By Deborah Borfitz

July 8, 2021 | In at least two, placebo-controlled randomized trials getting underway in the next year, participants will be purposefully infected with a strain of group A streptococcus (Strep A) causing acute pharyngitis (strep throat) in a human challenge test of candidate vaccines intended to confer protection. An earlier human challenge trial established the best dose of the Streptococcus pyogenes (a Strep A bacterial pathogen) to apply to their pharynx—meaning, potent enough to cause disease but without overwhelming their native defenses or vaccine-derived immunity, according to pediatric infectious diseases physician Joshua Osowicki, who led that research effort with Andrew Steer at the Murdoch Children’s Research Institute (MCRI) in Melbourne, Australia.

This is the only Strep A controlled human infection model currently available for clinical development, says Osowicki, a Ph.D. student in the tropical diseases research group at MCRI. In the initial study, a starting dose one-tenth of that used in human infection studies in the 1970s proved high enough, causing pharyngitis in 85% (17) of healthy adult volunteers.

Human challenge studies are an attractive, if sometimes misunderstood, means to accelerate vaccine development, he says. They can provide a read on efficacy at a fraction of the cost and number of participants in traditional clinical trials and may help sponsor companies reach a go/no-go decision point earlier in the development process.

The breakneck speed at which COVID-19 vaccines were developed was more of an anomaly, says Osowicki, noting the huge and justified public underwriting of the entire effort. This contrasts with the immense global burden of disease due to pathogens like Staphylococcus aureus and S. pyogenes that companies have generally found “a bridge too far” for vaccine development in terms of difficulty, risk, and expense.

Recruiting participants into human challenge studies can be tricky without an approach that specifically addresses concerns related to deliberate infection and safety. It can “depend on the source of recruits,” Osowicki says, citing work by the Oxford Vaccine Group (DOI: 10.12688/wellcomeopenres.15469.1) and the COVID-19 human challenge trials advocacy group 1Day Sooner (DOI: 10.1101/2021.03.14.21253548).  

Participants are motivated by a mix of motivations, including payment as well as the opportunity to contribute to science—a major driver of enrollment into the UK COVID Challenge. But no matter how noble the cause, not everyone can get on board with the concept of deliberate self-infection, Osowicki says. Recruitment requires communications dedicated to addressing initial reflexive reactions to the study concept, and creative approaches to delivering participant information and achieving informed consent are starting to emerge.     

The Long Wait

Scientists have been intentionally infecting patients with diseases for more than two centuries, says Osowicki, although modern controlled human infection studies with stricter ethical standards surrounding their conduct have steadily increased in number over recent decades. The World Health Organization issued regulatory guidance on human challenge trials for vaccine development in 2016 based largely on meetings organized by the International Alliance for Biological Standardization.

Human challenge trials describe both models of pathogen carriage, where participants tend to remain completely asymptomatic, and disease models where researchers seek to recreate a symptomatic syndrome, he explains. For the latter, the goal is to produce a “predictable, reproducible, and somewhat limited clinical [condition].” At least 25 bacterial, viral, and parasitic pathogens have been developed specifically for human infection studies worldwide.

Among the 25 are pathogens like malaria where the challenge comes by way of a mosquito bite or intravenous injection of Plasmodium falciparum sporozoites (or other malaria species). Malaria models are often outpatient models these days, with participants sent home after inoculation and returning regularly for PCR measurement of parasitemia, with approved or investigational malaria drugs administered at a predetermined PCR cut-off or first symptoms, says Osowicki. When vaccines are evaluated, they are administered prior to the challenge, with efficacy determined by the relative proportion of participants meeting clinical or microbiological endpoints in the vaccine compared to control group.

Relative to the malaria human infection model, Osowicki’s symptomatic pharyngitis model for Strep A is still relatively immature but it is not an entirely novel idea. Starting in the 1830s until almost a century later, scientists would use bodily fluids like snot and pus aiming to intentionally transmit scarlet fever to help understand the disease and the spectrum of syndromes we know now are caused by S. pyogenes.

Gladys and George Dick famously developed an antitoxin and vaccine for scarlet fever in 1924 (eclipsed by penicillin in the 1940s) and did so with experimental human infection studies, piloting an early correlate of protection from scarlet fever using intradermal injection of S. pyogenes extracellular toxins, which became known as the “Dick test.” As Osowicki explains, the test would either cause a small area of redness and induration (“Dick positive”) or it would not and, “if you were susceptible to the toxin, you were susceptible to Strep A disease [scarlet fever].”

By the 1930s, U.S. public health authorities were confident that the “Dick test” for determining susceptibility to scarlet fever and active immunization with a related vaccine could shut down outbreaks of scarlet fever that had been a huge problem for state-run institutions at the time, says Osowicki. However, the Dick test and vaccines were not infallible and with penicillin’s arrival, the specter of Strep A epidemics diminished along with scientific and public interest in Strep A vaccination.

But the hardships and losses associated with Strep A diseases—especially rheumatic heart disease and severe invasive infections like toxic shock syndrome and necrotizing fasciitis—have not disappeared, he stresses. Even in high-income countries like Australia and New Zealand, untreated or under-treated Strep A infections in indigenous communities combine with social determinants of health to cause rates of acute rheumatic fever and chronic rheumatic heart disease that are among the highest described anywhere in the world. Rates of rheumatic fever among these disadvantaged groups are at levels seen in cities like Melbourne in the 1960s, he adds.

Across the spectrum of Strep A diseases, even the most intensive and expensive disease control efforts have achieved only partial success, making the development of a vaccine the next best answer, says Osowicki. Even in well-resourced settings like New York state (home to Rory’s Regulation), Strep A infection can cause life-threatening sepsis, not to mention the inconvenience and lost time away from school and work from less severe infections like strep throat and impetigo (“school sores”).

