Clinical application of benzathine penicillin G as secondary prophylaxis and vaccines for patients with acute rheumatic fever and rheumatic heart disease: A comprehensive review

1. Background: definition, epidemiology, risk factors and pathophysiology

1.1. Definition

Acute rheumatic fever [1] is a serious multi-focal autoimmune reaction that can occur when Group A Streptococcal (GAS) infection produces pharyngitis [[2], [3], [4], [5], [6]]. This organism can have a devastating effect on the susceptible untreated individual. It takes around 2-3 weeks post S. pyogenes infection to induce RF [[7], [8], [9]].

ARF episodes can occur repeatedly or in a single, severe episode, and the resulting long-term cardiac damage which can cause heart failure, atrial fibrillation, and stroke are common complications of RHD, resulting in significant premature morbidity and premature mortality [[10], [11], [12]]. Thirty-five to forty percent of patients with RF develop rheumatic heart disease [13], which is the outcome of valve damage induced by the aberrant immune response, four to eight weeks or more after GAS infection [14].

RF is associated with fever and inflammation of the joints (arthritis), skin (rash), brain (chorea), and heart (carditis). While most effects of RF are transitory, carditis associated with RF may lead to permanent injury to heart valves. ARF causes an illness that manifests as a variety of symptoms, including fever, skin and subcutaneous signs, joint discomfort and swelling, cardiac valve regurgitation with potential for subsequent heart failure, and chorea. The acute disease can be quite severe, including dyspnea, high fevers, edema from heart failure, arthritis that is incapacitating, and chorea from movements that interfere with daily living activities [2].

1.2. Epidemiology of acute rheumatic fever and rheumatic heart disease

Acute rheumatic fever (ARF) and its consequence, rheumatic heart disease (RHD), cause significant morbidity and mortality in developing countries, yet they are under-recognized as global health problems [[14], [15], [16]]. It is a disease highly acquired in childhood among children living in poverty and overcrowded areas [17]. ARF is still now considered an endemic disease in developing countries and one of the major forms of chronic cardiac disease in the child-aged group. It covers 25-45 % of chronic cardiac diseases in developing countries [18].

GAS pharyngitis is most common in children 5–15 years [7,18,19] (and is responsible for 20–30% of sore throat presentations), although the infection can occur in adults (and may be responsible for 5–15% of sore throat presentations [20], with approximately 60% of people with ARF in endemic communities subsequently developing RHD [15]. The incidence of ARF is still high in poor countries (about 100-200) times greater than in developed countries [17,18]. Over the last decades, ARF has significantly decreased in occurrence in most developed countries due to improvements in socioeconomic conditions and the early initiation of penicillin in the treatment of upper respiratory tract infections [18].

In the early to mid-20th century, rheumatic fever (RF) and its major sequela, rheumatic heart disease (RHD), were highly prevalent in the United States and Western Europe, and patients with these conditions routinely occupied almost 25% of pediatric beds. Worldwide, RF and RHD continue unabated. RHD affects more than 39 million people and claims nearly 300 000 lives each year [21]. The majority of those affected are socioeconomically disadvantaged, living in low- and middle-income countries [22,23].

In a study in Ethiopia, a retrospective cross-sectional chart review of all patients referred for cardiopathy at the Tikur Ambessa Referral Cardiac Clinic from June 2015 to August 2018 showed that the prevalence of RHD is 54.8% of those who have a cardiac problem [24].

Although the burden has come down in developed countries, RHD continues to be the cause of morbidity and mortality in developing countries of the world [25]. While the global incidence of ARF and RHD has decreased, it remains endemic in regions that experience barriers to healthcare as well as crowded living areas [26]. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease was observed in Oceania, South Asia, and central sub-Saharan Africa [22,27].

1.3. Risk factors

Age. ARF has been documented in children as young as 2-3 years old, however it can also affect younger children. The age range of 5 to 14 is the group of children with the highest frequency of initial ARF occurrences. Although instances involving individuals older than thirty are uncommon, initial episodes can also happen to older teenagers and adults. On the other hand, recurring episodes are uncommon after the ages of 35 to 40 years old and frequently affect somewhat older children, teenagers, and young adults [2].

Sex. ARF affects both men and women equally in the majority of populations. However, RHD occurs more commonly in females. The reasons for this are intrinsic factors such as greater autoimmune susceptibility, as observed in systemic lupus erythematosus, and extrinsic factors such as greater exposure to GAS infection in women than in men as a result of closer involvement in child-rearing might explain the difference [2].

