Three RSV vaccines now recommended for many older adults; what about travellers? Free

Introduction

Recently published Global Burden of Disease (GBD) project data indicate that in 2019 [pre-coronavirus disease (COVID)-19], RSV was the 11th highest cause of lower respiratory tract infection (LRTI) in both children and adults. ¹ In the USA alone, most adult RSV disease cases occur among older adults, with an estimated 60 000–160 000 hospitalizations and 6000–10 000 deaths annually among adults aged ≥65 years.²

Globally, robust community-based RSV surveillance using polymerase chain reaction (PCR) or other viral detection methods is poorly developed with many data gaps.³ India provides one of the few prospective cohort studies in a major destination country showing an age-based risk-gradient that is similar to US data. From 2015 to 2017, the PCR-confirmed RSV incidence per 100 000 person-years in rural north India was 260 among adults 60–64 years, 760 among adults 65–74 years and 1010 among adults ≥75 years.⁴

Comparing high-income countries to the lowest income strata countries using the GBD data, LRTI rates are 4846 vs 49 000/100 000 in the over 70 year age group and 1149 vs 6000/100 000 in the 60–69 age group, highlighting the major burden of LRTI in lower income countries. A gradient of progressively increasing LRTI rates for the intermediate income strata countries exists. RSV in older and at-risk adults is a ubiquitous component of LRTI in all countries. Travellers are confirmed to be at increased risk of influenza and COVID-19.⁵ Similar increased risk for RSV infection during travel, especially to lower- and middle-income countries, would seem intuitive. In this review, we discuss travellers’ considerations for the new generation of RSV vaccines.

Two protein-based RSV vaccines were approved for persons ≥60 years of age by both the Food and Drug Administration (FDA) and European Medicines Authority (EMA) in 2023 based on large multinational clinical trials; additional observational efficacy data from the 2023 to 2024 winter season are available for the USA. RSVPreF3 (Arexvy, GSK) is a one-dose adjuvanted (AS01E) recombinant stabilized prefusion F protein (preF) vaccine. RSVpreF (Abrysvo, Pfizer) is a one-dose recombinant stabilized preF vaccine. Approval is in hand in the UK, Canada, Australia and is pending in other countries. An mRNA vaccine MRESVIA (Moderna) encoding the same PreF fusion protein was approved in the USA in June 2024. Data from the large multi-season Phase 3 clinical trial are available, but due to the recent approval, real-world observational data are pending for the 2024–25 season.

RSV vaccine trial data

Clinical trials for each of the three vaccines had different clinical endpoints, different age groupings, different periods of follow-up after vaccination and were conducted during different seasons. Nevertheless, Centers for Disease Control and Prevention (CDC) analysis synthesized an approximate comparison of clinical trial endpoint data for the most severe outpatient clinical endpoint defined for each individual vaccine.⁶ This endpoint was vaccine efficacy (VE) for the prevention of PCR-proven severe lower respiratory tract disease (LRTD) defined as greater than three symptoms, noting that the symptom list differed for each vaccines’ trials. VE for the first and second season after vaccination was: Abrysvo (Pfizer) 86 and 74%, Arexvy (GSK) 79 and 59% and MRESVIA (Moderna) 55 and 36%. Initially, per the FDA label, MRESVIA had shown a good short-term effect with a VE of 81% at 3.7 months and 61% at 8.6 months⁶; real-life data on Season 2 VE and beyond are needed to understand properly the duration of efficacy for MRESVIA.

