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Take a look at a selection of our recent media coverage:
28th April 2023
RSV infection leads to a global high morbidity and mortality burden in children aged 0-60 months. Moreover, the greatest risk for hospitalisation occurs during the first 6 months of life. In a recent study, RSV-associated acute respiratory infection, led to the hospitalisation of one in every 56 healthy term-born infants. Whether maternal vaccination can reduce such RSV-related infection in newborns and infants remains uncertain.
In the present, randomised, double-blind, phase 3 trial, pregnant women received a single dose vaccine or placebo, between weeks 24 and 36. The two primary efficacy endpoints were severe RSV-associated lower respiratory tract illness and medically attended, less severe illness. Assessment of these outcomes took place at 90 and 180 days after birth. A lower boundary of the confidence interval > 20% was the success criterion for vaccine efficacy.
Maternal vaccination and RSV-associated infections
Overall, 7358 women received either the vaccine (3682) or placebo. There were 6 cases of severe RSV in the vaccinated group and 33 in the placebo arm within 90 days of birth (vaccine efficacy = 81.8% 99.5% CI 40.6% – 96.3%). Within 180 days, the vaccine efficacy against severe infection was 69.4% (97.58% CI 44.3 – 84.1%). In contrast, vaccine efficacy was only 57.1% (99.5% CI 14.7 – 79.8) against less severe disease and did not meet the criteria for success.
Adverse events were similar in all groups within 1 month after injection or within 1 month after birth.
2nd February 2023
Moderna has announced that mRNA-1345, its investigational vaccine, met its primary endpoint and demonstrated a high vaccine efficacy against RSV-associated lower respiratory tract disease and which was defined by two or more, as well as three or more, symptoms.
The press release relates to the ConquerRSV trial which was a randomised, double-blind trial, designed to evaluate the safety and tolerability of the mRNA-1345 vaccine. The study sought to demonstrate the efficacy of a single vaccine dose in the prevention of a first episode of RSV-associated lower respiratory tract disease when compared to placebo, 14 days after vaccination, through to 12 months. In a site dedicated to the study, individuals are invited to screen for inclusion, highlighting how in the US alone, the virus causes 14,000 annual deaths.
ConquerRSV was reported to have recruited more than 37,000 adults 60 years of age and older. The study’s primary efficacy endpoints were based on two definitions of RSV-lower respiratory tract disease with either two or three or more symptoms.
According the press release, the efficacy of the vaccine was 83.7% (95% CI 66.1 – 92.2%, p < 0.0001) against RVS-associated disease as defined by two or more symptoms. The reported interim analysis was based on a total of 64 cases, 55 of which occurred in those given placebo. In addition, there were 20 cases of RSV-associated lower respiratory tract infections where patients presented with 3 or more symptoms, of which only 3 occurred in patients given the vaccine. This gave a vaccine efficacy of 82.4% (95% CI 34.8 to 95.3%, p = 0.0078) against RSV-associated disease with 3 or more symptoms.
An analysis of safety data showed that mRNA-1345 was well tolerated and there were no safety concerns identified, although this will continue to be monitored as the trial progresses. Commonly reported adverse effects were generally mild to moderate in severity e.g., injection site pain, fatigue, headache, myalgia and arthralgia. In fact, only 4% of systemic adverse reactions reported for the vaccine were grade 3 or higher (i.e., severe) and overall, there were only 3.2% of localised adverse reactions, at grade 3 or above.
Moderna also announced that these findings will be submitted for publication and presented at an upcoming conference and hope to submit all the data for regulatory approval in the first half of 2023.
15th November 2022
According to a press release by the manufacturer Astra Zeneca, nirsevimab (brand name Beyfortus) has been approved by the European Commission for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season. The product represents the first and only single-dose RSV passive immunisation for the broad infant population, including those born healthy, at term or preterm, or with specific health conditions. Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. Moreover, the rate of hospitalisation for primary infection is approximately 0.5% but can be as high as 25%
Nirsevimab is produced by a collaborative effort from Astra Zeneca and Sanofi which was agreed in 2017. Under the terms of this agreement, AstraZeneca leads all development and manufacturing activities, and Sanofi leads commercialisation activities and records revenue.
Nirsevimab is a long-acting, antiviral monoclonal antibody which binds to the RSV F (fusion) protein and effectively locks the protein into the pre-fusion conformation and thus inhibiting entry of free virions into cells, as well as inhibiting spread of cell-associated virus by cell fusion. The drug is designed for all infants for protection against RSV disease from birth through their first RSV season with a single dose.