Environmental factors. The vast majority of differences in risk between populations around the world can be explained by environmental factors. The relative contribution of each of these individual risks is difficult to elucidate given that many of them overlap and most are associated with poverty and economic disadvantageous [2,28,29].

1.4. Pathophysiology of acute rheumatic fever/rheumatic heart disease

The molecular pathways connecting group A β-hemolytic streptococcus (GAS) to ARF remain poorly understood, despite the fact that epidemiological and immunological studies have identified GAS as the etiologic culprit causing ARF in a susceptible host [15].

Streptococci categorized into groups A, B, C, F, and G based on the polysaccharides in their cell walls [30]. The S. pyogenes (GAS) is characterized by carbohydrates composed of N-acetyl-b-D glucosamine and rhamnos. The GAS contains the M, T, and R surface proteins and lipoteichoic acid involved in the attachment of bacteria to throat epithelial cells [14]. The M protein, which is the most significant antigenic structure, is structurally similar to other alpha-helical coiled-coil human proteins, including vimentin, cardiac myosin, tropomyosin, keratin, laminin, and several valvular proteins [14]. High amounts of antibodies to M protein are present in ARF patients, and this can function as a superantigen by inducing an augmented immune response and autoimmunity. It is thought that following the apparent convalescence of non-treated streptococcal pharyngitis, breakdown products of the Streptococcus with molecular similarity to human tissues are recognized by the immune system, initiating an autoimmune response [19].

When pharyngeal GAS infection occurs, neutrophils, macrophages, and dendritic cells phagocytose bacteria and transfer antigens to T lymphocytes. Following exposure to GAS infection, B and T cells first generate antibodies (IgM and IgG), which subsequently triggers the activation of T cells, primarily CD4⁺ cells [31]. Molecular mimicry is a mechanism by which antibodies specific to Streptococcus spp. and T cells mediate autoimmune reactions against host organs (e.g., the heart, brain, joints, and/or skin) triggered by the host response against GAS in vulnerable individuals [11]. The process by which the host and the bacterium share T cell epitopes or antibodies is known as molecular mimicry. This allows the host to fight off the infection by producing antibodies or T cells that both detect and combat the infectious disease. These host antigens, in the instance of ARF, are found in organs like the brain and heart [2].

1.5. Generation of a cross-reactive immune response in ARF

After Group A Streptococcus (GAS) adheres to and penetrates the pharyngeal epithelium, GAS antigens activate both B and T lymphocytes [30]. Molecular mimicry between the host heart, brain, or joint tissues and GAS group A carbohydrate or serotype-specific M protein can trigger an autoimmune response, resulting in the major symptoms of acute rheumatic fever (ARF) [32]. As a result of the formation of immune complexes caused by the cross-reactive immune response, which causes the formation of immune complexes leading to Sydenham's chorea as the antibodies bind to basal ganglia and neuronal cells cause erythema marginatum and subcutaneous nodules in the skin as antibodies bind to keratin and lead to inflammation of both heart valves and the myocardium [2].

RF causes permanent damage only to the cardiac valves. Clinically the mitral aortic, tricuspid, and pulmonary valves are involved in the order of frequency. Mitral valve damage is the commonest and pulmonary valve damage is rare. However, pathological evaluation of valves from patients dying of acute RF indicates that microscopic involvement of tricuspid and pulmonary valves occurs in almost 100 percent of cases. Cardiac valve damage is the basic reason why RF needs to be controlled to minimize the morbidity and mortality related to RF [25]. Due to compensatory dilatation of the left ventricle and left atrium, patients with mitral incompetence can stay largely asymptomatic for up to ten years before the onset of left ventricular systolic dysfunction. Tricuspid regurgitation can occur as a result of volume overload, usually caused by mitral stenosis(Fig. 1) [33].

Fig. 1.

The Group A Streptococcus (GAS) cross-reactive immune response in the heart.

Antibodies (produced by B cells) against the group that binds carbohydrates to the valve surface and increases the surface expression of vascular cell adhesion molecule 1 (VCAM1) on the valve endothelium have an impact on the heart. T cells that express integrin α4β1 (often referred to as VLA4) are able to attach to the endothelium and extravasate into the valve due to the overexpression of VCAM1. T lymphocytes, mainly CD4⁺ T cells, invade the inner valve, causing granulomatous lesions or Aschoff bodies to develop beneath the endocardium. Damage to the endothelium and infiltration of T cells into the valve remodels the valve structure, including the chordae tendineae, with malformation of the valve leading to regurgitation or stenosis of the valve. Breakdown of the valve releases collagen and results in further immune-mediated damage to the valve [2].

