Team working on superbug vaccine

The day after Ries Langley’s son turned one, his knee swelled up, turning hot and red. He couldn’t put any weight on his leg and he cried constantly. It was the start of a horrible month in hospital. The little boy had osteomyelitis, a bone infection caused in his case by Staphylococcus aureus, commonly known as S. aureus, Staph aureus or just “staph”.

Langley, a senior research fellow in Molecular Medicine and pathology at the University of Auckland, had already spent years studying staph.

He still felt as helpless as any father watching his son suffer. The experience cemented his determination to understand the tricky bacterium better.

Today, Langley’s son is 14 and healthy, but his father’s resolve has only strengthened. As co-principal investigator of a team led by his longtime mentor, Professor John Fraser, Langley is working on a project to develop an mRNA vaccine for staph. The project is funded by Wellcome Leap, within the R3: RNA Readiness and Response programme, which has put the Auckland team in touch with a global consortium of teams working on various dimensions of mRNA technology.

“A successful vaccine could keep people out of hospital, shorten their time in hospital or potentially save their lives,” says Senior Research Fellow Fiona Radcliff, the project’s other co-principal investigator. “That’s what gets me out of bed in the morning.”

A foe with many faces

Under a microscope, staph doesn’t look like much – just little round blobs. In a sense, though, it has many faces.

Staph is commonly carried on people’s skin and in their nostrils. Most of the time it doesn’t cause any symptoms. Sometimes it can cause minor skin infections or food poisoning. It can also be deadly. It’s the most common cause of hospital-acquired, surgical, and medical implant infections. It can also cause bloodstream infections, bone and joint infections, toxic shock, pneumonia and infective endocarditis, a life-threatening heart infection.

To make matters worse, staph can rapidly develop resistance to most antibiotics. It’s good at sharing bits of genetic information – meaning genes that carry antibiotic resistance are easily transferred between strains of bacteria. This ability is a major reason why staph is listed in the World Health Organization’s list of priority pathogens.

Around the world, the commonest form of antibiotic resistance is Methicillin-resistant Staphylococcus aureus (MRSA), a “superbug” that’s highly resistant to commonly used antibiotics.

In the United States, hospital-acquired MRSA bloodstream infections caused 20,000 deaths in 2017 alone and healthcare costs associated with staph are estimated to be US$15 billion a year, says Langley.

Nor are things better in New Zealand.

“We have some the highest rates of staphylococcal infection in the developed world. It’s particularly prevalent in Māori and Pacific populations,” says Langley. “This makes it a health equity issue.”

Knowing the enemy

Fraser, Radcliff and Langley know staph better than just about any other team in the world. Fraser, who is dean of the Faculty of Medical and Health Sciences, started working on the bacterium some 30 years ago when he was part of a team that made the major discovery of a set of proteins called superantigens that were unique to staphylococcus and streptococcus bacteria.

Langley did his PhD under Fraser and returned to the same lab after a postdoctoral fellowship in the United States. He has been publishing research on staph for 20 years.

Radcliff came to the field through a more circuitous route but has been familiar with staph since her days growing up on a dairy farm in Tasmania. Staph is the most common cause of mastitis – udder infections – in dairy cows. It’s a major economic issue for farmers because an infection can lead to a whole tanker load of milk being thrown out, says Radcliff, who has worked in Fraser’s lab for 15 years and has a background researching both bacteria and vaccines.

This deep knowledge is part of why Fraser believes he and his team can do better than previous teams have in producing a vaccine against staph.

“Why a vaccine? Simple answer is, we’re running out of antibiotics,” says Fraser. “Vaccines have been tried for staph before, taking a relatively simple approach – generating antibodies to surface molecules and hoping those antibodies kill the bacteria. They’ve all failed, some spectacularly, because they were based on the assumption that what we need to do is sterilise the body from staph. It’s such a common bacterium and it hides in so many places in the body, we don’t think that’s possible.”

A new type of vaccine

The other reason Fraser and his team believe they’ll be able to produce a breakthrough staph vaccine is because vaccine technology has improved.

As the Covid-19 pandemic upended the world, enormous resources were poured into vaccine research. Covid vaccines were produced with unprecedented speed. The safest and most effective were a new type of vaccine – mRNA vaccines.

Traditional vaccines use inactivated virus or virus particles to teach the body’s immune cells to recognise them and thus mount a speedier defence when active virus invades the body. mRNA vaccines work differently. They use bits of messenger RNA that can enter cells and teach them to create just one part of the virus – in the case of Covid, the characteristic spike protein. The body’s immune system thus learns to recognise and attack these spike proteins without having been exposed to the virus itself.

While the Covid vaccines really were developed quickly, research into mRNA vaccines had been going on for decades.

“The Covid vaccines have been a vindication of what people have been saying about mRNA for a long time,” says Fraser. “There’s huge potential for this technology.”

The challenges of a staph vaccine

Making an mRNA vaccine for staph is trickier than making one for the coronavirus that causes Covid-19. The SARS-CoV-2 virus makes few proteins and has an obvious target for a vaccine – the spike protein that initiates binding to host cells.

Staph, being a bacterium rather than a tiny virus, consists of thousands of proteins. However, Fraser and his team are familiar with its virulence factors – the molecular characteristics that help it attack a host and evade its defence mechanisms. They chose three of these virulence factors to target at once in a single mRNA vaccine. Results in animal studies have been promising.

“We have shown that if we infect vaccinated mice with S. aureus, these animals recover more rapidly and have a substantially reduced burden of bacteria in major organs such as their livers and spleens than our unvaccinated control mice,” says Radcliff, who leads the animal model part of the research.

A staph-vaccinated future?

There’s still a lot of science to do. While the team has shown that its vaccine stimulates a robust neutralising antibody response in mice, it’s still working to understand which immune cell populations contribute most to the protective immunity seen in the animals. More work also needs to go into ensuring safety before humans can be inoculated.

Without the massive resources poured into Covid-19 vaccines, things won’t go as fast. Still, the team believes its vaccine will be ready for human clinical trials within a few years. Clinical trials will take longer than the Covid vaccine trials did because S. aureus doesn’t infect people at anywhere near the rate of a major Covid wave, so results won’t come in as fast.

The team does, however, have every intention of seeing its vaccine through. It will be able to take advantage of the linkages formed through the Wellcome Leap R3 programme, including with groups working on producing clinical-grade mRNA and groups researching ways to produce vaccines and other products on a smaller and less expensive scale. It’s already talking to potential industry partners in New Zealand.

“This will be the world’s first antibacterial mRNA vaccine if successful,” says Kerryn Kilkenny, the UniServices business development manager (health) who’s been working with the team. “That would be huge for New Zealand. It would put us at the forefront of vaccine technology globally.”

The staph vaccine will probably never be one that requires a near-universal rollout. Most healthy people can co-exist with S. aureus without problems. A vaccine, however, might be effective when used to build up immunity before major surgery, or in particularly vulnerable populations such as dialysis patients or residents of aged care homes, says Fraser.

“A successful vaccine would reduce healthcare costs, because the longer you spend in hospital, the more expenses are incurred,” says Radcliff. “Not to mention the negative effect on people’s lives if you have to fight off a massive staph infection. In the end, the goal is improving and saving lives.”