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Associate Professor of Medicine
Division of Infectious Diseases
Department of Medicine
University of Rochester
Rochester, New York
Angela Branche, MD, has disclosed that she has received research support from Cyanvac, Merck, and Pfizer; has served as a consultant for AzurX Biopharma, GlaxoSmithKline, and Janssen; has served as an advisor for AzurX Biopharma, GlaxoSmithKline, and Janssen; and has served as a speaker for AzurX Biopharma, GlaxoSmithKline, and Janssen.
Several developments have been made over the past decade toward the goal of producing an effective respiratory syncytial virus (RSV) vaccine. Although the current vaccine development program is directed at developing a vaccine for 3 patient groups—infants, pregnant women, and older adults—the vast majority of trials currently are being conducted in older adults, who experience more severe disease than their younger adult counterparts. We are closer to having an effective vaccine than we ever have been, which is very exciting for me, and I’d like to share some recent developments.
An Atypical RSV Season
Before updating you on progress made on RSV vaccine development over the past 6 months or so, I should mention that there have been some challenges in assessing vaccine efficacy due to this year’s atypical RSV season—most likely due to the public health measures put in place for the COVID-19 pandemic. Indeed, the 2021/2022 RSV season was both very short and very mild, meaning that case numbers were much lower than usual. Therefore, I am not sure whether the incidence of measurable disease in ongoing vaccine trials is yet sufficient to fully assess efficacy. The trials conducted during this season may need another 1-2 years before efficacy can be demonstrated.
However, we may see a higher than normal number of RSV cases this summer, as we did in the summer of 2021, which will allow further data to accumulate. Overall, I think it is great that investigators are moving ahead with these trials because these vaccines are needed, but the COVID-19 pandemic definitely has created a much more complicated landscape in which to conduct this research.
mRNA-1345 Vaccine: Entering Phase III
The mRNA-1345 vaccine received fast track designation from the FDA in August 2021 for evaluation in older adults. Interim data from a phase I trial of the vaccine in adults aged 65-79 years were released late last year, showing that a single mRNA-1345 dose of 50 µg, 100 µg, or 200 µg increased neutralizing antibody titers against RSV-A and RSV-B by nearly 14-fold and 10-fold, respectively, and all doses were well tolerated.
The vaccine then entered phase II/III evaluation in the randomized, observer-blinded, placebo-controlled ConquerRSV trial, enrolling adults aged 60 years or older, including those with certain chronic medical conditions (heart failure and chronic obstructive pulmonary disease). In February 2022—after receiving endorsement from the Data and Safety Monitoring Board based on preliminary phase II safety and tolerability data—it was announced that the phase III portion of the study would be initiated. In this phase, trial investigators plan to enroll approximately 34,000 participants. In addition, the randomized, observer-blinded, placebo-controlled phase III RSVictory trial has begun, recruiting adults aged 50 years or older to evaluate the safety and efficacy of a single dose of mRNA-1345 administered with or without a quadrivalent influenza vaccine.
Prefusion F Subunit Vaccine: New Breakthrough Designation
The large, randomized, double-blind, placebo-controlled phase III RENOIR study was initiated in September 2021 to assess the safety and efficacy of the bivalent prefusion F subunit vaccine candidate, RSVpreF, in adults aged 60 years or older. The study completed enrollment at the end of January 2022, and investigators are currently conducting the surveillance that will be needed to determine efficacy.
Of importance, this vaccine candidate received breakthrough therapy designation from the FDA for this population in March 2022 based on positive results of a proof-of-concept phase IIa study evaluating the safety, immunogenicity, and efficacy of a single dose of 120 µg in a human viral challenge model in healthy adults aged 18-50 years.
Ad26.RSV.preF-Based Vaccine: Updated Data From CYPRESS Trial
In 2019, Ad26.RSV.preF also was granted breakthrough therapy designation in older adults. Results from the randomized, double-blind, placebo-controlled phase IIb CYPRESS trial assessing Ad26.RSV.preF vs placebo in 5782 adults aged 65 years or older were presented at both IDWeek 2021 and the European Scientific Working Group on Influenza 2021 conference. In the study, vaccine efficacy was 80% for preventing ≥3 symptoms of lower respiratory tract infection (LRTI), 75% for preventing ≥2 symptoms of LRTI, and 69.8% for preventing ≥2 symptoms of LRTI or ≥1 symptom of LRTI with ≥1 systemic symptom (all P values <.00005). Furthermore, investigators showed that participants in the vaccine group experienced less severe symptoms vs the placebo group, as assessed with an RSV-specific patient-reported Respiratory Infection Intensity and Impact Questionnaire. The randomized, double-blind, placebo-controlled phase III EVERGREEN trial was initiated in September 2021 in adults aged 60 years or older based on these positive results.
RSVPreF3: Clinical Trial in Pregnant Women Paused; No Impact on Trial in Older Adults
Based on interim results from a phase I/II study of RSVPreF3 in 1005 healthy adults aged 60-80 years demonstrating that the vaccine was well tolerated and elicited an approximately 10-fold increase in RSV antibodies vs baseline, the randomized, observer-blinded, placebo-controlled phase III AReSVi 006 trial was initiated. This candidate vaccine incorporates a subunit prefusion RSV antigen (RSVPreF3) with the AS01 adjuvant, which has been used in a highly effective shingles vaccine. Of note, the phase III GRACE trial, which was assessing a single unadjuvanted dose of the RSVPreF3 vaccine in pregnant women, was paused in February 2022 based on an observation from a routine safety assessment, but this does not appear to be impacting the AReSVi 006 trial in older patients, where it is anticipated that data will be available in the first half of 2022.
These studies are just beginning to illuminate the many unanswered questions about RSV vaccines in older patients. Some questions that should be answered over the next few years include whether 1 dose of the vaccine will be sufficient or multiple doses will be needed and if it will require annual boosters. These questions need to be answered, and having an abnormal RSV season has interfered somewhat with our ability to do so thus far. We will follow new data with interest to begin to answer these and other key questions.
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