1.6. Diagnosis of acute rheumatic fever and rheumatic heart disease

The main clinical characterstics of ARF are stated in the Jones Criteria [34], which were established in 1944 and then subsequently modified [35] and updated (panel) [36], and revised in 2015 [37] by the American Heart Association. Every revision increased the specificity but decreased the sensitivity of criteria [38], largely in response to the steadily declining incidence of ARF in developed countries. In regions of the world where ARF is endemic or epidemic, however, and where the risk associated with missed diagnosis and lack of provision of secondary prophylaxis to prevent recurrent ARF and worsening RHD might outweigh the consequences of over-diagnosis, the 1992 Jones criteria might not now be sufficiently sensitive.

As such, the 2002–2003 WHO guideline which, among other things, specified less strict requirements for the diagnosis of recurrent ARF in patients with established RHD should probably be adopted (panel). The Jones and the WHO criteria are only diagnostic guidelines however and should be adapted in certain circumstances, for example, to increase the sensitivity of diagnosis in populations at high risk of ARF [39].

ARF is a systemic inflammatory autoimmune reaction that happens in 2–4 weeks following GAS pharyngitis with major manifestations including carditis (50–78%), arthritis (35–88%), erythema marginatum (<6%), and subcutaneous nodules (<1–13%). Additionally, 2–19% of patients present with Sydenhams’ chorea, a neurological condition characterized by involuntary movements and behavioral changes [15]. PR prolongation, less severe joint symptoms, fever, and increased inflammatory markers are examples of minor signs [37]. The diagnostic criteria consist of major manifestations of arthritis, carditis, subcutaneous nodules, chorea, and erythema marginatum. Rheumatic carditis resulting in more or less permanent damage to the heart is the main virulent manifestation of RF (Table 1).

Table 1.

Revised Jones criteria for acute rheumatic fever diagnosis.

A. For all patient populations with evidence of preceding GAS infection Diagnosis:
initial ARF	2 Major manifestations or 1 major plus 2 minor manifestations
Diagnosis: recurrent ARF	2 Major or 1 major and 2 minor or 3 minor
B. Major criteria
Low-risk populations∗	Moderate- and high-risk populations
Carditis • Clinical and/or subclinical	Carditis • Clinical and/or subclinical
Arthritis • Polyarthritis only	Arthritis • Monoarthritis or polyarthritis • Polyarthralgia
Chorea	Chorea
Erythema marginatum	Erythema marginatum
Subcutaneous nodules	Subcutaneous nodules
C. Minor criteria
Low-risk populations∗	Moderate- and high-risk populations
Polyarthralgia	Monoarthralgia
Fever (≥38.5 °C)	Fever (≥38 °C)
ESR ≥60 mm in the first hour and/or CRP ≥3.0 mg/dL	ESR ≥30 mm/h and/or CRP ≥3.0 mg/Dl
Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)	Prolonged PR interval, after accounting for age variability (unless carditis is a major criterion)

Keynotes: ARF = acute rheumatic fever; ESR = erythrocyte sedimentation rate; CRP= C-reactive protein; and GAS = group A streptococcal infection.

Those who reside in areas with high incidence of ARF (incidence >30/100 000 annually in children aged 5-14) or RHD (all-age prevalence >2/1000) are considered to be high-risk populations (Table 2) [40]. The two most common first symptoms of ARF are arthritis and carditis; nevertheless, carditis is accountable for the disease's morbidity and death, with the other major symptoms going away entirely and having no lasting effects [18].

Table 2.

