RSV the skyborne stowaway

Understanding how respiratory syncytial virus behaves is the first step in discovering how to stop its nasty impact on the young and not-so-young. Vaccine research is ramping up but this tricky ‘quiet one’ will need vigilance and caution.

By Eric Martin

An unexpected outcome of the interruption of global travel during the COVID pandemic was that shut borders and geographic isolation led to a complete absence of Australian cases of RSV during the winter of 2020.

Professor Peter Richmond

“In fact, we were we were one of the first countries to report that RSV (respiratory syncytial virus) was disappearing,” according to WA vaccine expert Professor Peter Richmond.

He heads the Vaccine Trials Group at the Wesfarmers Centre of Vaccines and Infectious Diseases based at the Telethon Kids Institute, as well as being head of paediatrics at UWA and head of immunology at Perth Children’s Hospital.

“As a paediatrician who has seen our hospitals full every year, we always assumed that it was circulating within older children and that it would simply continue and wouldn’t be affected by shutting our borders,” he said. “But instead, we saw this complete absence.”

The subsequent RSV epidemic came out of season – instead of occurring in the middle of winter, it happened over Christmas. 

“And that particular outbreak, which occurred in WA and in the eastern states, was due to one strain of the virus, whereas previously from, our studies, we knew there were multiple strains circulating all the time,” he said.

“We looked at the strains across different countries over a three-year period and it was really quite detailed molecular epidemiology: sequencing the genome of these viruses, examining how they related to each other, and what might explain how they tracked across the globe.

“It appeared that like influenza, RSV is spread in part through air travel – that’s why we’re getting this introduction of new strains that arise by ‘chance’ in countries around the world. I think we are all aware this also occurs with SARS-CoV-2, and it does have significant implications. 

“We have the emergence of strains that may be resistant to one or more of the monoclonal antibodies that have been developed for use both in pregnancy and older adults, which could spread quite quickly and limit the impact of those vaccines. It also explains the unexpected results that we saw during the pandemic, when RSV suddenly went away and came back the way it did once air travel returned.

“The most surprising thing when we did the modelling was that we could trace the predominant spread along frequently flown air traffic routes. Five years ago, I would not have said that was the case.

“The other thing was understanding that RSV actually does change, and we need to be aware of how we can track this efficiently as part of our public health programs. 

“RSV is not as diverse as SARS-CoV-2 or influenza, so it tends to be a bit more stable, yet it is clearly changing from time to time, and we still haven’t had a highly effective drug treatment. It’s important research that we need to keep doing and having the local ability to do this, while tracking the results globally, enables us to look at the bigger picture and reveal these novel findings.”

Professor Richmond said his team had been working on several prevention strategies for RSV infections, particularly focusing on studies in children and infants, using a monoclonal antibody and nirsevimab, a new drug still in the last phases of clinical trials.

“Our new understanding of clades has helped us track them with greater certainty and we can identify where they’re first appearing and then where they might go – much like bird-flu.”

“One of the important parts of protection, particularly for monoclonal antibodies, is that small changes in the critical binding site can render the antibody unviable. This has certainly been well described for COVID, but it is also the case for some RSV monoclonal antibodies that looked very promising – where a mutation meant they were ineffective. 

“A global consortium has been established to search for these mutations that might predict whether we have circulating strains that will be harder to prevent through vaccination, and to try and decrease the severity of infection. That work has been going on for several years.

“Our new understanding of clades has helped us track them with greater certainty and we can identify where they’re first appearing and then where they might go – much like bird-flu.

“In some tropical countries we see that RSV seems to circulate all year round and similarly in northern Australia. The Northern Territory, Kimberley and far North Queensland – even greater parts of Queensland – seem to have a much longer RSV season. This is important knowledge when you’re going to target children being born throughout the year. We might have an effective intervention, then suddenly it becomes more complicated to work out the best way to prevent a new strain of RSV.”

Professor Richmond explained that the F-protein (or fusion protein) was critical for the initial cell entry and infectivity of the RSV, akin to the spike protein in a coronavirus. 

“The protein structure also changes shape significantly when it binds to a cell – forming the elongated shape unique to RSV – which is why we talk about prefusion F-protein or pre-F-protein, and post-fusion protein or post-F-protein,” he said.

“Understanding that was one of the reasons we were able to develop effective vaccines and monoclonal antibodies, because the earlier vaccines used the post-fusion construct, yet the better the F-protein can be conserved in that prefusion structure, the more effective it will be. 

“The G-protein tends to be more variable and has a slightly different role in the pathogenesis of RSV and may be the reason for overall viral variation. There have been several people developing vaccines that include the G-protein, or adjust against it, but they have not been able to progress to advanced-stage efficacy trials yet.”

Professor Richmond pointed out that a downside of less variability within RSV’s structure was that it was less likely that mutations, which have resulted in higher rates of transmission but less severe symptoms in the coronaviruses, would occur with RSV. 

“Because it has been around for such a long time, it’s in a relatively steady state, but we don’t know for sure. These viruses are very good at adapting and finding new ways to spread,” Professor Richmond said.

“It is important that we don’t start to say this type of research is of ‘academic interest’ only – and that applies to infectious disease much more broadly, not just respiratory diseases. We need to invest in a population health strategy that endeavours to understand what is circulating in our particular part of the world and that will help us identify the next outbreak of a virus or bacteria that’s going to cause global problems.

“This type of research needs to become a bigger part of our public health approach to reduce the burden of infectious diseases and the technology is such that the cost of doing it has come down rapidly.”

Professor Richmond said there were several other key healthcare principles that the team drew from the study, based on the discovery that RSV was spread primarily through droplets rather than pure airborne transmission – making it somewhat less likely to spread throughout a plane.

“You need to have closer contact and, as such, it appears that preschool and primary school-aged children are probably the population most responsible for dissemination of new strains in the community,” he said.

“If your child is unwell with a new cold, particularly if you’ve just returned from overseas, dropping them off at daycare or at primary school to share it with their classmates is probably not the best thing to do. 

“And that’s an important message for the parents of small children who can’t wear masks – if your child is sick and you’ve just come back from overseas or had contact with other children who have been unwell, don’t send them to school to spread the new strain of the virus. 

“And, somewhat controversially, wearing a mask while traveling on airplanes may be a much more frequent event. And it’s not pleasant. I’m not one who loves putting on a mask and wearing it for a 20-hour flight to the Northern Hemisphere.

“But I do know that it is the time you are most likely to be exposed and contract one of these viruses. When putting yourself at risk by traveling overseas, you need to think about masking up.”

Professor Richmond said that while the original study used the defined context of children hospitalised with RSV, his team was already looking at conducting broader studies on transmission in daycare centres and the community. 

“We need more understanding to identify the most important groups to vaccinate to try and stop the spread of RSV because the mAb monoclonal antibody that we’re currently using won’t necessarily stop transmission of the virus,” he said.

“Other vaccines, like pneumococcal for infants, actually stop babies and toddlers from spreading them to the rest of the community. That’s perfect, and we think that with newer RSV vaccines coming down the line, that might be possible. 

“But, for now, it’s vital to understand how RSV spreads. It can be difficult to tell the difference between RSV, influenza and COVID, but the good news for GPs is that we now have a range of tests that can target multiple viruses with a single swab. We’re very lucky in WA that we have the capacity for these viruses to be sequenced. 

“The most important thing to remember is that we have a very effective RSV prevention strategy for young children that’s currently provided free by the WA government. We need to use this to its fullest extent to make sure as many children as possible can be protected against RSV in early childhood.”