Real-world observational data for hospitalization for both Arexvy and Abrysvo from select US hospitals during the 2023–24 winter showed that VE ranged from 75 to 85% against RSV-associated hospitalization, ED visits or critical illness. VE was similar among adults aged 60–74 years and ≥75 years.⁷

For each of the three vaccines, clinical trials included a small subset of subjects who were revaccinated after 12 months. With each vaccine, neutralizing antibody titres were boosted moderately, but in non-older adults ≥60 years of age, the GMT did not rise to the levels seen after the initial vaccine dose.⁸ The conclusion, at least based on this limited current data, is that the VE after an annual booster might not be as high as after the initial dose. Preliminary VE data from GSK indicate that VE against RSV LRTD in Season 2 after initial vaccination does not differ between those with or without revaccination at 12 months, so that the second dose provides no booster effect on VE. The somewhat limited duration of protection and lack of evidence for a meaningful booster effect with a second annual dose, at least using current vaccine formulations, is of concern for any strategy that errs on the side of an overly broad recommendation for vaccinating persons too young or without significant enough risk of severe RSV outcomes. These persons should be a very low priority for vaccination until we have either a vaccine, initial dosing regimens, or booster regimens that can protect persons on an ongoing basis as they age.

Safety

For the protein-based vaccines, Arexvy and Abrysvo adverse events are generally mild with no excess severe adverse events. Guillain–Barre syndrome (GBS) has been reported with rates of 5.0 and 1.5 reports/million doses of Abrysvo and Arexvy vaccine, respectively, among US adults ≥60 years, both of which were higher than background rates. However, detailed analysis of experience to date with persons ≥60 years old for whom vaccine is recommended shows a large benefit on hospitalizations and lives saved that far outweigh the risk of GBS for those who meet the currently recommended vaccine criteria. More data are still needed given the relatively low vaccine uptake in the USA during the first season of use. Risk-benefit analysis in younger age groups is pending. Much less experience is available for MRESVIA but in the clinical trials no severe AE’s, no cardiomyopathy and no GBS cases (N = 18 369 vaccinees) were reported.⁹

2024 CDC ACIP routine recommendations for older adults

Routine

• Recommended for all adults 75 years of age.

• Recommended for adults 60–74 years with certain chronic medical conditions or other factors that increase risk of severe RSV disease.

  • Definition of increased RSV risk:

    • Lung disease, cardiovascular disease, moderate or severe immune compromise, diabetes mellitus with end-organ damage, neurologic or neuromuscular conditions, chronic kidney disease that is advanced, hematologic disorders, liver disorders, severe obesity (body mass index  ≥ 40 kg/m²) and other factors determined to increase risk of severe disease due to respiratory infection.

    • Healthcare providers have discretion to vaccinate persons with other chronic medical conditions or risk factors that they determine might increase the risk of severe disease due to respiratory infection.

    • Frailty

    • Residence in a nursing home or long-term care facility

By far the most important co-morbidities are chronic obstructive pulmonary disease or congestive heart failure. The risk of serious outcomes following RSV infection in these adults ≥60 years is at least double compared to individuals without these conditions. Although they were excluded from the large clinical trials, vaccine protection appears to be reasonable in persons ≥60 years with immunocompromising conditions, who are recommended to receive the RSV vaccine given the potential for significant benefit.

At this time, RSV vaccination is not yet recommended for adults 60–74 years of age who are not at increased risk of severe RSV. CDC Advisory Committee on Immunization Practices (ACIP) has deferred any use recommendation pending more data on safety, duration of efficacy and optimal booster intervals. FDA, but not yet EMA, has recently approved Arexvy (GSK) vaccine for persons between 50 and 60 years of age with co-morbidities but no recommendation for use is in place to date.

Proposed considerations for travellers

Travel destination, time of year, planned activities and level of accommodations all affect RSV risk and recommendations for travellers. Cases in temperate climates typically peak during the winter months. In the northern hemisphere, RSV is typically seen from October/November to April/May. In contrast, in the southern hemisphere, the main season is from May to September. In contrast, tropical climates typically see year-round transmission with a pattern of outbreaks during hot humid rainy seasons. In Alaska and tropical areas of the USA including parts of Florida, Hawaii, Puerto Rico, the US Virgin Islands and Guam, RSV can circulate year-round. The typical seasonal recommendation for use of the vaccine would not apply to travellers to the tropics or to these US areas.