2020 Australian Criteria for Acute Rheumatic Fever diagnosis.

The definite initial episode of ARF	•2 major manifestations + evidence of preceding group A streptococcal infection, OR •1 major + 2 minor manifestations + evidence of preceding group A streptococcal infection‡
The Definite recurrent‡ episodes of ARF in a patient with a documented history of ARF or RHD	2 major manifestations + evidence of preceding group A streptococcal infection, OR 1 major + 2 minor manifestations + evidence of preceding group A streptococcal infection, OR 3 minor manifestations + evidence of a preceding group A streptococcal infection
Probable or possible ARF (first episode or recurrence§)	A clinical presentation in which ARF is considered a likely diagnosis but falls short in meeting the criteria by either: •one major or one minor manifestation, OR •no evidence of preceding group A streptococcal infection (streptococcal titres within normal limits or titres not measured) Such cases should be further categorized according to the level of confidence with which the diagnosis is made: •probable ARF (previously termed “probable: highly suspected”) •possible ARF (previously termed “probable: uncertain”)
Major manifestations	Carditis (including subclinical evidence of rheumatic valvulitis on echocardiogram) Polyarthritis or aseptic monoarthritis or polyarthralgia Sydenham chorea Erythema marginatum Subcutaneous nodules	Carditis (including subclinical evidence of rheumatic valvulitis on echocardiogram) Polyarthritis Sydenham chorea Erythema marginatum Subcutaneous nodules
Minor manifestations	•Fever ≥38 °C •Monoarthralgia§§ •ESR ≥30 mm/h or CRP ≥30 mg/L •Prolonged PR interval on ECG	•Fever ≥38.5 °C •Polyarthralgia or aseptic monoarthritis •ESR ≥60 m/h or CRP ≥30 mg/L •Prolonged PR interval on ECG

CRP = C‐reactive protein; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; RHD = rheumatic heart disease.

2. Treatment of acute rheumatic fever: secondary prophylaxis

Secondary prophylaxis of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) comprises the use of long-term antibiotic therapy for individuals diagnosed with ARF or RHD, to prevent ARF recurrences caused by recurrent group A streptococcal (GAS) infection, and therefore prevent the development of RHD or worsening of existing RHD(1). Antibiotics are given to patients who have had RF in the past as a secondary prophylactic measure to stop GAS infection, RF recurrence, and slow the diseases progression to RHD [7,41]. The cornerstone of treating rheumatic fever and rheumatic heart disease is secondary antibiotic prophylaxis [42,43]. Secondary prevention with intramuscular benzathine penicillin (BPG) has been known for many years to be effective in preventing recurrences of acute rheumatic fever (ARF) and preventing the development of chronic rheumatic heart disease (RHD) [[44], [45], [46]]. Regular BPG is an evidence-based treatment, that decreases the risk of recurrent ARF by 87–96% [45].

Up to 3% of untreated group A streptococcal (GAS) tonsillar-pharyngeal infections result in rheumatic fever (RF). Although acute fatalities from RF are uncommon, 40–80% of cases result in carditis, and 90% of them go on to develop chronic rheumatic heart disease (RHD). RHD is the primary cause of CV death in the first 50 years of life and accounts for 1/3 to 1/2 of all cardiac hospital admissions in developing nations. Prevention or treatment of GAS infection is the key to preventing RF/RHD. Preventing RF recurrences reduces the major side effects and morbidity/mortality of RHD by slowing or stopping the progression of valvular disease [47].

Injections of benzathine penicillin G (BPG) are the gold standard treatment for preventing initial or repeated episodes of RF [13,47,48]. Infections brought on by Streptococcus pyogenes (Group A Streptococcus; Strep A), which produce episodes of ARF, are better treated with benathine penicillin G than with oral penicillin and non-penicillin antibiotics [49]. The majority of guidelines in place today, which date back to research done in the 1950s, call for a secondary prophylactic dose of 900 mg [1.2 million international units (MIU)] of benzathine penicillin G to be given by deep intramuscular (IM) injection every 2-4 weeks for a minimum of 10 years. The benzylpenicillin is injected, and it separates from the benzathine moiety and enters the plasma compartment [47,50,51].

For extended periods of time, a monthly intramuscular injection of 1.2 million units of benzathine penicillin G has been widely approved as a secondary preventive measure against rheumatic fever [47,52]. The recommended dosage of BPG for children is different depending on the guidelines: in Australia, it is 450 mg (0.6 million IU) up to 20 kg; in the American Heart Association, it is 450 mg up to 27 kg; and in the World Health Organization, it is 450 mg up to 30 kg. [53]. A macrolide antibiotic, usually oral erythromycin, is the first-line recommendation in cases of proven penicillin allergy [54].

