By Deborah Borfitz 

November 2, 2022 | Best practice surveillance protocols for seven diseases caused by group A Streptococcus (strep A) were recently released, and public health researchers are now actively working to identify several key sentinel sites to implement them. Harmonizing case definitions and the surveillance methodologies is a key step in accelerating development of a safe, effective, and affordable strep A vaccine to prevent these diseases, according to Chris Van Beneden, M.D., MPH, co-chair of the Strep A Vaccine Global Consortium (SAVAC) Burden of Disease Working Group responsible for development of the protocols. 

The “interesting and challenging” aspect of strep A bacteria is that they cause a broad range of diseases that range from mild to extremely dangerous and life-threatening infections, she says. “The seven diseases for which protocols were developed are the key ones—either because they are very common—like pharyngitis or impetigo—or are a part of the pathway [immune sequelae] to more severe endpoints, such as acute rheumatic fever and rheumatic heart disease.” 

Van Beneden directed the epidemiologic research, public policy development and public health response for group A strep infections for the Centers for Disease Control and Prevention for over 20 years and has a long history of working on both domestic and international surveillance for bacterial infections, retiring in 2020. She currently works as a consultant. 

An international collective of researchers and clinicians comprising a 13-member strong Burden of Disease Working Group from seven geographically diverse countries led the protocol development project, working collaboratively with disease-specific international experts on the project, she says. This was an integral part of the epidemiology workstream of SAVAC, based at the International Vaccine Institute in South Korea. 

Once a vaccine is licensed, the expectation is that it will reduce the economic and societal burden caused by the strep A disease syndromes, says Van Beneden. These include infectious disease syndromes—such as bacterial pharyngitis and acute rheumatic fever—caused primarily by strep A, and other common illnesses such as cellulitis that are also caused by other etiologies besides strep A, including group B streptococci and animal bites.  

The surveillance protocols were recently published by the Infectious Diseases Society of America in Open Forum Infectious Diseases (DOI: 10.1093/ofid/ofac210) and are therefore widely available for adoption. The effort covers standardization of epidemiological surveillance of pharyngitis (DOI:  10.1093/ofid/ofac251), impetigo (DOI: 10.1093/ofid/ofac249), cellulitis (DOI: 10.1093/ofid/ofac267), invasive group A streptococcal infections (DOI: 10.1093/ofid/ofac281), acute rheumatic fever (DOI: 10.1093/ofid/ofac252), rheumatic heart disease (DOI: 10.1093/ofid/ofac250), and acute poststreptococcal glomerulonephritis (DOI: 10.1093/ofid/ofac346). 

Ideally, through the efforts of SAVAC, several sentinel surveillance sites will be established to monitor the impact of strep A vaccines among populations in various geographic regions, Van Beneden says. Several strep A vaccines are currently in development, most of them still in phase 1 clinical trials.  

Regional Variations 

To get a true estimate of the total disease burden from strep A infections requires an estimate of the burden of each of the important endpoints, says Van Beneden. But the degree to which those endpoints are perceived as a significant public health problem varies by country and region, as does the capacity to diagnose and track them. 

The U.S. has low rates of acute rheumatic fever and rheumatic heart disease relative to countries like Australia, New Zealand, and Uganda, she offers as an example. Surveillance for acute rheumatic fever and rheumatic heart disease is therefore much more rigorous in these countries. And unlike the U.S. and several European countries, some nations don’t track pharyngitis—the main precursor to acute rheumatic fever—because it is viewed purely as a self-limiting and mild infection.  

One advantage of having good disease burden estimates broken out by region is that it strengthens support for strep A vaccine development and evaluation, as well as recognition of the importance of prevention by public health agencies in affected regions, says Van Beneden. 

In the summary article on the strep A standardized protocols, the authors highlight the importance of clear case definitions, detailed case classifications, and well-defined case ascertainment methodologies, especially for non-specific clinical syndromes. These critical surveillance elements enable more robust disease burden estimates. In South Africa, for example, the incidence of all-cause pneumonia was found to be 30% lower using an existing passive surveillance system compared to active surveillance from a prospective birth cohort that incorporated more in-depths training on case ascertainment and classification. 

