Rheumatic Fever (RF) is an inflammatory condition that develops as a complication following an infection. It can cause long-term health consequences, most notably permanent damage to the heart valves, known as Rheumatic Heart Disease (RHD). Despite decades of research into this global health problem, there is currently no licensed vaccine available to prevent Rheumatic Fever. The need for a preventive vaccine is high, especially in communities where the disease remains prevalent.
The Link Between Strep Throat and Rheumatic Fever
The trigger for Rheumatic Fever is an infection caused by the bacterium Streptococcus pyogenes, commonly referred to as Group A Streptococcus (GAS). This bacterium is responsible for common illnesses such as strep throat and certain skin infections. The subsequent development of RF is not caused by the bacteria itself, but by the body’s own immune response to the infection.
Rheumatic Fever is classified as an autoimmune disease, meaning the immune system mistakenly attacks healthy human tissue. Antibodies generated to fight the GAS infection recognize certain bacterial proteins that are structurally similar to proteins found in the body’s own cells. This phenomenon directs the immune response toward healthy host tissue, causing inflammation in the heart, joints, skin, and brain.
Repeated episodes of GAS infection and subsequent RF attacks can lead to progressive and irreversible damage to the heart valves, resulting in Rheumatic Heart Disease. This chronic condition is the most severe outcome of RF in children and young adults globally.
Obstacles in Developing a Strep A Vaccine
Developing a vaccine against Group A Streptococcus is a complex scientific challenge, largely due to two biological hurdles. The first obstacle is the extensive antigenic variability of the bacteria. GAS strains are classified into over 200 different serotypes, each possessing a distinct surface protein called M-protein.
Because immunity to GAS is highly type-specific, a vaccine must induce protection against most circulating strains to be globally effective. Creating a single vaccine that incorporates antigens from a sufficient number of serotypes to provide broad coverage is difficult. The prevalence of these serotypes also varies across different geographic regions, complicating vaccine design for worldwide use.
The second hurdle is the concept of molecular mimicry, which is directly related to the M-protein. This protein, the primary target for protective immunity, shares structural segments with human proteins found in heart tissue, such as cardiac myosin. Scientists fear that an M-protein based vaccine could inadvertently prime the immune system to attack the body’s own heart, potentially causing the autoimmune disease it is intended to prevent. This risk has historically slowed vaccine development as researchers seek non-cross-reactive bacterial components.
Vaccine Candidates Currently Under Investigation
Despite the scientific obstacles, various vaccine candidates are advancing through the research pipeline, primarily focusing on two distinct strategies. One approach is the development of multivalent M-protein vaccines, engineered to overcome the variability problem by including multiple M-protein fragments in a single shot. For instance, candidates containing up to 30 different M-protein fragments have been constructed to provide broad protection against the most common global serotypes.
These multivalent vaccines are designed using only the amino-terminal portions of the M-protein, which elicit protective antibodies and are less likely to cause cross-reactivity with heart tissue. One such candidate, a 30-valent vaccine, has successfully completed early-stage Phase 1 clinical trials in healthy adult volunteers. This trial demonstrated encouraging safety and immunogenicity data.
The second strategy involves non-M-protein vaccines, which aim to avoid the molecular mimicry issue entirely by targeting other highly conserved bacterial surface proteins. These conserved antigens, such as C5a peptidase, are found across nearly all GAS strains, offering the potential for universal protection regardless of the serotype. Such candidates are typically in the preclinical or early development stages, representing a promising avenue for a vaccine with a reduced risk of autoimmune complications.
Current Strategies for Prevention and Management
Since a vaccine is not yet available, the current public health approach to controlling Rheumatic Fever relies on two forms of antibiotic-based prevention. Primary prevention focuses on treating the initial GAS infection promptly to prevent the first episode of RF from occurring. This involves the timely diagnosis of strep throat and the administration of a full course of antibiotics, typically penicillin.
However, many GAS infections are asymptomatic or mild, meaning they are often not diagnosed or treated, which limits the effectiveness of primary prevention. When an individual has already been diagnosed with Rheumatic Fever, they must undergo secondary prevention (prophylaxis). This involves the long-term use of antibiotics to prevent any future GAS infections.
Secondary prevention usually consists of administering intramuscular injections of long-acting Benzathine Penicillin G every three to four weeks. This regimen prevents recurrent GAS infections, which could trigger additional RF attacks and cause cumulative damage to the heart valves. Prophylaxis is often continued for a minimum of 10 years after the last RF episode or until the patient reaches adulthood, depending on the severity of any resulting Rheumatic Heart Disease.