The Group A streptococcus (GAS) or Strep A, Streptococcus pyogenes, is the biggest infectious killer that no one has heard of. Infection with Strep A causes 500,000 annual deaths. Rheumatic Heart Disease (RHD) is a late immunological consequence of untreated Strep A infections of childhood, causing death from congestive heart failure or stroke in the 3rd or 4th decades of life in roughly 320,000 persons per year, while invasive Strep A infection, which includes sepsis, skin and soft tissue infections, has an estimated annual mortality of 150,000. RHD has nearly disappeared from high-income countries (HIC) as a result of access to treatment for acute Strep A pharyngitis and tonsillitis, but is extremely common in low- and middle-income countries (LMIC). Consequently there is little awareness of Strep A infections among the public, policy makers, and biomedical scientists in HIC, and there is little perceived incentive for major vaccine manufacturers to engage in vaccine development activities. In LMIC, attention is focused on vaccine preventable diseases of young children, and a late-manifesting, immunological consequence of Strep A infections of childhood is lethal, silent and largely undocumented.

The clinical spectrum of Strep A disease includes suppurative complications (pharyngitis, invasive disease, impetigo), non-suppurative immune-mediated syndromes (acute rheumatic fever (ARF), rheumatic heart disease (RHD), and acute post-streptococcal glomerulonephritis), and toxin-mediated diseases such as scarlet fever and streptococcal toxic shock syndrome.

The relationship between Strep A, ARF and RHD is critical and causal. Infection with Strep A, typically untreated pharyngitis or potentially skin infection, is followed weeks later by the presenting signs and symptoms of ARF. More than 60% of individuals have evidence of RHD with the initial episode of ARF. RHD is a chronic heart disease characterized by scarring and dysfunction of the heart valves. RHD causes heart failure, atrial fibrillation, endocarditis and stroke. In cohort studies of RHD in Africa, approximately 10% of patients die each year. RHD causes deaths in pregnant women and their children, and causes maternal morbidity and mortality after delivery.

Poverty and overcrowding. Low socioeconomic status is a known risk factor for Strep A disease, particularly RHD, in many different settings and countries. The near elimination of ARF and reduction in the prevalence of RHD in HIC during the late 20th century was attributed in part to improvements in socioeconomic conditions and the widespread use of penicillin to treat streptococcal pharyngitis. Despite these improvements, high prevalence and mortality due to RHD continue to be reported in the poorest regions, including Africa, South Asia, and the Pacific Islands.

Increased risk of RHD is associated with overcrowding and unemployment. For example, in Uganda, there is an association between overcrowding and distance from the nearest health center, suggesting that the effect of overcrowding on the risk of acquiring RHD increases with every kilometer increase from the nearest health center (Okello E, et al. PLoS One 2012).

Low- and middle-income countries (LMIC) are affected the most. Strep A infections cause substantial worldwide morbidity and mortality. The combined mortality associated with RHD and invasive infections is the fifth leading cause of infectious disease deaths behind HIV, tuberculosis, malaria and S. pneumoniae. RHD is one of the leading cardiovascular causes of DALYs lost in those aged less than 25 years. In Africa, the median age of death from RHD is 28 years. The impact is disproportionately distributed in LMIC. In 2015, the countries with the largest estimated numbers of cases of RHD were all LMIC (Watkins DA, et al New Engl J Med 2017). The Global Burden of Disease (GBD) study estimated that RHD affects 33.4 million people worldwide, with more than 319,400 deaths per year. The GBD analysis did not separately account for invasive Strep A disease, but it is conservatively estimated that invasive disease results in at least additional 160,000 deaths per year. RHD contributes to over 10 million disability-adjusted life-years (DALYs). Despite large gaps in data, underestimation of disease burden due to the difficulty in ascertaining cases of RHD seems likely. Thus, the current estimates of global impact may understate the problem, especially related to mortality. Numerous echocardiography studies have revealed that valvular lesions of RHD are found with high prevalence in LMIC (Carapetis JR, et al. Lancet Infect Dis 2005).