Nirsevimab clinical efficacy
In a phase IIb trial, infants were randomised in a 2:1 ratio to receive nirsevimab, at a dose of 50mg in a single intramuscular injection, or placebo at the start of an RSV season. The results showed that the incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower with nirsevimab prophylaxis compared to placebo. Further data came in a second trial in which infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo (in a 2:1 ratio) before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. Medically attended RSV-associated lower respiratory tract infection occurred in 1.2% of those given nirsevimab 5.0% in the placebo group, corresponding to an efficacy of 74.5% (95% CI 49.6 – 87.1, p < 0.001). Moreover, hospitalisation for RSV-associated lower respiratory tract infection occurred in 0.6% of those given nirsevimab compared to 1.6% in the placebo group. However, this was associated with a lower efficacy (62.1%), and which was not significant (p = 0.07).
According to the EMA, nirsevimab should be given before the RSV season or as soon as possible after birth for those infants born during the RSV season.
19th October 2022
RSV vaccine candidate, RSVPreF3, manufactured by GSK provided a high overall efficacy in a phase 3 trial among older adults according to a press release by the manufacturer.
Respiratory syncytial virus (RSV) is one of the common viruses that cause coughs and colds and causes severe respiratory illnesses in infants and older adults who frequently require hospitalisation. The condition creates a severe disease burden upon sufferers and the global number of hospital admissions for RSV-acute respiratory infections (ARI) in older adults has been estimated at 336000 and which lead to an estimated 14 000 in-hospital-related deaths. Currently, not a single RSV vaccine has been approved although in September 2022, it was reported that Pfizer was ready to file for FDA approval of its candidate RVS vaccine.
The GSK press release relates to their randomised, placebo-controlled trial which was designed to evaluate the efficacy of the RSVPreF3 at preventing lower respiratory tract disease (LRTD) caused by RSV in adults ≥ 60 years of age following a single dose of the vaccine. GSK announced preliminary findings from the study in June 2022 although no data was presented in the release apart from the fact that the vaccine showed statistically significant and clinically meaningful efficacy in adults aged 60 years and above. While the current findings have yet to be published in a peer-reviewed article, the press release does provide plenty of data.
RSV vaccine results
The findings show that among those assigned to RSVPreF3 there were 7 lower respiratory tract RVS cases compared to 40 in the placebo group, giving an overall vaccine efficacy of 82.6% (96.95% CI, 57.9 – 94.1, p < 0.0001). The vaccine also demonstrated a high efficacy against both type A (84.6%) and type B (80.9%) RVS.
In addition, there was a consistently high vaccine efficacy across a range of pre-specified secondary endpoints. For example, among those with a severe lower respiratory tract infection, there was only 1 case in the RSV vaccine group compared to 17 in the placebo arm, giving an efficacy of 94.1% (95% CI, 62.4 – 99.9, p < 0.0001). Among patients with pre-existing comorbidities, such as underlying cardiorespiratory and endocrino-metabolic conditions, vaccine efficacy was 94.6% (95% CI, 65.9 – 99.9) and 93.8% (95% CI, 60.2-99.9) in adults aged 70-79 years.
Among patients with RSV confirmed acute respiratory infections, vaccine efficacy whilst lower, was still high with an overall efficacy of 71.7% and again, this was similar for type A (71.9%) and type B (70.6%).
The RSV vaccine was also well tolerated with observed solicited adverse events typically mild-to-moderate in severity and transient, with the most frequent being injection site pain, fatigue, myalgia, and headache.
The company expects to undertake regulatory submissions based on the phase III data in the second half of 2022.
11th August 2022
Dexter Wiseman is a registrar at Royal Brompton and Harefield NHS Trust, London, but has also been working at the National Heart and Lung Institute based at Imperial College, where he has just submitted a PhD. Part of his research involved working with the RESCEU (REspiratory Syncytial virus Consortium in EUrope) Project, a European group investigating the burden of respiratory syncytial virus (RSV) across Europe, with a work package focusing on older adults with chronic lung disease.
We had the pleasure of speaking with him about his work, the condition, and how he feels research will progress in the future.
Please tell us about RSV?
Dr Wiseman explained that respiratory syncytial virus (RSV) is an RNA virus that was first discovered in the 1950s and found to be pathogenic, initially in chimpanzees but then also in humans. There are two common strains – A and B – that differ in the proteins present on the viral membrane. The virus is spread via respiratory droplets and has an incubation period of four to five days. Dr Wiseman added that although the virus enters via the nasopharyngeal route, ‘it can also be transmitted through the conjunctival membrane and then spreads into the lower airways and replicates in the ciliated cells.’ The resultant humoral and T cell immune response causes cell necrosis, pushing the debris into the airways. Interestingly, he also described how in a healthy adult, human challenge study with the virus, where bronchoscopy was performed before and after infection, it was found that ‘even when the symptoms had subsided from RSV, there was still evidence of macroscopic inflammation, so that RSV might be doing a lot more than we realised when it comes to inflammation.’ A further problem among those who become infected with RSV, Dr Wiseman continued, was that that immunity to the virus is short-lived, so that individuals remain susceptible to re-infection throughout their life. In fact, he mentioned how other human challenge studies have suggested that an individual can be susceptible to re-infection in as little as two months after their initial infection. Why immunity wanes so quickly he says is still unclear, although what is known is that among older adults both immunosenescence and inflammaging can be detrimental such that their immune system appears to work against them with respect to the virus.