There is debate on the ideal period of secondary prophylaxis [53]. The length of secondary prophylaxis is determined by various factors, including age, RHD severity, the probability of future GAS exposure, and the period since the last ARF episode, according to most standards. It is also critical to determine patient preferences and to ensure that decisions to continue or stop prophylaxis are made in agreement between the treating physician and the patient. Age is significant because ARF recurrences decrease with age due to either increased GAS immunity with time [54] or increased immunological maturity, which lowers the likelihood of an aberrant immune response following GAS infection, or a combination of both factors [54]. In general, ARF is less common in individuals over 25 [54] nevertheless, it can still rarely be observed in older adults in highly endemic environments. Thirty-two clients were found to have experienced an ARF episode after the age of forty in a certified audit conducted on 343 older people getting secondary prophylaxis for ARF from northern Australia between July 10 and August 3, 2017 [55]. According to most criteria, secondary prophylaxis should last at least ten years. [23]. For severe situations, it could be advised to take BPG regularly for the rest of one's life [53].

2.1. Preparations of benzathine penicillin G for injection

BPG is a crystalline powder produced by reacting two molecules of penicillin G with a single molecule of dibenzyl ethylenediamine base (in a 2:1 M ratio) [20,56]. Intramuscular injections of BPG provide protracted serum penicillin concentration detectable for weeks. This ‘slow release’ profile means that BPG can be administered every 2, 3, or 4 weeks to people with a history of ARF to reduce the risk of recurrent GAS infections and ARF episodes [43].

BPG forms a depot in muscle tissue following intramuscular administration, slowing its release into the bloodstream and producing prolonged therapeutic serum concentrations. After intramuscular injection, BPG is changed to penicillin G via hydrolysis. It is the hydrolytic conversion to penicillin G, combined with the slow absorption of BPG from the intramuscular injection site, which leads to the lower, but prolonged, plasma levels found in humans. BPG is typically available in three doses, standardized to international units (IU), which are 600 000 IU, 1.2000,000 IU, and 2.4000,000 IU equivalent to 450 mg, 900 mg, and 1.44 gm respectively. The IU of penicillin was developed as a standard measure of potency when the drugs were developed. By definition, the IU of penicillin is the penicillin activity contained in 0.6 mg of the crystalline sodium salt of penicillin G [20].

2.2. Pharmacokinetics of benzathine penicillin G

Benzathine benzylpenicillin G (BPG) is a beta-lactamase antibiotic developed in 1951, which is administered intramuscularly, BPG has low in vivo solubility, producing prolonged serum penicillin concentrations. This makes BPG suitable for treating penicillin-sensitive organisms responsive to extended, low serum penicillin concentration [57].

Long-term serum concentration offers great protection against GAS infection [53]. Peak serum penicillin concentration in adults occurs 3 to 6 h following injection of benzathine penicillin G(58). The same spectrum of antimicrobial activity is displayed by BPG as by aqueous crystalline penicillin G; both are active against most members of the Streptococci infection. The serum half-life of penicillin G after intramuscular administration is only 30 min, with levels undetectable after 3–6 h, while BPG has a much longer half-life of 4.1 days due to its low solubility [20].

2.3. Challenges in BPG secondary prophylaxis

2.3.1. Pharmaceutical challenge

Worldwide, BPG is available in two main formulations as Lyophilized powder and viscous liquid. The vast majority of the world uses the powdered form of BPG(20). Relatively inexpensive, generic, lyophilized powders are frequently utilized in low-resource environments. The formulations in powder form are instantly reconstituted into an aqueous suspension before to administration and do not require a cold chain [47].

A branded liquid formulation, premixed and prepackaged is available in some high-resource settings which are relatively expensive and require refrigeration [47,57]. Powdered.

BPG may suffer from variable quality and efficacy in comparision with the premixed suspension form [58]. Significant pharmacokinetic differences were found between brands of powdered BPG, so where available, the premixed suspension is preferred over powdered BPG(59).

2.3.2. Pharmacokinetic challenge

Based on the MIC of penicillin for Strep A, a goal of 20 ng/mL (0.02 mg/L) is anticipated for the bulk of the inter-injection time [50]. A longterm pharmacokinetic study was carried out in Australia between March 2017 and November 2017 on children and adolescents receiving secondary prophylaxis over the course of six monthly cycles of BPG. Samples of dried blood spots were analyzed using LC-MS/MS. Non-linear mixed-effects modeling was used to examine the concentrations of benylpenicillin; further simulations were conducted using weight-for-age and BMI-for-age data that had been published. A total of eighteen subjects provided 256 concentrations for examination. None of them exhibited concentrations of benzylpenicillin higher than 0.02 mg/L over the whole interval between intramuscular injections. For individuals with lower BMIs (<25 kg/m2) who also had lower weights, the median time exceeding this objective was 9.8 days; for those with higher BMIs (≥25 kg/m2), it was 0 days. After a typical dose of BPG, the fat-free mass was a major predictor of benzylpenicillin exposure; however, a higher BMI affected absorption and nearly doubled (an increase of 86%) the measured half-life [59]. Benzylpenicillin G is stable in DBS for approximately 12 h at room temperature (22 °C), 6 days at 4 °C, and 1 month at 20 °C(51).

