The past three years have been dominated by the ongoing COVID-19 pandemic, which overwhelmed the NHS, leading to an increase of 50% in the number of patients waiting for ‘routine’ care, a growing waiting list for elective surgical procedures and delays to referrals for urgent care for cancer and other serious disorders1. The ongoing disruption caused by serial waves of COVID-19, despite high levels of vaccination and the potential re-emergence of other respiratory viral illnesses – influenza and respiratory syncytial virus (RSV) – commonly associated with increased hospitalisations during winter months, highlights the need for urgent consideration of the deployment of measures to reduce the burden of these illnesses on the NHS as the winter approaches. What elements do we have in our toolkit and how can these be effectively deployed to reduce the anticipated burden of illness within the NHS this winter?
Adequate surveillance is key to understanding the timing of arrival, spread and eventual disappearance of infection within the community. The strands of surveillance include case recognition and rapid diagnostic confirmation of the causative organism. Case definitions for influenza, COVID-19 and RSV illness have multiple common features, including acute onset, fever, cough and dyspnoea, making these disorders clinically indistinguishable. To correctly identify the infectious agent causing the illness in a specific case, further diagnostic testing is required, to enable real time tracking of the nature of the epidemic illness and also to allow timely access to treatment for eligible treatment2.
The most sensitive diagnostic approach is polymerase chain reaction (PCR) testing for viral RNA. Multiplex testing to diagnose a number of respiratory viral infections is available within the NHS, but is commonly overlooked in non-hospitalised cases other than among GP practices participating as sentinel centres for surveillance testing. This service has been severely curtailed by the COVID-19 pandemic, which has disordered GP consultations. However, experience gained in the context of the COVID-19 pandemic has confirmed that patient self-sampling is an adequate substitute for sampling by a healthcare professional (HCP)3 and patients could be given access to rapid laboratory testing directly for other viral illnesses, as has been done for COVID-19.
An alternative, albeit less sensitive than PCR4, is the use of home testing using antigen assays, or lateral flow tests. Antigen assays testing for influenza, RSV and SARS-CoV2 are available for point of care use and the SARS-CoV-2 assays have been widely used in the UK to enable self-testing during the COVID-19 outbreak. Based on this experience it seems reasonable to extend the use of antigen testing for influenza and RSV to home use. Several manufacturers have developed multiplex antigen test kits for influenza and SARS-CoV-2, but these have not yet been approved for use in the UK. Multiplex antigen test kits would be considerably simpler to use than multiple individual test kits.
The use of home testing supplemented by rapid access to laboratory-based testing could enable rapid confirmation of the specific illness affecting the patient, not only enabling effective surveillance of the frequency of various viral illnesses within the community, but also enabling early access to effective treatment with the objective of reducing the burden of hospitalisations and deaths from these disorders.
Vaccination vs SARS-CoV-2 has transformed the severity of COVID-19 illness, protecting against the need for hospitalisation and reducing mortality rate among vaccinated groups5. However, the emergence of highly infectious variants with reduced sensitivity to existing vaccines, together with rapid declines in antibody levels post vaccination has resulted in reduced vaccine effectiveness in most populations despite completion of the full primary course6,7. Regular boosters have been deployed to sustain protection in the highest risk populations (the elderly and immunosuppressed), with third and fourth vaccine boosters having been deployed in these populations in the UK.
Looking to the future studies completed by Moderna investigating immune response to boosting with either monovalent ancestral strain or bivalent vaccines containing various viral variants have provided some data suggesting that bivalent booster shots may increase the overall immune response to booster vaccination and also widen the antibody repertoire post boost, offering potential for greater protection vs a broader range of viral variants8. Bivalent vaccines containing an Omicron variant provided the highest immune response to the Omicron strains now dominating in most regions9. Similar data have been presented by Pfizer-BioNTech10. Based on this data, albeit limited, both the WHO Technical Advisory Group on COVID-19 Vaccine Composition11 and the FDA12have recommended manufacturers develop bivalent vaccines including the ancestral strain and an Omicron variant strain for future booster shots. Whether these will be available for use in the UK as part of the recently announced autumn 2022 booster campaign is currently uncertain.
