19. Respiratory syncytial virus

RSV is a major cause of upper respiratory tract infection (URTI) in adults. By adulthood, individuals are unlikely to be immunologically naïve to RSV, with repeat exposures occurring throughout our lifetimes.[3] Most infected adults experience mild to moderate clinical disease. RSV-associated hospitalisation rates increase exponentially from the age of 60 years. For those with immunocompromise and older age, RSV infection can result in hospitalisation for severe lower respiratory tract disease (LRTD), viral pneumonia and exacerbation of underlying comorbidities.[4]

RSV is a highly prevalent disease and the virus has been identified as the causative agent in up to 12 percent of medically-attended acute respiratory illnesses.[4] It is associated with exacerbation of pre-existing illness in adults and with excess deaths predominantly in elderly adults. Hospital admission is on average three to six days and overall mortality is 6–8 percent in adults. Among hospitalised adults with a positive-RSV test, 10–31 percent require intensive care admission and 3–17 percent need mechanical ventilation.[4]

Risk factors for progression of RSV infection to viral pneumonia include Down syndrome, immunocompromise, underlying lung or heart disease, increasing age from 65 years, frailty, living in long-term care facilities and living at high altitudes.[4] Further factors associated with more severe RSV-LRTD include vitamin D deficiency, colder weather, air pollution and exposure to tobacco smoke.[4] The burden of RSV in adults is likely to be higher when consideration is given to the exacerbation of underlying disease, such as heart and lung disease, beyond those recorded as having RSV-LRTI.[5] In New Zealand, being of Māori or Pacific ethnicity, and/or living in areas of high deprivation independently increases the risk of RSV-associated hospitalisation.[6]

Compared with less than one percent of all adults, a higher proportion (around 12 percent) of young children with RSV require hospital care. Risk factors for poor outcomes in infants are: age under 3 months and gradually decreasing with increasing age, congenital heart disease, chronic conditions diagnosed before age 6 months, including congenital heart, congenital lung and chronic lung disease or neurological disease; prematurity (born before 37 weeks gestation) and extreme prematurity (born before 32 weeks gestation).[7,8,9] Another risk factor for hospitalisation with RSV-LRTI in infants are young maternal age (under 20 years). Preschool and primary school children in the household are significant sources of infection to infants.[10] In New Zealand, being of Māori or Pacific ethnicity, and/or living in areas of high deprivation is also independently associated with an increased risk for RSV-associated hospitalisation of infants.[11]

More than 80 percent of children are infected with RSV at least once by the age of 2 years, and half of these have been infected twice.[12] Globally, RSV is associated with a substantial burden in young infants and is the most common cause of hospitalisation of infants under 2 years for acute LRTI. The virus is also linked to an increased risk of childhood asthma.[9,13]

In adults, the available epidemiology of RSV is less robust than for children. The frequency of clinical testing is lower, and in ambulatory settings, adults often present later to clinical care. Despite this, RSV is a highly prevalent disease associated with excess deaths predominantly in the older adults. The incidence of medically-attended RSV infection in adults generally increases with age, and RSV-associated pneumonia in adults age 65 years and over has the highest annual mortality rate (7.2 per 100,000 persons per year).[4] The odds of an adult with comorbidity being hospitalised with RSV acute respiratory illness is approximately four times that of individuals without comorbidity.[5] The burden is likely to be underestimated, and would be greater if exacerbation of underlying diseases, such as heart and lung disease, due to RSV infection was considered.

RSV is not a notifiable disease in Aotearoa New Zealand, but the Institute of Environmental Surveillance and Research (ESR) maintains several surveillance systems to monitor respiratory virus activity and severity for the Public Health Agency. Virus detection forms part of the surveillance for community respiratory infections and severe acute respiratory infection (SARI) hospitalisation, including RSV testing. In 2023, like other seasonal respiratory viruses, RSV was predominantly detected in the community during the winter months but RSV-SARI occurred throughout the year.[14]

One study examining the RSV-associated hospitalisation rates in adults in Auckland during 2012–2015 found that approximately 8 percent of SARI hospitalisations were associated with RSV infection and 90 percent of these cases occurred during winter.[6] Adults aged over 80 years had the highest incidence of RSV-SARI, at 190.8 (95% CI 137.6-244.0) per 100,000 compared with 23.6 (21.0-26.1) per 100,000 for all adults. The incidence rate ratio was over 30 times higher for oldest adults than those aged under 50 years.[6]

New Zealand approved vaccine (unfunded)