Women are affected the most. Two-thirds of those afflicted by RHD are women, and importantly, the complications of RHD have a profound and detrimental impact on pregnant women and their children. During pregnancy a marked increase in circulating blood volume is accompanied by a 30-50% increase in cardiac output, which can precipitate cardiac decompensation in patients with RHD. A report found that nearly 40% of pregnant women with RHD had worsening of cardiac status. RHD accounts for almost 90% of all heart disorders in women of childbearing age in LMICs (Carapetis JR. European Heart Journal 2015; Carapetis JR, et al. Nature Reviews 2016). Worldwide, roughly 25% of maternal deaths are classified as indirect. In a study in South Africa, 41% of these indirect deaths were from cardiac origin, predominantly RHD (71-84%) (Watkins DA, et al. BMC Cardiovasc Disord 2012) and in a Senegal study of 50 pregnant women with heart disease, 46 had RHD, resulting in 17 maternal deaths (34%) (Diao M, et al. Arch Cardiovasc Dis 2011). In addition, RHD in a mother is associated with poor pregnancy outcomes, including intrauterine growth retardation and prematurity (Hameed A, et al. J Am Coll Cardiol 2001).

Programs to prevent Strep A disease are chronically underfunded, despite the huge burden. Strep A disease has been neglected by the research community. In particular, research on development of a Strep A vaccine remains extremely limited. Across a range of diseases, RHD received the least funding relative to disease burden when compared to 15 other infectious diseases (Macleod CK, et al. Trans R Soc Trop Med Hyg 2019).

RHD is not going away. When compared to HIV, TB and malaria (and other vaccine preventable disease such as invasive pneumococcal infection or rotavirus diarrhea) the estimated global mortality from Strep A (1990 – 2016) has remained stubbornly around 300,000. The Global Burden of Disease survey has also estimated the impact of important diseases of global health in 2040. This is particularly interesting because it attempts to model present efforts in disease prevention and treatment against future impact. Not surprisingly, despite declines in most major infectious diseases, Strep A associated mortality from RHD (note, the GBD study tracks RHD not all Strep A infection including invasive Strep A) remains substantial in 2040. These data suggest that, even under optimal conditions for development over the next 20 years, RHD associated disease will remain a major problem. The relative resistance of RHD mortality to 20 years of continued economic development highlights the importance of access to effective health care, a health equity issue that has poverty at its core. In the absence of a vaccine, it is likely that persistent inequity in access to affordable and effective care for Strep A infection, will continue, in 2040, to result in hundreds of thousands of deaths in LMIC.

Rising AMR is one of the greatest health challenges the world currently faces. One estimate places current global annual deaths from AMR at a minimum of 700,000. A World Bank simulation projects that the global economy could lose as much as 3.8% of its annual gross domestic product by 2050 in a worst-case scenario (Bloom DE, et al. PNAS 2018). Among the knowledge gaps identified, a better understanding of the epidemiology of AMR and Strep A in LMICs is needed and requires funding.

Vaccination as a solution has been largely undervalued. Vaccines can counteract AMR through multiple pathways (Lipsitch M and Siber GR. MBio 2016). While vaccination can directly reduce the incidence of resistant infections, it also reduces both appropriate and inappropriate use of antimicrobials by reducing overall disease incidence, including infections caused by susceptible pathogens. This reduced antimicrobial use further diminishes pressure toward resistance among bystander members of the normal human flora.

This latter mechanism is the strategy by which vaccination against Strep A could massively reduce prescription of antibiotics – sore throat is among the top 3 reasons worldwide for prescription of antibiotics. If knowledge of vaccination status would reduce the likelihood of antibiotic prescriptions (given that Strep A is the only common cause of sore throat requiring treatment with antibiotics), then antibiotic use could be substantially reduced. In the US alone, there are 20 million visits per year for sore throat, and antibiotics are prescribed for more than 50% of children and 70% of adults. Vaccination against Strep A could have substantial secondary benefits in slowing development of AMR related to antibiotic overuse.

The World Health Organization (WHO) prioritized a vaccine for Strep A in 2014, and beginning in 2016 organized a series of consultations around the development of documents critical to Strep A vaccine development.

In Africa, RHD has been recognized as a major public health problem. In 2015, African Union Heads of State and Government at their 25th summit endorsed the Addis Ababa Communiqué on Eradication of RHD in Africa, which recommends several key actions for consideration by African governments.

World Health Assembly resolution on RHD in 2018. The 71st World Health Assembly resolution report (12 April 2018) by the Director General of the World Health Organization (WHO) calls for action against RHD, including the development of a Strep A vaccine (http://apps.who.int/gb/ebwha/pdf_files/WHA71/A71_25-en.pdf?ua=1). The prevention, control and elimination or eradication of RHD is increasingly recognized as an important developmental issue by Member States.