Data from Australian patients with RHD receiving benzathine penicillin G and healthy male recruits for the military show that very few patients are able to sustain concentrations greater than 20 ng/mL (0.02 mg/L) for the duration of the interval between doses [50,60].

A randomized, crossover, population pharmacokinetic study was conducted in healthy adult volunteers to compare the pharmacokinetic profile of benzathine penicillin G according to different routes of administration, 15 healthy males participated in a randomized crossover study to receive benzathine penicillin G by either SC or IM routes, with ten weeks of washout time prior to the second dosage administered by the alternate route. Benzathine Penicillin concentrations were measured for 6 weeks following injections. The study shows the principal absorption half-life after SC injection was 20.1 days compared with 10.2 days following IM administration. Lower peak and higher trough penicillin concentrations resulted following SC injection [50].

In a 2007 trial done in the USA, 329 participants received 1.2 million units of BPG IM, and they also received sera one day after injection and twice more over the course of four weeks at staggered time points. Using tandem mass spectrometry and liquid chromatography, the levels of serum penicillin G were determined. The half-life of serum penicillin G was 4.1 days. By day 11, mean levels were <0.02 μg/ml, and by day 15 < 0.01 μg/ml. On day 9, levels in over 50% of the individuals were below 0.02 μg/ml, and on day 16, <0.01 μg/ml. These data indicate that in healthy young adults serum penicillin G levels become less than protective <2½ weeks after injection of 1.2 million units of BPG [60].

At Ayder Comprehensive Specialized Hospital, a prospective cohort research was carried out from February to October 2018. The final PK model contained 190 penicillin concentration samples from 74 patients. As a result, during the 28-day treatment cycle, the concentrations that stayed above 20 ng/mL and 10 ng/mL were 42.5% and 73%, respectively. Most Ethiopian patients getting BPG as secondary prophylaxis to prevent RHD do not attain goal concentrations(20 ng/ml) for more than two weeks during each four weekly injection cycle [41].

2.3.3. Administration challenge

The powdered BPG forms a suspension when reconstituted before administration The poorly soluble powdered formulations are difficult to inject because they clump and block even large-gauge needles, and the injections themselves can be painful. Studies conducted in Australia in 2006 used Powdered BPG up to 40% of injections were affected by needle blockages [53].

2.3.4. Adherence challenge

Adherence to secondary prophylaxis with BPG is often sub-optimal. Lack of access to high-quality benzathine penicillin G together with the frequency and pain associated with IM injections or anaphylaxis and high out-of-pocket costs are reported as barriers to adherence [50,61].

There are widespread reports of adverse drug reactions in people with severe RHD receiving BPG for secondary prophylaxis. Many of these incidents have resulted in abrupt deaths, and scared healthcare professionals and patients have occasionally substituted less potent oral options for BPG, which in certain circumstances has lowered market demand [22]. Most low-income countries have a shortage of skilled healthcare personnel at the primary-care level and poor access to, or inability to afford, diagnostic facilities for taking and processing throat swabs [33], low level of awareness of the disease in the community [39] and living long distance to the health facilities [62]. Lack of awareness of the significance of BPG for secondary prophylaxis is the most common reason for poor adherence [61].

2.3.5. Adverse drug reactions

According to the WHO an adverse drug reaction is defined as "a toxic and unexpected reaction to a medication that happens at dosages typically used in humans for disease prevention, diagnosis, or treatment [63]. ADRs might be confined to the site of administration or systemic, affecting the entire body.

• A.Systemic adverse reactions

Systemic ADRs can be classified into Type A reactions (dose related, pharmacologic, effects of the drug including side effects, toxicity, and drug interactions) and Type B reactions (unpredictable, dose-independent, hypersensitivity). Type B reactions are the predominant concern in the use of beta-lactam antibiotics. These can be considered immunologic or idiosyncratic, where the mechanism of the adverse reaction is poorly understood [64,65].

