Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study

Abstract

Background: Respiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model.

Methods: In this double-blind, placebo-controlled study, healthy adults aged 18-50 years were randomized 1:1 to receive 1 × 1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days postimmunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assessments included viral load (VL), RSV infections, clinical symptom score (CSS), safety, and immunogenicity.

Results: Postchallenge, VL, RSV infections, and disease severity were lower in Ad26.RSV.preF (n = 27) vs placebo (n = 26) recipients: median VL area under the curve (AUC) quantitative real-time polymerase chain reaction: 0.0 vs 236.0 (P = .012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 vs 109; RSV infections 11 (40.7%) vs 17 (65.4%); median RSV AUC-CSS 35 vs 167, respectively. From baseline to 28 days postimmunization, geometric mean fold increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated.

Conclusions: Ad26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease.

Clinical trials registration: NCT03334695; CR108398, 2017-003194-33 (EudraCT); VAC18193RSV2002.

Keywords: Pre-F protein; RSV fusion protein; adenoviral vectors; adults; challenge study; respiratory syncytial virus; vaccine.

Figure 1.

Volunteer disposition. *One volunteer was screened and randomized, but not immunized. ^†Three volunteers were lost to follow-up, and 1 volunteer was discontinued per the investigator’s decision (not due to an adverse event [AE]). ^‡Three volunteers were lost to follow-up, 2 volunteers were discontinued per the investigator’s decision (not due to an AE), and 1 volunteer was discontinued due to a positive cotinine test, an exclusion criterion. Abbreviation: RSV-A, respiratory syncytial virus subtype A.

Figure 2.

Efficacy as determined by viral load as determined by real-time polymerase chain reaction (rt-PCR) and quantitative culture, and disease severity as determined by total clinical symptom score (CSS) and mucus weight over time following intranasal viral challenge with respiratory syncytial virus subtype A (RSV-A) after receiving immunization with either Ad26.RSV.preF or placebo intramuscularly (intent-to-treat challenge population). A, Viral load as determined by rt-PCR. B, Viral load as determined by quantitative culture over time. C, Total CSS over time. On the x-axis, A indicates afternoon; E, evening; M, morning. D, Total mucus weight over time. Viral load as determined by rt-PCR, viral load as determined by quantitative culture, CSS, and mucus weight are shown from viral challenge at day 0 until 12 days postchallenge in the intent-to-treat challenge set. From days 2 to 12 postchallenge, nasal wash samples were collected (twice daily from days 2 to 11, once daily on day 12), and symptom score cards were completed by volunteers (thrice daily from days 2 to 11, once daily on day 12) and reviewed by the attending physician. Mucus weights were determined every 24 hours. Placebo and Ad26.RSV.preF were measured at the same timepoints, jitter was applied to ensure both Ad26.RSV.preF and placebo means, and confidence intervals are visible even if close to each other. Abbreviations: CSS, clinical symptom score; SD, standard deviation; VL, viral load.

Figure 3.

Kaplan-Meier curves of time to the first of 2 (A) respiratory syncytial virus (RSV) real-time polymerase chain reaction–positive (B) viral cultures, following intranasal viral challenge with RSV subtype A after receiving immunization with Ad26.RSV.preF or placebo intramuscularly (intent-to-treat challenge population). From days 2 to 12 postchallenge, nasal wash samples were collected (twice daily from day 2 to day 11, once daily on day 12). Positive was defined as above the lower limit of quantification (LLOQ). Results below the LLOQ were allocated 0. Abbreviations: CI, confidence interval; LLOQ, lower limit of quantification; n, number of volunteers; rt-PCR, real-time polymerase chain reaction; VE, vaccine efficacy.

Figure 4.

Titers of neutralizing antibodies to respiratory syncytial virus (RSV) A2 strain over time, and proportion of infected volunteers vs prechallenge titers of neutralizing antibodies to RSV A2 strain following immunization with either Ad26.RSV.preF or placebo intramuscularly (per-protocol immunogenicity set). A, Titers of neutralizing antibodies to RSV A2 strain are shown from baseline to 28 days postchallenge in the per-protocol immunogenicity set. Geometric mean titers with 95% confidence intervals (CIs) are shown. The majority of the volunteers had their 28-day postimmunization sample taken between 22 and 33 days after immunization. One volunteer had 2 prechallenge samples taken at day 45 and day 70; these 2 samples are not part of the analysis. Infection was defined based on the symptomatic and asymptomatic definition: if a volunteer had ≥2 quantifiable real-time polymerase chain reaction (rt-PCR) measurements above the lower limit of quantification (LLOQ). B, Infected and noninfected volunteers receiving Ad26.RSV.preF were plotted vs their prechallenge titers of neutralizing antibodies to RSV A2 strain. Generalized linear regression was used to model the probability of those in the Ad26.RSV.preF group being infected using the log-transformed prechallenge titers of neutralizing antibodies to RSV A2 strain as an independent variable. The solid lines represent the estimated probability of being infected and the shaded area around it represents the 95% CI. Infection was defined based on the symptomatic and asymptomatic definition: if a volunteer had ≥2 quantifiable rt-PCR measurements above the LLOQ. Abbreviations: IC₅₀, half-maximal inhibitory concentration; RSV, respiratory syncytial virus.