Passive immunisation vs SARS CoV2
Immunocompromised patients comprise a sizable population of individuals (~500,000 in the UK) that are unable to respond adequately to vaccination. This group include a wide range of adults and children, including those with congenital immune deficiencies, with acquired immune deficiency conferred by HIV infection, or by other concomitant disorders including cancer and inflammatory disease treated with immune suppressing therapies eg cytotoxic chemotherapy or B cell depleting agents. This group of patients have been repeatedly immunised but remain at risk of infection and complicated illness as patients do not develop antibody and may not develop cellular immune responses at a level required to prevent infection or prevent more serious disease once infected.
Passive immunisation with monoclonal antibodies has been demonstrated to prevent infection and illness in high risk adults. In the UK, the combination antibody product Evusheld was granted emergency approval in February 2022. Evusheld is indicated for the pre-exposure prophylaxis of COVID-19 in adults who are not currently infected with SARS-CoV-2, who have not had a known recent exposure to an individual infected with SARS-CoV-2 and who are unlikely to mount an adequate immune response to COVID-19 vaccination or for whom COVID-19 vaccination is not recommended. This recommendation reflected data from a pre-exposure study in which Evusheld reduced the incidence of COVID-19 in a high risk population by 80%13. Evusheld is not currently available for clinical use in the UK for reasons which are unclear given sustained activity against the omicron strain circulating earlier in the year. More recent data suggest reduced sensitivity of the BA.4 and .5 strains against one of the two antibodies in the mixture, although the combination remains effective in vitro, albeit requiring a higher dose14,15. The efficiency of pre-exposure prevention depends on the community attack rate and the effectiveness of the product; the PROVENT study was conducted at a time when the community attack rate was relatively low (1% incidence in the placebo group during the period of observation). However, community attack rates exceeding 5% have been the norm in the Omicron era, and earlier use of this product in the immunocompromised population may have reduced hospitalisation rate in this highly vulnerable population. No cases of COVID-19 were observed in a small case series of subjects with haematological cancer that had received 300 mg Evusheld during the early Omicron wave in New York16.
A more efficient route to passive prevention would be to intervene with the agent following known exposure to an infected case – post exposure prophylaxis. This was successfully demonstrated in a household setting using the combination antibody product Ronapreve, given subcutaneously within 4 days of exposure to a household case17and for the monotherapy product bamlanivimab given as an IV infusion within 7 days of exposure to a case in a nursing home setting18. Both interventions were at least 80% effective in preventing subsequent illness among treated patients. Regrettably the post exposure trial with Evusheld was not successful in preventing illness when given at a dose of 300mg within 8 days of exposure to a case in the post exposure prevention trial STORM CHASER19. The most likely reason for this is that exposure post intramuscular (IM) injection was insufficient to achieve antiviral concentrations when given during the incubation period of infection. In contrast, there was clear protective effect observed in a later time period, reflecting the long half-life of this antibody combination in humans. If the dose used in this study had been higher, or treatment had been given intravenously, it is possible that similar effectiveness may have been observed, particularly as 600mg IM Evusheld given within 7 days of onset of symptoms reduced hospitalisation and death by 50% in a treatment study20.
The specificity of monoclonal antibodies against variants of SARS-CoV-2 has reduced relative to effectiveness against the ancestral Wuhan strain. Hence rapid real-time availability of in vitro and in vivo virus neutralisation data for any new variant is required to ensure effective use of these agents for prevention or treatment of COVID-19. Newer monoclonal antibodies are currently being developed to replace those that have lost efficacy against the Omicron strains. Currently, the only monoclonal antibody with retained activity vs Omicron is bebtelovimab, for which antiviral efficacy has been demonstrated in a small phase II trial21. Bebtelovimab has emergency use approval in the USA, but not elsewhere21. Given the repeated demonstration of clinical effectiveness for anti-virals that reduce viral burden early in the disease, it would seem reasonable to allow earlier access under expanded access protocols to develop the clinical dataset in real time, an approach already in place for a monkeypox therapeutic22.
Vaccination against influenza is already well established in the UK, but vaccine effectiveness varies from year to year, dependent on the degree of matching between the strains contained within the vaccine and the circulating strains causing infection and illness. Vaccination against influenza is targeted at the groups at highest risk of complicated illness, hospitalisation and death, overlapping the groups also susceptible to covid. Hence, this season the JCVI has advised a broad autumn vaccination campaign against both influenza and SARS-CoV-2 in the same patient groups. The WHO recommends the strain types to be included in vaccines twice yearly, based on viral strains detected in the community. The strains to be used in the 2022-23 vaccine were recommended in February 202223. Previous work has already documented that SARS-CoV-2 and influenza vaccination can be safely co-administered which will provide greater efficiency in vaccine delivery as we approach the winter24.25,26.