One way the protocols are harmonized is that they incorporate the same components as the published surveillance standards of the World Health Organization for vaccine-preventable diseases, Van Beneden points out. They are each “like a recipe” for how to set up surveillance for a different outcome and wherever possible follow the same steps so the estimates they produce can be compared to other infectious diseases and countries.  

Estimating the burden of common diseases caused by multiple pathogens such as cellulitis and pharyngitis involves calculating the “attributable fraction” of cases that are due to group A strep, she notes. The many ways to detect strep A as the etiology of these diseases through microbiological tests is one key component of the published protocols. 

The characteristics of surveillance systems, another component of the protocols, also differ with each strep A endpoint—e.g., passive surveillance for severe disease outcomes such as invasive strep A infections (e.g., meningitis, necrotizing fasciitis) where infected individuals typically seek medical treatment may involve regular review of hospital discharge records while passive surveillance for milder disease with a higher community-level burden of disease (e.g., pharyngitis) may more appropriately be in a primary healthcare or school setting.  

Potential Benefits 

Multiple countries, states, and municipalities already have surveillance studies underway for some of the seven diseases with strep A etiology. But differences in methodologies for identifying cases and the case definitions themselves often make it impossible to make “clear and defendable” comparisons from place to place, Van Beneden says.  

In a recently completed systematic review on global pharyngitis, researchers concluded that differing estimates of incidence are due to diverse approaches to surveillance. Of 26 studies examined, no two utilized comparable methodologies for case ascertainment and surveillance type (eClinicalMedicine, DOI: 10.1016/j.eclinm.2022.101458). 

It is hoped that public health entities that have not yet started surveillance in their studies will adopt the standardized approach outlined in the newly published protocols, Van Beneden says. The standards should make it easier to initiate surveillance by giving agencies a roadmap to follow. 

Their ease of use is highlighted in a press release about the universal protocols, one of which is already being put into practice by the Telethon Kids Institute in Perth, Western Australia. Recommendations in the pharyngitis protocol are being followed for a 12-month sore throat study involving 1,050 healthy Australian children. The study “will evaluate how many children got sore throats, what was the most common cause of a sore throat, and how sore throats could change during different seasons of the year, which will help inform how a vaccine could be used to prevent a wide range of illnesses caused by strep A,” according to Jonathan Carapetis, director of the Institute as well as a member of the SAVAC Executive Committee and co-chair of the Burden of Disease Working Group.  

It is well recognized that strep A is taking a huge toll on public health with over 600,000 deaths a year and 600 million new infections annually, based on current estimates, Van Beneden says. “You don’t necessarily need perfect disease estimates to develop a vaccine, but you do have to have standardized, rigorous ongoing surveillance to evaluate its impact.” 

Accurate disease estimates can reveal trends and identify groups at highest risk based on characteristics such as their age and underlying health conditions to guide the focus of prevention efforts and decision-making about who to target for initial vaccination, as was seen with rollout of the COVID vaccines, she continues. Eventually, the information gleaned from good surveillance systems will also be useful in establishing sentinel sites for evaluating candidate strep A vaccines. 

One objective in developing the surveillance protocols is to address the uneven quality and quantity of disease burden estimates around the world, says Van Beneden. “We need better estimates in low-middle-income countries ... if the burden of some common strep A diseases, such as pharyngitis or rheumatic fever, is poorly captured and therefore under-appreciated, they are not going to realize the potential benefit of introducing a vaccine.” 

Sometimes people “underestimate the value of good surveillance,” she says. “If you have bad surveillance, it can even be more detrimental than no surveillance.” 

Surveillance that markedly underestimates the frequency of a certain group A infection will not only mislead public health agencies about the true burden of disease, Van Beneden says. If surveillance practices improve after a public health intervention is introduced, it could cause them to erroneously conclude the effort was unhelpful. “We’ve seen that before with other bacteria.”