RSV displays a seasonality for infection, which is traditionally from October to March, although due to the COVID-19 pandemic and greater hand hygiene and the use of face masks, the seasonality was disrupted. Nevertheless, he noted that in countries such as Australia, where there has been a lot of epidemiological work on RSV, while some evidence has revealed a winter spike in cases, it seems that RSV might no longer being following its traditional pattern.
What are the main symptoms of RSV?
Dr Wiseman said that the symptoms of RSV are very non-specific, which poses a diagnostic challenge for clinicians, making it difficult to differentiate RSV from other more common viral infections. Typically, he says, adults would present with ‘nasal congestion, sore throat, cough, shortness of breath, sputum, wheeze and fever. They will also get headache, fatigue and myalgia.’ He mentioned how a study conducted in the pre-COVID era found that the symptomology of several different viral infections was broadly similar, so that making a diagnosis of RSV based solely on symptoms was impossible. While RSV can be identified through PCR testing, if this is not performed within the first few days of symptom onset, the result if often negative (i.e., a false negative) in older adults. This, he explained was a phenomenon encountered in one of his COPD trials where patients were asked to keep a symptom diary and record when they developed any specific symptoms such as a runny nose. As Dr Wiseman explained, ‘as they [patients] become more unwell, short of breath, having a cough with productive sputum, they would test negative on PCR but when we did the serology, we would find that they did have an RSV illness.’
Given the non-specific nature of the symptoms, what is known about the prevalence of RSV?
Although as Dr Wiseman explained, pretty much everyone will have had exposure to RSV by the age of 2, ‘we don’t really know much about the burden of RSV or what it does from older childhood to adulthood where people are healthy, and that’s a very understudied area.’ Nevertheless, the information that is available does suggest that RSV has a considerable burden upon adults. He mentioned a 2015 meta-analysis undertaken of studies in Western countries that found a prevalence of 1.5 million acute cases of RSV, of which 200,000 required hospitalisation. Furthermore, a seminal 2005 paper revealed that RSV led to an estimated 14,000 deaths every year in the USA among older adults and which was significantly greater than the 1 to 500 deaths per year among US children. Other analyses have demonstrated that the burden of RSV increases with age, such that an estimated 1 hospitalisation per 10,000 cases in those aged 65 years and older can be expected to occur, although this increases to 5 per 10,000 cases in those over 80 years of age.
Dr Wiseman also described how RSV is known to be a trigger of COPD and asthma exacerbations. He said that a recent study in older adults ‘had estimated a prevalence of around 6% per year in community dwelling older adults’ when testing was done with nasal swabbing and a PCR test, together with serology to diagnose RSV throughout two seasons. He added that an interesting observation from this study was how the duration of symptoms was 19 days, and that in a third of cases a visit to a physician was required.
While it is possible for anyone to become infected with RSV, Dr Wiseman explained how there are risk factors associated with a poor outcome such as a longer symptom duration, hospitalisation or even death. These include chronic lung conditions, e.g., COPD, asthma, chronic heart conditions such as heart failure, and being immunocompromised. He added that a further complication for heart disease patients is that RSV ‘promotes the increase of certain inflammatory markers such as IL-6 and tumour necrosis factor that can promote plaque destabilisation and can mean that some of these patients end up with an MI [myocardial infarction] from RSV.’ He cited another vulnerable group was care home residents due to the highly contagious nature of RSV and who are generally older and have a number of comorbidities.
Might RSV levels reduce in the coming years because people are now more wary of respiratory viruses because of COVID-19?
Dr Wiseman felt that COVID-19 mitigation strategies such as mask-wearing and self-isolation once an individual develops respiratory symptoms might help reduce the future spread of RSV. However, because immunity to RSV is often short-lived, individuals are still at an increased risk because they become ‘immune-naïve to RSV again and it is known that people with higher quantities of antibodies to the F protein in their blood are less likely to have symptomatic illness with RSV.’ He cited early data from Australia that has revealed how ‘RSV has kicked up post-COVID much more so than influenza’, although recent molecular studies have shown that RSV now has fewer strains so that the heterogeneity of RSV has decreased significantly. Precisely what long-term effect this might have remains unclear, however.