Despite BPG's favorable safety profile [66], a few severe adverse reactions have been reported since it was first marketed in 1954. The well-known adverse drug reaction of BPG administration is related to the risk of immediate-type hypersensitivity reactions such as anaphylactic shock and possibly death [66,67].

• B.Local Adverse Reactions

Nicolau syndrome (NS) is a rare complication of an intramuscular injection characterized by severe pain, skin pigmentation, and different degrees of tissue necrosis [68,69].

3. Vaccine development for RHD

3.1. Rationale for vaccines against GAS

Although GAS pathogens remain sensitive to penicillin, recent developments regarding the emergence of new GAS strains that are less sensitive to penicillin derivatives is alarming [70]. GAS pharyngitis is prevalent in regions with poor healthcare infrastructure, where early diagnosis and treatment are often challenging. Hence, developing a safe, effective and affordable vaccine would significantly reduce the burden on human health from GAS disease and eliminate the diseases worldwide.

Since 1923, efforts have been made to develop a vaccine that would prevent GAS infections. The US FDA halted GAS vaccine research in the 1970s for more than 30 years because the initial vaccines were ineffective and extremely reactogenic, which raised concerns about the possibility that immunizations could enhance ARF predisposition. These worries were probably unjustified or exaggerated. Beginning in the early 1960s, the development of a vaccination for RHD involved purifying M proteins from crude cell walls. Although research on vaccine creation has increased over the last 20 years due to developments in immunomics, proteomics, and genomes, the majority of vaccines are still in pre-clinical testing, and only a small number have advanced to phase I and II trials [71].

In general, selection of vaccine candidates for any pathogen is based on few characteristics such as; sub-cellular localization of the target protein, ability to induce immune responses, no molecular mimicry between target and host tissue proteins, conservation of target protein among all the available genomes of the species and possibility of cloning the target protein [72].

In the following section, we summarize the recent developments of GAS vaccine candidates in pre-clinical and clinical trials [73].

3.1.1. M protein-based vaccine candidates

One of the 26-valent vaccination candidates that was created and assessed is StreptAvax. It demonstrated a beneficial effect on the total burden of streptococcal infections in people by lowering the incidence of pharyngitis and other infections linked to streptococci [74]. The StreptAvax vaccine candidate did not provide protection against the GAS strains found in Asia and the Pacific continents, but it seemed to exclusively target the strains that are frequently encountered in Western nations [74].

StreptAnova a 30-valent vaccine candidate was designed using N-terminal peptides from 30 M proteins. This vaccine candidate evoked opsonic antibody production protecting against GAS infections in rabbits [75], although the protection has not been firmly established using animal challenge models. In preclinical experiments, these rabbit-derived opsonic antibodies eliminated non-vaccine serotypes of GAS in addition to the isolates utilized to create the vaccine. Over 40% bactericidal activity was measured against a randomly chosen set of non-vaccine serotypes [76]. Beyond the M protein serotypes, this suggests neutralizing potential and wide coverage. In the clinical phase I investigation, 23 patients [77]. showed no signs of autoimmunity or cross-reactive antibodies. Nevertheless, another study raised safety concerns in areas where RHD is prevalent [77]. Crucially, the 30-valent vaccination only reaches around 33% of the antigenic coverage in the GAS genomes' vaccine targets [74].

A 29-amino acid peptide sequence from the M protein's C terminus conjugated to the carrier protein is present in J8 (MJ8VAX). Similar to the previously stated vaccine candidates, J8 induced the synthesis of opsonic antibodies in mice, which was associated with defense against models of intraperitoneal and intranasal GAS infection [78].

Mice similarly demonstrated J8-mediated protection when the SpyCEP immunogenic fragment was present [78]. MJ8VAX was shown to be safe and immunogenic in a phase I clinical trial that was double-blind and randomized [79].

3.1.2. Non-M-protein vaccines

A different strategy for creating a GAS vaccine makes use of streptococcal antigens, which are essential to the infection process. Reverse vaccinology approaches, supported by proteomics, whole genome sequencing, bio-informatics, and microarray technologies, have helped identify several promising vaccine candidates in recent years. Many of these, including the fibronectin binding protein FbaA, streptococcal secreted esterase (Sse), SpyCEP, and streptococcal pyrogenic exotoxin (SpeA), are controlled by the covRS operon [80].