Immunogenicity of adjuvanted RSVpreF vaccine, Arexvy

One dose of adjuvanted RSVpreF vaccine (Arexvy) induces robust RSV-A and RSV-B neutralising antibodies that are likely to be seroprotective for at least one year after vaccination in older adults (aged ≥60 years).[16] The T cell profile is strongly CD4+ Th1-driven, and there is no evidence of induction of CD8+ T cells associated with risk for vaccine-associated enhanced respiratory disease.[17] An anamnestic response is seen after a booster dose given 20 months after the first dose.[18] Although clinical trials evaluated a two-dose primary course, it appears that one dose induces an adequate immune response to provide protection for longer than one year.[16,17]

RSVpreF vaccine has similar immunogenicity in adults aged 18-50 years to that seen in older adults. Similar efficacy is also seen in those aged 50-59 years with comorbidities that increase the risk of severe RSV (study to date included chronic heart failure, disease, chronic respiratory disease, advanced renal or liver disease, diabetes mellitus type 1 or 2, but exclude those with immunocompromise).[19,20] Further data is anticipated over more than two RSV seasons, in special high-risk groups and immunocompromised groups.

No clinically relevant interference of antibody responses were shown following coadministration of RSVPreF3 with aQIV (FluAd Quad), or for RSVPreF3 with rZV (Shingrix) when compared with sequential administration.[21,22] Further coadministration data is anticipated for other vaccines given to older adults.

Efficacy of adjuvanted RSVpreF vaccine, Arexvy

Vaccine efficacy of adjuvanted RSVpreF was consistently high among adults aged from 60 years against RSV-LRTI, severe RSV-LRTD and RSV-ARI during a first RSV season in a phase 3 RCT (NCT0488659).[23] Over one RSV season, vaccine efficacy was around 83 percent (96.95% CI: 58 – 94 percent) against RSV-LRTI; 94 percent (97.5% CI: 62 – 99.9 percent) against severe RSV-LRTD; and 72 percent (56 – 82 percent) against RSV-ARI in adults aged from 60 years,[23] and was similar in adults over 70 years. Similarly, efficacy of 95 percent (66–99.9 percent) was also shown against RSV-LRTD in those with at least one comorbidity that increases the risk of severe RSV.[19] A second dose, given a year after the first, provided little additional benefit than that provided by one dose over two seasons.[24] The efficacy of one dose over two seasons (adjusted for seasonality) was maintained around 80 percent (53–92 percent) against severe RSV-LRTD and 67 percent (48–80) against all RSV-LRTI.[24] Further data is required to assess the optimal timing of revaccination.

Efficacy of palivizumab

Licensure was based on the IMpact-RSV randomised control trial, conducted during the 1996-1997 RSV season, which included 1502 infants and young children born at or before 35 weeks gestation (some with chronic lung disease (CLD) associated with prematurity).[25] Compared with the placebo cohort (RSV hospitalisation rate of 10.6 percent), an absolute reduction of 5.8% (p < 0.001) was seen in hospitalisation of those who received palivizumab (4.8 percent); equivalent to a relative risk reduction of 54.7 percent.[25] A second clinical trial in 1287 children with haemodynamically significant congenital heart disease reported an absolute reduction in hospitalisation of 4.4 percent (p < 0.003; 9.7 percent in placebo group and 5.3 percent in palivizumab group); with relative risk reduction of 45.3 percent.[25]

There is limited and conflicting data on effectiveness of palivizumab. Whilst retrospective studies have not shown consistent increases nor decrease in RSV-related hospitalisation for those born 29–35 weeks receiving palivizumab, many did not examine cohorts separately based on comorbidities, such as chronic lung disease of prematurity, and acknowledge that adherence with injections is challenging.[25,26,27] A systematic review reported that palivizumab reduces hospitalisation due to RSV infection by 56 percent (relative risk 0.44; 95% CI 0.30-0.64), but evidence is uncertain around mortality (relative risk 0.69; 0.42-1.15).[28]

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store at +2°C to +8°C. Do not freeze. Protect from light.

Adjuvanted RSVpreF vaccine, Arexvy

A single 0.5 mL dose of Arexvy is administered by intramuscular injection (see section 2.2.3).

This vaccine requires reconstitution prior to administration. It consists of two components, a vial containing powder of recombinant prefusion F protein and a vial containing a suspension of adjuvant, AS01_E. Draw up the adjuvant suspension into a syringe and add the entire contents into the power. Gently swirl until the powder is dissolved. Use within 4 hours of reconstitution.

Both vials have a non-latex, butyl rubber stopper.

Palivizumab

Palivizumab is administered by intramuscular injection, monthly according to infant weight at 15 mg/Kg. Injection volumes of over 1mL should be given as a divided dose. Single-use vials contain 50 mg / 0.5 mL or 100 mg / 1.0 mL of palivizumab.

