By Elizabeth V. Robilotti, MD, MPH
Assistant Attending Physician, Division of Infectious Diseases, Hospital for Special Surgery, New York, NY
SYNOPSIS: In older patients who are at risk for severe disease caused by respiratory syncytial virus (RSV) two new distinct vaccine candidates based on the stabilized prefusion F protein demonstrated efficacy and prevented RSV lower respiratory tract disease in patients greater than 60 years old.
SOURCES: Papi A, Ison MG, Langley JM, et al; AReSVi-006 Study Group. Respiratory syncytial virus prefusion F protein vaccine in older adults. N Engl J Med 2023;388:595-608.
Falsey AR, Williams K, Gymnopoulou E, et al; CYPRESS Investigators. Efficacy and safety of an Ad26.RSV.preF-RSV preF protein vaccine in older adults. N Engl J Med 2023;388:609-620.
Respiratory syncytial virus (RSV) is a highly morbid respiratory virus with a somewhat predictable seasonal circulation. At-risk groups, including the very young and the very old, suffer significant morbidity and mortality from RSV lower respiratory tract disease (LRTD). On a global scale, RSV infects 3 million newborn children and kills more than 100,000 worldwide annually.1 In older patients who are at increased risk for severe disease, in-hospital deaths from lower-respiratory track RSV number several thousand each year.
Treatment options are extremely limited, with the oft disputed ribavirin as the only antiviral option. Both RSV-specific intravenous immunoglobulin (IVIG) and RSV-specific humanized monoclonal antibody, palivizumab, failed to show clinical benefit in randomized controlled trials (RCTs), albeit, in children, and no longer are available for treatment. Supportive care remains the mainstay of therapy. Palivizumab continues to be available as prophylaxis in highly select infants and children who meet specific prematurity and comorbidity criteria. For a newer monoclonal antibody, nirsevimab, recently reported data from two trials showed efficacy in preventing LRTD infants, including those with congenital heart disease (CHD).2,3 These limited treatment and prevention therapeutics make vaccination an essential addition to RSV LRTD prevention strategies for vulnerable populations.
The first trial, reported by Papi et al, enrolled international patients 60 years of age and older in a 1:1 randomized ratio to receive either RSVPreF3 OA vaccine or placebo. Researchers evaluated 24,966 participants and documented 47 RSV LRTD (seven in vaccine recipients and 40 in the placebo group) for a vaccine efficacy (VE) of 82.6% (confidence interval [CI], 57.9 to 94.1) against RSV-related LRTD. Enhanced protection against severe disease was noted (94.1% efficacy, [CI, 62.4 to 99.9]). Subtype-specific VE was 84.6% for RSV A and 80.9% for RSV B, although two-thirds of the RSV LRTDs were caused by RSV B in the cohort. Subtype-specific reactogenicity was evaluated in a sub-cohort including 1,799 participants and measured both RSVPreF3-specific immunoglobulin G (IgG) and RSV-A and RSV-B neutralizing antibodies before and one month after vaccine/placebo administration.
Adverse events were mild and self-limited, with injection site pain and fatigue being reported more commonly in vaccines than in placebo recipients. Serious adverse events, such as organ class and nervous system disorders, were equal across the two groups (0.1%). Participants had a median follow-up time of 6.7 months.
In a second trial, from Falsey et al, 5,782 participants ages 65 years and older were enrolled across 40 U.S. centers and randomized to receive Ad26.RSV.preF-RSV preF protein vaccine vs. placebo. Participants were followed from injection administration until the end of RSV season. More than one quarter of participants were 75 years of age or older (26.3%). Investigators evaluated correlates of immunity for RSV A and RSV B through neutralizing antibody titers, and profiled immunogenicity through RSV PreF IgG serum antibody and RSV F protein-specific T-cell responses. Serious adverse events were equivalent in vaccines and placebo recipients (4.6% vs. 4.7 %). Minor adverse events, including fatigue, headache, myalgia, nausea, and pyrexia, were more common among vaccine recipients within seven days of injection than among patients receiving placebo (41.4% vs. 16.4%)
Investigators calculated VE based on various case definitions, leading to a variable VE of 80% (94.2% CI, 52.2 to 92.9) for the least restrictive case definition to a VE of 69.8% (94.2% CI, 43.7 to 84.7) for the most inclusive definition that captured all RSV-related acute respiratory infections in the trial population.
COMMENTARY
Vaccine efforts against RSV have lived in the long shadow of a failed 1960s candidate vaccine that exaggerated immune response to natural RSV infection in vaccine recipient children, resulting in hospitalization for treatment of “enhanced respiratory disease” of > 70% of vaccine recipients (18 of 23). Interrogation of this exaggerated response led to a decades-long quest to understand RSV immunogenicity that has been elegantly summarized in an accompanying New England Journal of Medicine Perspective by Dr. Barney Graham.4
Graham, the former deputy director of the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center and prior chief of the Viral Pathogenesis Laboratory, optimistically outlined the coming era of structure-based vaccine design and provided the historical account of research steps leading up to identification of the enhanced neutralizing potency of antibodies that bind prefusion conformation, or preF, of RSV. The consequences of vaccine-induced “enhanced respiratory disease” also have been reviewed previously in an earlier summary by Dr. Philip Fischer. (See Infectious Disease Alert, February 2022.)
The two studies outlined earlier offer hope in the quest to prevent RSV LRTD in vulnerable populations, such as the elderly. Despite the robust VE and immunogenicity data reported in each trial, some questions remain.
First, both trials evaluated VE during the course of one RSV season, and for Ad26.RSV.preF. This season was truncated by the emergence of the SARS-CoV-2 pandemic in March 2020. The RSVpreF3 OA trial had a median follow-up of 6.7 months, which may be sufficient time to cover an RSV season, but so far it is unclear if recipients will have waning immunity requiring an annual RSV vaccination. Vaccine durability evaluations are ongoing in this trial.
A second limitation in both of these trials is the lack of participants with serious or uncontrolled comorbidities. A Phase II trial with Ad26.RSV.preF did include some older patients with comorbidities, such as mild-to-moderate cardiac or pulmonary disease, controlled chronic kidney disease, and diabetes mellitus. Notably missing from these initial reports is the performance of prefusion F protein vaccines in immunocompromised hosts, such as solid organ transplant recipients, patients with hematologic malignancies, and hematopoietic stem cell transplant (HSCT) recipients, who all are highly susceptible to RSV LRTD. In summary, these two trials employing different platforms to leverage the immunogenicity of preF to provide protection against RSV LRTD offer a significant step forward against this perennial respiratory scourge.
REFERENCES
- Fischer PR. Optimism for new interventions to prevent respiratory syncytial virus infections. Infect Dis Alert 2022;41:54-56.
- Domachowske J, Madhi SA, Simões EAF, et al; MEDLEY Study Group. Safety of nirsevimab for RSV in infants with heart or lung disease or prematurity. N Engl J Med 2022;386:892-894.
- Hammitt LL, Dagan R, Yuan Y, et al; MELODY Study Group. Nirsevimab for prevention of RSV in healthy late-preterm and term infants. N Engl J Med 2022;386:837-846.
- Graham BS. The journey to RSV vaccines – Heralding an era of structure-based design. N Engl J Med 2023;388:579-581.