The uncontrolled global burden of Strep A diseases has not led to the sense of urgency that fast-tracked COVID-19 shots into arms inside of a year. “If we could produce a vaccine for Strep A in 100 months, let alone 100 days, it would [still] be a huge acceleration on a vaccine that the world has wanted in a variety of ways for over 100 years.”

Preventing Strep A infection would aid in the fight against the growing problem of antibiotic resistance, Osowicki points out. Although the pathogen is susceptible to penicillin, many children and adults who see a physician complaining of a sore throat end up being prescribed a broad-spectrum antibiotic without first testing for the culprit bug. If a vaccine were available, “the one thing [the doctor would] know is that it’s not Strep A, the only common cause of sore throat to consider treating with antibiotics at all.”

Such a vaccine will ultimately save more lives in undeveloped rather than high-income countries, he says. So, having an early read on efficacy before embarking on large and expensive phase 2 and 3 trials will be a financial imperative for sponsoring life science companies.

CARB-X, a public-private partnership funding projects helping to fight antimicrobial resistance,  announced in March that it is providing funding to GSK Biologicals and its affiliate, GSK Vaccines Institute for Global Health, to develop a vaccine against Strep A infection. Previously, CARB-X funded Strep A vaccine development by San Diego company Vaxcyte.

Avoiding Booby Traps

Scientists do not have a strong sense of who might unexpectedly have a violent reaction to even a small dose of a known bacterial inoculant, so a lot of forethought was put into development of the Strep A strain Osowicki and his MCRI colleagues used in their study as well as the individuals allowed to participate. The trial enrolled only healthy adults who were closely monitored in an inpatient setting.

While human challenge trials share much in common with standard early phase trials, there is a central and important qualitative difference, particularly in the initial dose-finding studies to establish a model for further use, he says. Rather than giving participants an investigational product in the hope they have no symptoms other than perhaps boredom, the goal with a challenge study is to establish carriage of a pathogen or to make them sick.

His study followed strict infection control protocols (now familiar to everyone due to COVID) and participants were monitored as inpatients, as with many other early-phase clinical trials, he notes. But unlike a trial involving a novel drug where the risks are uncertain, “we had 200 years of evidence to tell us what could happen. We were watching and waiting for a classic strep throat syndrome to emerge… and 24 hours [following treatment] we discharged them home.”

The Strep A human challenge strain was “put through an obstacle course” in the lab and compared to a range of other Strep A strains, including one used in 1970s Strep human challenge studies in Florida, he says. Relative to the strains causing the most problems around the world, it seemed to be less virulent—so much so that investigators were initially worried it might not produce pharyngitis in any of the 20 to 80 volunteers they planned on challenging with escalating doses.

Researchers also had to convince themselves that the strain was susceptible to a range of antibiotics, despite Strep A generally being a self-limited disease even without treatment, says Osowicki. “We didn’t only want to make the symptoms go away, but [also to] eradicate the strain from the back of the throat, and that ended up happening for 100% of the participants.”

Unlike viruses, which tend to have a few key parts that stick to a receptor to help them enter cells and begin replicating, bacteria often have hundreds of antigens “under the hood” that work hard to subvert immune responses, Osowicki shares. Strep A has a diverse armamentarium of these virulence factors, but those that cause the worst infections have been reasonably well characterized, enabling the human challenge researchers to “avoid the worst booby traps.”

Next Steps

The MCRI team plans to soon start testing candidate Strep A vaccines being developed by researchers in Australia and overseas in randomized trials in which about 50 participants would receive a course of either the vaccine or placebo followed by the Strep A challenge. The primary outcome will be whether the vaccine prevents symptomatic disease and secondary objectives will consider vaccine safety, immunogenicity, and the immunological, biochemical, and microbiological results supporting the clinical results, Osowicki says.

At least two trials will take place and perhaps many more, based on the backlog of preclinical Strep A vaccine candidates now under study, he continues. One with commercial backing that is moving into trials is a product being developed by James Dale, M.D., an infectious diseases specialist at the University of Tennessee Health Science Center, which uses pieces of different Strep A proteins to protect people against as many strains as possible. His company, Vaxent, owns the license that once belonged to GSK.

Other Strep A vaccines with active plans for human challenge trials have been developed by Michael Good, Ph.D., with his colleagues at Australia's Griffith University. These vaccines use a single “conserved” fragment of the M protein, common among Strep A strains, to broaden its protection against most of the strains seen around the world, says Osowicki.

Both Dale and Good were co-authors with Osowicki on the dose-finding human challenge study recently published in The Lancet Microbe (DOI: 10.1016/S2666-5247(20)30240-8).    

The forthcoming human challenge trials will follow phase 1 trials of the current generation of candidate Strep A vaccines. The human challenge trials will expand on the safety data for each respective vaccine at the preferred dose level emerging from phase 1, and then evaluate each vaccine’s protection against symptomatic Strep A pharyngitis, sometimes described as phase 1b/2a trials. “The traditional clinical trials terminology does not always neatly fit controlled human infection research,” says Osowicki.

The model is unlikely to be popular for treatment trials since penicillin and other antibiotics are reliable in the treatment of strep throat. However, one of the first trials in the model is trying to establish the penicillin level that protects against strep throat to inform development of improved long-acting penicillins for secondary prevention of rheumatic heart disease, Osowicki says.

The model may also be useful in testing novel diagnostics, which is a common use of challenge studies in general, he adds. Additionally, these Strep A challenge trials are contributing to detailed studies of Strep A pathogenesis and the immune response in humans, the only species the organism naturally infects.