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This Concise Critical Appraisal delves into the impact of respiratory syncytial virus (RSV) and explores a recent trial that led to U.S. Food and Drug Administration approval of the first RSV vaccine. The Adult Respiratory Syncytial Virus (AReSVi-006) clinical trial is an ongoing, international, randomized, placebo-controlled trial that assesses the safety and effectiveness of a single dose of an RSV vaccine in nearly 25,000 patients.
Respiratory syncytial virus (RSV) is a highly contagious RNA virus that circulates seasonally and causes significant morbidity and mortality. In adults over age 65 years, the U.S Centers for Disease Control and Prevention (CDC) reports up to 160,000 hospitalizations and 10,000 deaths anually.1 From July 2017 through February 2023, five distinct RSV epidemics occurred: three before the COVID-19 pandemic and two during the pandemic. The seasonal circulation changed from October through December in 2017-2020 to May through January in 2021-2023. RSV epidemics begin earliest in the southeast, peaking in November in Florida, and can continue through March.
Atypical seasonal RSV epidemics were attributed to nonpharmaceutical interventions during the COVID-19 pandemic, such as masking and school closures. The impact of RSV in older adults may be similar to that of nonpandemic influenza. In the United States, the economic burden in older adults is more than $150 million annually.2 Until recently, no licensed RSV vaccination existed. Multiple vaccines were in late-stage clinical trials until May 3, 2023, when the U.S. Food and Drug Administration (FDA) approved the first RSV vaccine for individuals aged 60 years and older.3
In this Concise Critical Appraisal, we will discuss the recent FDA approval of an RSV vaccine. FDA approval was based on the ongoing, international, randomized, placebo-controlled Adult Respiratory Syncytial Virus (AReSVi-006) clinical trial assessing the safety and effectiveness of a single dose of an ASO1E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3). RSV lower respiratory tract disease (LRTD) and RSV-related acute respiratory tract infection were confirmed by reverse transcription polymerase chain reaction (RT-PCR). To meet the primary objective, the vaccine required an efficacy estimate of more than 20%.
A total of 24,966 patients were included, of which 12,467 received one dose of the RSVPreF3 vaccine. Over a 6.7-month follow-up period, the vaccine reduced the risk of developing LRTD by 82.6%, severe LRTD by 94.1%, and RSV-related acute respiratory infection by 71.7%. Efficacy was similar for both RSV groups A and B. The most commonly reported side effects were injection site pain, fatigue, muscle pain, headache, and joint pain. Atrial fibrillation within 30 days of vaccination was reported in 10 patients in the vaccine arm versus four patients in the placebo arm. Two patients in the vaccine arm developed acute disseminated encephalomyelitis (ADEM) within 22 days, one of whom died. In one patient, Guillian-Barré syndrome (GBS) was reported nine days after vaccination. Evaluations for signals of GBS, ADEM, and atrial fibrillation are currently being sought.
The four principal methods of diagnosing RSV are culture, antigen detection (by immunofluorescence assay or enzyme immunoassay), RNA detection (by RT-PCR), and serology. Unfortunately, clinical features such as nasal congestion, fever, and nonproductive cough are indistinguishable from those of other flu-like viruses. RSV rapid diagnostic tests have a sensitivity of 75.3% and specificity of 98.7%.4 Availability of a rapid RSV testing can reduce emergency department length of stay by 40 minutes.5 Since RSV is believed to be spread by large droplets and fomites that can survive on surfaces for hours, contact with contaminated surfaces and autoinoculation is required for transmission.6
RSV is especially problematic in certain adult populations, including people who are elderly, have cardiopulmonary disease, or are immunocompromised. Complication rates in patients with RSV include pneumonia in up to 55% and death in up to 53%.7 RSV infects 5% to 10% of nursing home residents per year, with pneumonia rates of 10% to 20% and mortality rates of 2% to 5%.8 Treatment of RSV in elderly patients is largely supportive, comprising fluids and oxygen.
Ribavirin is the only approved agent for the treatment of RSV. Unlike for infants, in which both ribavirin and immunoglobulin therapy have been evaluated in placebo-controlled trials, only anecdotal results exist for adults. The NIAID Collaborative Antiviral Study Group is currently evaluating early ribavirin with or without RSV immunoglobulin by in adults.7 However, prevention via RSV vaccination offers the best hope to reduce disease burden. FDA approval of this new vaccine is a game changer.
RSV is composed of a nucleocapsid core, phosphoprotein, and polymerase proteins. The virion RNA is surrounded by a host cell membrane with three glycoproteins: G attachment protein, fusion protein, and small hydrophobic protein. Infection is initiated with the G protein binding to the host cell receptor, followed by F protein-mediated fusion, and finally penetration into the cytoplasm. Although two groups of the virus exist—A and B—group A is more prevalent within geographically confined epidemics. In nosocomial outbreaks in nursing homes and bone marrow transplant units, both groups A and B viruses were identified.8 Since natural RSV infection results in incomplete immunity, recurrent infections are common.
Passive immunization with monoclonal antibodies, including palivizumab and nirsevimab, is limited to infants at high risk for RSV disease.9-11 Prevention is the key to reducing the burden of RSV in both children and adults. The newly approved vaccine was well tolerated and effective in people with underlying health conditions, including chronic respiratory and heart disease—those at highest risk of morbidity and mortality. A second vaccine was also recently approved by the FDA based on data from the RENOIR trial.12 FDA approval of two new vaccines offers renewed hope for curtailing the global burden of LRTD from RSV. Clinicians who have grown accustomed to managing this burden in the ICU are excited to see the impact of these two new vaccines on their patients.
Posted: 6/14/2023 | 0 comments
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