Respiratory syncytial virus (RSV) is one of the main causes of acute lower respiratory infection (ALRI) and commonly leads to pneumonia or bronchiolitis. The pattern of RSV infection in humans shows a U‐shaped age curve, with peak disease rates in those younger than 5 years and older than 65 years27. Several studies have shown that RSV is an important cause of illness in community‐dwelling older people, resulting in a similar burden of disease to non‐pandemic influenza A in older age groups28,29. There is no approved vaccine available for the prevention of RSV in adults or children, however GSK announced successful results from a large phase III study of their investigational vaccine, RSVPreF3 OA, in older adults, with regulatory submissions targeted for this year30. In the event that this vaccine is approved in the UK, its immediate deployment to older adults may reduce the burden of illness due to RSV in the elderly this winter and this should be urgently considered.
Breakthrough infections; vaccine uptake
Despite vaccination however, breakthrough infection and illness leading to hospitalisation for COVID-19 has been observed among vulnerable adults and children, particularly during the Omicron wave. In addition, vaccine uptake, while high, is variable, with ~31% of those eligible yet to accept booster vaccination for SARS CoV231 leaving a large number of patients at risk of complicated disease. Annual influenza vaccination uptake is lower still32. In addition, the potential for poor vaccine strain match can result in a substantial number of people hospitalised for influenza in some winters. Hence, there remains a pool of unvaccinated people at risk of complicated disease. Antiviral treatment may provide an additional mechanism to reduce burden of illness and need for hospital care in affected patients.
The combination antibodies bamlanivimab/estevimab, Ronapreve and Evusheld given within 5-7 days of onset of symptoms can reduce the need for hospitalisation and death by 60-80% in high-risk outpatients with mild-moderate symptomatic COVID-1920, 32,33,34. In addition, sotrovimab monotherapy has also been shown to reduce hospitalisations and deaths from COVID-19 when given IV within 5 days of symptom onset35. With the exception of Evusheld and bamlanivimab/estevimab, which can be administered IM/SC respectively, these antibodies must be given by IV infusion, requiring patients to attend an infusion centre for drug administration, putting themselves and potentially others encountered during the journey at risk of infection. IM/SC injections could be self-administered or given in a community setting more readily.
All of the trials leading to emergency approval of these agents as treatments for COVID-19 were conducted in the pre-omicron era. As discussed previously many of these antibodies are no longer effective in vitro against omicron variants. However some protective activity may be retained despite loss of in vitro neutralisation potency as demonstrated in an in vivo murine model36. Trials in hospitalised patients were largely unsuccessful because treatment began too late for the antiviral effect of treatment to be beneficial in these patients, most of whom are affected by a multi-system inflammatory disorder and well past the peak of viral replication. The exception to this general rule was Ronapreve, which was investigated in the Recovery trial. In patients presenting to hospital who were seronegative on admission Ronapreve treatment in addition to standard of care reduced mortality due to COVID-19 from 30% in the usual care group compared to 24% among Ronapreve recipients37. Based on these data the UK continue to recommend sotrovimab therapy for high risk immunocompromised patients presenting in the community or who become nosocomially infected when in hospital38,39. Given the reduced in vitro effectiveness of sotrovimab against Omicron variants, this position is questionable particularly given the reduced evidence of effectiveness reported in Omicron infected patients treated in the USA40. Data reported from the UK included only patients treated between December 2021 and February 2022, and compared risk adjusted rate of hospitalisation/death following receipt of sotrovimab to that following molnupiravir. There was no comparison to an untreated population so the absolute efficacy of either agent remains unknown. The incidence of hospitalisation was low (1.4%) in the study, but was lower in patients treated with sotrovimab (0.9%) compared to those given molnupiravir (2%)41. Importantly, hospitalisation reported by a number of patients treated with sotrovimab was excluded from this analysis as it was not possible to determine whether the hospitalisation was for 24 hours or more or was a short-term attendance to receive the infusion/follow up. This was further confounded by the observed similarity between the two treatment groups with respect to all cause hospitalisation/death in recipients of these two treatments (3.7% for sotrovimab recipients and 4.4% among molnupiravir recipients) compared to outcomes linked specifically to COVID-19. These features make the interpretation of the data from this study difficult, as the observations may be confounded. It is hoped that the data deficiencies leading to these difficulties can be corrected for future studies of outpatient treatments in the UK to enable robust comparison of outcomes.