Travellers ≥60 years with co-morbidities have greater intrinsic risk for severe respiratory disease, solely because of the circumstances of travel to a risky destination at a risky time of year. As per the above considerations, healthcare provider discretion is allowed for a lower level of tolerance for milder manifestations of comorbidities. A pre-travel consultation is an appropriate setting where RSV vaccination might be specifically brought up, and these travel-related considerations can be discussed on a case-by-case basis with travellers aged 60–74 years.

Less importantly at this time, travel advisors might consider broader discussion for RSV vaccine usage with travellers aged 50–60 years with significant co-morbidities, especially COPD or CHF. Arexvy (not the other vaccines) is approved by FDA for this age cohort, so use would not be off-label even if currently unreimbursed in many settings. Detailed analysis of the risk benefit for Arexvy in this age cohort is underway, though further data are pending, before a specific blanket recommendation for any use in this age cohort can be made.

RSV vaccine administration issues

• The dose/schedule is 0.5 ml IM one time only for all three vaccines.

  • At present persons who have already received RSV vaccination are currently NOT recommended to receive another dose.

  • Adults may need additional doses of an RSV vaccine in the future, but ideal revaccination timing is not yet known.

• RSV vaccination will have the most benefit if given in late summer or early fall (August–October in the northern hemisphere or April–June in the south) in temperate climates such as the USA. RSV vaccine for protection during travel should be timed around RSV seasonality in the travel destination.

• Coadministration of RSV vaccines with any other adult vaccines is acceptable. Although some small decrements in humoral response was noted with coadministration of influenza and RSV vaccines, the clinical significance of that is not known. When given together, RSV and COVID-19 vaccines resulted in higher rates of reactogenicity, although were still well tolerated. The CDC recommends co-administration of adult vaccines as the best way to ensure wide-scale vaccination. For those who wish to receive vaccines separately, that is also a reasonable approach.

Future considerations

A better understanding of initial dosing regimens, booster regimens or improved vaccine constructs that can protect persons on an ongoing basis as they age is needed before recommending broader age-groups or risk factors for vaccination. A larger safety database especially for neurological adverse effects will also drive better risk–benefit evaluation. The 2024 CDC ACIP guidelines, discussed here, are evolving as more follow-up clinical trial and real-world data on both efficacy and adverse effects become available. A strategy of a single multi-component annual respiratory virus vaccination would be ideal and is hopefully already on the drawing board by the vaccine industry. Genomic surveillance of respiratory swabs that includes RSV in returning travelers at 8 US international airports has just begun <https://wwwnc.cdc.gov/travel/page/travel-genomic-surveillance>

For seasonal influenza, CDC specifically recommends that travellers who want to reduce their risk for influenza should consider influenza vaccination, preferably at least 2 weeks before departure when travelling on a cruise ship or organized tourist group to any location at any time of year <https://www.cdc.gov/mmwr/volumes/72/rr/rr7202a1.htm>. The reason is that such exposures will likely include persons from other areas of the world where influenza viruses are circulating. Respiratory viruses are the most common vaccine-preventable diseases of travellers.¹⁰ With the new availability of the RSV vaccine, a new VPD will now be on the list, although the risk of severe disease is limited to an older segment of the population. Such travel-related situations have yet to be discussed by guideline-making bodies due to priority considerations for own-country highest-risk older populations. We are thus issuing a call for discussions by guideline-making groups on additional considerations for RSV vaccination of travellers especially going to very high-risk destinations in-season.

Author contributions

David O. Freedman (Conceptualization [lead], Data curation [lead], Validation [equal], Writing—original draft [lead], Writing—review & editing [lead]) and Camille N. Kotton (Conceptualization [equal], Formal analysis [supporting], Validation [supporting], Writing—review & editing [supporting])

Conflict of interest: None declared.

References