What management strategies are available for patients?
Dr Wiseman said that at the present time there are no specific interventions for adults infected with RSV, either in the community or hospital. Treatment is therefore symptomatic and directed towards any underlying comorbidities, which tend to worsen due to the infection. He mentioned how infected patients’ oxygen levels can drop, warranting supplementary oxygen, and as their condition deteriorates, either non-invasive or mechanical ventilation might be needed. The virus effects can reduce patients’ blood pressure, necessitating additional fluids and, in some cases, inotropes, and typically worsens both chronic heart failure and COPD. Additionally, infection with RSV, especially in those with an underlying lung disease, can lead to a bacterial infection and bacterial pneumonia. Dr Wiseman explained that while RSV can itself cause pneumonia in older patients with a reduced immunity, leading to inflammaging which can be fatal, it is more often the case that an exacerbation of a comorbidity due to infection that is usually the cause of death in most patients.
How useful is screening for RSV?
Currently, Dr Wiseman said many hospitals include RSV on their viral multiplex panel for PCR testing, adding how, while less accurate in the past, point-of-care test kits are now much better at detecting the virus. In clinical studies rather than rely on PCR testing, it is more usual to perform baseline serum samples, and where there is a clinical suspicion of an RSV infection, serum testing is repeated to determine if there is a rise in RSV antibody levels.
Dr Wiseman said that while there is an ongoing debate over the value of screening for RSV, especially given the absence of a specific treatment, he believes that screening does have a value, particularly considering data suggesting worse outcomes from RSV infection compared with influenza and how knowledge of the infecting virus allows clinicians to instigate vigilance measures. As he explained, with research showing that ‘mortality was greater at one year for those hospitalised with RSV than for those with influenza and because RSV is contagious, if you can identify someone in the care home or the hospital ward having RSV, you might then implement barrier nursing or some procedures to try and stop the spread of the virus to other vulnerable people in the facility.’
What do you see as the barriers to wider RSV screening?
Dr Wiseman thinks that the cost of PCR testing is certainly an important barrier in some countries. However, perhaps a more important factor is simply lack of awareness of the virus among clinicians. He cited research which ‘found that when patients were eventually diagnosed with RSV during their admission, it was only in about a third of those cases that a viral PCR swab at the point of admission was considered.’ He believes there needs to a cultural shift within the medical profession before the diagnosis of RSV is considered more widely, especially among older adults. A further hurdle limiting awareness among medical staff is that unlike influenza, RSV is not a reportable disease, although he said this is slowly changing, and it has already happened in Australia.
A further obstacle is the lack of availability of point-of-care tests within emergency departments, despite the fact that many currently available panels are multiplexed and able to identify a whole range of viral pathogens including RSV. Dr Wiseman believes there is an argument for point-of-care testing to be carried out in general practice. This, he feels, would be invaluable for the older and more vulnerable adults with viral symptoms and comorbidities, enabling doctors to monitor individuals who test positive for RSV and might also then lowering the threshold for a subsequent hospital admission.
What is the role of anti-viral therapies in RSV?
Dr Wiseman described how studies of anti-virals against RSV have been met with limited success, though there has been some benefit for a subset of patients, e.g., those who are immunosuppressed. However, overall, there is no statistically significant evidence that anti-viral therapy helps with RSV.
How do you see the future progressing with RSV and what would you like to see happening?
Dr Wiseman feels that greater awareness of RSV in older adults would be very important first step but believes that this is already happening with a greater propensity to send PCR swabs for multiplex testing from hospital wards. A further important development will be the introduction of an RSV vaccine. He noted that provisional data appears to be promising in terms of reducing symptom burden and even reducing poorer outcomes, adding more concrete data will arise from Phase IV trials. While anti-virals have not demonstrated much use in patients already infected with RSV, Dr Wiseman thinks there is a need to examine whether the early use of anti-virals could reduce or prevent hospitalisation. He also would like to see the collection of more data on the effect of RSV in younger, healthy adults, particularly given how there is bronchoscopy evidence of residual inflammation even after symptoms have resolved. Dr Wiseman feels that the continued presence of inflammation in the lungs might explain why RSV is such a burden for those with lung diseases, leading to poorer outcomes.
Finally, Dr Wiseman believes that greater awareness of RSV is needed among government bodies and those directing health policy. With the available data suggesting that patients hospitalised with RSV often have more severe disease, a longer hospital stay, and even higher mortality than those with influenza, now is the time to raise awareness of this under-recognised, yet potentially fatal, viral pathogen.