Co-administration with other vaccines

RSVpreF vaccine can be given concomitantly with standard and adjuvanted seasonal quadrivalent influenza vaccines. RSVpreF can also be given concomitantly with rZV, preferably in separate limbs. Note that mild to moderate reactions, such as injection-site pain and fatigue, can occur more frequently with coadministration than when these are given separately due to receiving additional AS01 adjuvant.

Palivizumab can be administered with any routine childhood immunisations. Since the monoclonal antibody in palivizumab is specific for RSV, it is not expected to interfere with the immune response to vaccines, including live viral vaccines.

RSVpreF (Arexvy) is indicated for active immunisation for the prevention of lower respiratory tract disease (LRTD) caused by respiratory syncytial virus RSV-A and RSV-B subtypes in adults 60 years of age and older.

It is currently unfunded. It can be considered for individuals who are aged over 60, especially the very elderly and those with multiple comorbidities that increase the risk of severe RSV-ARI.  Offered as one dose of RSVpreF vaccine given prior to the start of the RSV season in late autumn or as soon as possible during the RSV season in the winter.

For use in infants at high risk of severe RSV-LRTI, particularly recommended for those aged under 1 year prior to or during the RSV season:

• born preterm up to 28 weeks gestation
• born preterm up to 32 weeks gestation with chronic lung disease of prematurity
• with haemodynamically significant congenital heart disease
• severely immunocompromised infants.

RSVpreF (Arexvy) is indicated from the age of 60 years and is not recommended for use in pregnancy or while lactating/breast-feeding.

Palivizumab is not indicated for adolescent or adult use.

Although safety and immunogenicity data are not yet available in immunocompromised adults, as a non-live vaccine, there are no safety concerns around giving RSVpreF to individuals who are immunocompromised and who are at increased risk of being hospitalised with severe RSV infection. Individuals receiving immunosuppressive therapy or who have immunodeficiency could have a reduced immune response to RSV vaccine.

Palivizumab is available for use in infants with immunocompromise, particularly those with severe immunodeficiencies, that increases their risk of severe RSV-LRTD up to age 24 months.

There are no specific contraindications to RSVpreF (Arexvy) or palivizumab, except for anaphylaxis to a previous dose or any component of the vaccine.

The RSVpreF, Arexvy, is not recommended for use during pregnancy. During a single clinical trial, a 1.5-times increase in preterm births was observed in the vaccinated cohort compared to placebo following administration of an investigational unadjuvanted formulation of RSVpreF3 to 3,557 pregnant women; the clinical trial was discontinued. Stratification by economic region showed that the increase in preterm births was seen in low-income and not in high-income countries.[29] The mechanism for this is unknown.

During clinical trials, RSVpreF was well-tolerated in adults aged from 18 years and aged from 50 years. The most frequently reported responses were injection-site pain, headache, fatigue, myalgia and arthralgia.[23] Co-administration with seasonal influenza vaccine increased the incidence of pain at the RSV vaccine injection site but there are no concerns about safety.[30]

The reported responses to palivizumab were not significantly different from placebo and the adverse event profiles were similar during clinical studies.

No serious adverse events or potential immune-mediated disease were attributed to RSVPreF3 OA in diverse older populations (aged over 60 years)[23] or in adults aged 50­-59 years with comorbidities that increase the risk for severe RSV.[31] Clinical trial safety follow-up has been reported for at least 18 months, to date.[24] One case of Guillain-Barré syndrome (GBS) was temporally associated with vaccination but diagnosis of this was inconclusive as it did not meet the Brighton Collaboration Working Group case definition.[16]

Consistent with clinical trial data, early findings reported by the CDC identified a potential safety concern for GBS in adults aged 60 years and over who received RSVpreF vaccines. Reports of GBS were more common than expected background rates in those who received Abrysvo (5.0 excess cases per million doses, based on 11 reports that met the case definition) and Arexvy (1.5 excess cases per million doses, based on 17 reports that met the case definition).[32] It was noted that VAERS data cannot determine an causal association between the adverse event and the vaccination.

When RSVPreF was coadministered with adjuvanted influenza vaccine (FluAd Quad) to clinical trial participants aged 65 years and over, most solicited responses were mild or moderate and transient. Serious adverse events were balanced between the coadministration and control groups, and none were considered due to coadministration of these vaccines.[21] Another clinical trial demonstrated no safety concerns around giving RSVPreF and rZV (both contain AS01 adjuvant). Mild to moderate solicited local AE at either injection site and systemic AE were reported by 74 percent of coadministered participants, 60 percent of controls post-RSVPreF only and 49 percent of controls post-rZV only. For both groups the duration of AE were short and most frequently reported were pain, fatigue and myalgia.[22]

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