3.1.3. Streptococcal C5a peptidase

There is 98% amino acid sequence similarity between the tested GAS serotypes and the ScpA, a large surface multi-domain protein expressed on the cell envelope. In particular, ScpA cleaves the chemotaxin C5a from the surface of polymorphonuclear leucocytes, making it one of the key mediators of resistance to phagocytosis. ScpA was found to be highly immunogenic in children with acute pharyngitis and to produce antibodies in the convalescent sera obtained four weeks after infection, according to GAS isolates from throat swabs. Mice that were immunized with ScpA mutants showed elevated IgG1 and T cell titres. Additionally, ScpA was demonstrated to activate highly active T cell-dependent populations when coupled with short synthetic polysaccharides of the GAC, indicating that ScpA might be used as a carrier protein in the development of "combinational" GAS carbohydrate-based vaccines. The cell wall-attached endopeptidase C5a peptidase (SCPA) plays a crucial part in the pathogenicity of group B, C, and G streptococci as well as GAS [81].

3.1.4. Streptolysin O

Viral M1T1 GAS isolates and other dominant genotypes have been shown to have elevated levels of SLO, a secreted GAS pore-forming toxin. GAS resistance to phagocytosis in the human immune system is facilitated by SLO. By inhibiting the neutrophil oxidative burst and obstructing the migration path, it also modifies neutrophil function, which aids the infection in surviving in the host bloodstream.

The mouse models inoculated with a mutant (non-pore-forming) version of streptolysin O showed high titres of IgG, IgM, and anti-SLO antibodies, suggesting passive protection in animals infected with GAS. Due to its capacity to reverse neutrophil function and produce protective immunity against the deadly GAS challenge, this study proposed the significance of the SLO toxoid in multi-component vaccine composition. SLO is a highly conserved protein that theoretically covers 99% of all isolates of GAS [71].

3.1.5. Streptococcal pyrogenic exotoxins

SpeA and SpeC are members of the Spe family of extracellular toxins released by GAS. By promoting the synthesis of inflammatory cytokines, Spe exotoxin expression causes the noticeable rash and "strawberry" tongue associated with scarlet fever [82].

3.1.6. Multi-component vaccines

Broad coverage and protection against multiple serotypes, including newly developing GAS strains, are essential characteristics of a potential GAS vaccine candidate. The best course of action would therefore be to create a multi-component vaccine, which might provide protection based on elements like sequence conservation in the majority of GAS serotypes, high immunogenicity, and antigenic diversity. For instance, the Combo5 vaccine candidate, a multi-component vaccine made up of GAS antigens like trigger factor, arginine deiminase, streptolysin O, and Streptococcus pyogenes cell envelope proteinase, was demonstrated to lessen tonsillitis and pharyngitis after vaccination [72].

4. Conclusion and recommendation

Acute rheumatic fever resulting from group A β-hemolytic Streptococcus infection continues to be a serious cause of morbidity and mortality in developing countries. Except for the valve lesions, all other manifestations of acute rheumatic fever resolve without sequelae. Benzathine penicillin G (BPG) is the most efficacious antibiotic for this purpose; however, adverse events associated with BPG administration have been anecdotally reported. Using Benzathine penicillin G 1.2 MU once every 2-3 weeks is an effective prophylaxis of recurrent by maintaining serum concentration ≥0.02 μg/ml but patient adherence to the treatment is a big issue due to pain and adverse drug reaction. Administering BPG with 1% can decrease the pain related to an injection without changing the penicillin concentration in body fluids.

There is no doubt that a vaccine for prevention of GAS infections and associated sequelae is warranted. Development of a vaccine that does not show cross-reactivity with human tissue and allows broader coverage poses major challenges to researchers worldwide. Moreover, the assessment of vaccine efficacy against skin infection, in addition to pharyngitis, is also critical if the vaccine is to have global utility. Vaccination represents a transformative opportunity to combat RHD by targeting the root cause—GAS infections. Despite substantial challenges, progress in vaccine research offers hope for a sustainable solution to reducing the global burden of RHD.

CRediT authorship contribution statement

Getinet Nibret: Writing – original draft, Validation, Supervision, Data curation. Mengistu Abebe Messelu: Writing – review & editing, Visualization, Formal analysis, Data curation, Conceptualization. Abebe Dagne: Writing – review & editing, Visualization, Supervision, Data curation.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Getinet Nibret reports administrative support and writing assistance were provided by Debre Markos University. Reports a relationship with that includes:. Has patent pending to. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.