Small Molecule Antiviral Therapies
Small molecule antiviral medications approved for the treatment of COVID-19 in the UK include the IV antiviral remdesivir and the oral medications molnupiravir and nirmatrelvir-ritonavir. A study of treatment with IV remdesivir conducted in the USA suggested that 3 days treatment with once daily IV therapy started within 7 days of symptom onset reduced hospitalisation and death following COVID infection in high-risk subjects by ~87%42. Similarly, outpatient treatment with molnupiravir reduced hospitalisations and deaths by ~30% compared to standard of care43, while treatment with nirmatrelvir-ritonavir reduced severe outcomes by ~89% when started within 5-7 days of onset of symptoms in high risk unvaccinated subjects44. All of these studies were conducted in 2020-21 prior to the Omicron era and included unvaccinated high-risk patients. Efficacy in vaccinated subjects is being investigated in the PANORAMIC study: data for molnupiravir are anticipated in August 2022. Use of Paxlovid is complicated by its incorporation of the potent cytochrome P450 (CYP) inhibitor ritonavir, which limits use of the agent in subjects taking a range of medications for whom drug-drug interactions may cause severe side effects; these include patients taking oral anticoagulants, statins and other treatments co-metabolised by CYP3A4. As a result, careful assessment of concomitant medications being taken by patients is required prior to dispensing Paxlovid therapy.
The use of outpatient antiviral treatment in the UK is currently restricted to the highest risk patients, most of whom are severely immune compromised. However, efficacy in the clinical studies has been documented in a broader range of patients including those aged 50 or greater with a larger range of concomitant conditions. Hospitalisations for covid in the UK remain high, with weekly admissions exceeding 10,000 patients during the recent epidemic wave. The demographic features of this population suggest that these include patients with characteristics that confer higher risk of serious illness but that do not conform with those enabled to access antiviral medications, despite being at higher risk of more severe disease/death than younger adults with no co-morbidities. It may be wise to consider whether to broaden access to treatment to this larger population to further reduce the burden of COVID-19 as the winter season approaches. The US and New Zealand have extended prescription of oral antivirals for COVID into the pharmacy sector in order to facilitate easier access to therapy. A similar approach should be considered in the UK; pharmacists are well positioned to advise on potential interactions with concomitant medications and thereby to be able to correctly select the most appropriate antiviral for a specific patient45,46.
The antivirals oseltamivir, zanamivir and baloxavir are approved in the UK for the treatment and prevention of influenza in adults and children47,48,49. Treatment of influenza in high-risk patients can reduce the incidence of hospitalisation and death and there is existing guidance on the use of these agents for the treatment of influenza and for post exposure prophylaxis in high-risk adults and children in the UK50. Given the risk of cocirculation of influenza virus this winter, reiteration of this advice would be appropriate. None of these agents are likely to interact with Paxlovid or molnupiravir and concomitant use can be considered where needed for patients with coinfection with SARS-CoV-2 and influenza, particularly as coinfection appears to confer higher risk of more severe outcomes51.
There are no currently approved antiviral treatments for RSV infection, although a number of agents have shown efficacy in RSV challenge studies and are being further investigated in naturally acquired infection52,53,54,55. The human challenge model is highly predictive of efficacy in natural infection, provided that treatment is started rapidly following first onset of symptoms – a feature all respiratory viral infections have in common. Given the significant pressures within the NHS and the potential resurgence and overlap of coexisting epidemics of seasonal respiratory viruses, consideration could be given to an expanded access program to accelerate development of these agents, in collaboration with the companies that produce them. While it is acknowledged that there is no definitive proof of effectiveness in natural infection currently, by analogy with experience with antiviral treatment of influenza and of SARS-CoV-2, it seems rational to at least explore the possibility that intervention with antivirals for RSV may also reduce the burden of illness among higher risk patients. The results of this experience, if positive, could also accelerate early approval of treatments found to be effective for future deployment.
The forthcoming winter is likely to be characterised by waves of respiratory illness, hospitalisations and deaths associated with concomitant consecutive epidemics of different respiratory viral infections. Tools to mitigate these include wider spread use of vaccines, allied to considered broader use of antiviral therapies in patients at highest risk of complicated disease. Evidence suggests that effective treatment may reduce the rate of more severe illness and thereby protect the NHS from usual winter pressures, enabling staff to continue activities to reduce waiting lists and enable return to more normal functioning for the benefit of the public in the UK. We have the tools, we need to use them.
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