

Conflict of interest

J.B.D. is the inventor of certain technologies related to the development of group A streptococcal vaccines which have been licensed by the University of Tennessee Research Corporation to Vaxent, LLC. J.B.D. is the Chief Scientific Officer of Vaxent and has a financial interest in the LLC.

All other authors have no potential conflicts to disclose that could influence the content of this manuscript.

Acknowledgments

Funding to support this collaborative was provided by the Decade of Vaccines Consultancy and the World Health Organization's Initiative for Vaccine Research. Altaf Lal of the Decade of Vaccines provided thoughtful guidance and comments during the preparation of the manuscript.

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