Evaluation of Recombinant Live-Attenuated Respiratory Syncytial Virus (RSV) Vaccines RSV/ΔNS2/Δ1313/I1314L and RSV/276 in RSV-Seronegative Children

Abstract

Background: This United States-based study compared 2 candidate vaccines: RSV/ΔNS2/Δ1313/I1314L, attenuated by NS2 gene-deletion and temperature-sensitivity mutation in the polymerase gene; and RSV/276, attenuated by M2-2 deletion.

Methods: RSV-seronegative children aged 6-24 months received RSV/ΔNS2/Δ1313/I1314L (106 plaque-forming units [PFU]), RSV/276 (105 PFU), or placebo intranasally. Participants were monitored for vaccine shedding, reactogenicity, and RSV serum antibodies, and followed over the subsequent RSV season.

Results: Enrollment occurred September 2017 to October 2019. During 28 days postinoculation, upper respiratory illness and/or fever occurred in 64% of RSV/ΔNS2/Δ1313/I1314L, 84% of RSV/276, and 58% of placebo recipients. Symptoms were generally mild. Cough was more common in RSV/276 recipients than RSV/ΔNS2/Δ1313/I1314L (48% vs 12%; P = .012) or placebo recipients (17%; P = .084). There were no lower respiratory illness or serious adverse events. Eighty-eight and 96% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 recipients were infected with vaccine (shed vaccine and/or had ≥4-fold rises in RSV antibodies). Serum RSV-neutralizing titers and anti-RSV F IgG titers increased ≥4-fold in 60% and 92% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 vaccinees, respectively. Exposure to community RSV during the subsequent winter was associated with strong anamnestic RSV-antibody responses.

Conclusions: Both vaccines had excellent infectivity and were well tolerated. RSV/276 induced an excess of mild cough. Both vaccines were immunogenic and primed for strong anamnestic responses.

Clinical trials registration: NCT03227029 and NCT03422237.

Keywords: RNA regulatory protein M2-2; RSV; immunogenicity; live-attenuated viral vaccine; neutralizing antibodies; respiratory syncytial virus.

Figure 1.

Symptom days in participants with respiratory or febrile illness reported after receipt of vaccine or placebo. Each row represents 1 participant, grouped by candidate vaccine or placebo. Day 0 is day of vaccination. The boxes depict the duration of episodes of respiratory or febrile illness that occurred in the first 28 days after receipt of study product in 16 of 25 (64%) who received RSV/ΔNS2/Δ1313/I1314L vaccine, 21 of 25 (84%) who received RSV/276 vaccine, and 7 of 12 (58%) placebo recipients. Nasal washes (NW) were performed on study days 0, 3, 5, 7, 10, 12, 14, 17, and 28 and in the event of respiratory illness (upper respiratory illness: rhinorrhea, pharyngitis, or hoarseness; cough; acute otitis media; lower respiratory illness) or fever. NW during illnesses were tested for common adventitious agents by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Vaccine virus in NW was quantified by immunoplaque assay and by RT-qPCR. Blue denotes illness episodes with vaccine virus alone detected in 1 or more days during the illness, yellow denotes vaccine virus plus additional virus(es), and hatch denotes episodes without vaccine virus (either other virus isolated or no viruses).

Figure 2.

Vaccine virus shed in nasal wash (NW) specimens from vaccinees. Data are for RSV/ΔNS2/Δ1313/I1314L vaccine (A and B) and RSV/276 vaccine (C and D). Titers (closed circles and open diamonds) and peak titers (open diamonds) for individual participants are shown along with median titers (solid line). NW specimens were collected from vaccinees during study days 0, 3, 5, 7, 10, 12, 14, 17, and 28 visits (window, indicated study day ± 1 day) after inoculation on day 0, and titers were determined by immunoplaque assay (A and C) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) (B and D). The lower limits of detection (dashed lines) were 0.5 log₁₀ plaque-forming units (PFU)/mL and 1.7 log₁₀ copies/mL for immunoplaque assay and RT-qPCR, respectively.

Figure 3.

Serum respiratory syncytial virus (RSV) antibody titers in vaccine and placebo recipients. Serum RSV 60% plaque reduction neutralizing titers (PRNT₆₀) (A) and anti-RSV fusion (F) immunoglobulin G (IgG) titers (B) were determined by means of complement enhanced 60% plaque reduction neutralization assay and IgG-specific enzyme-linked immunosorbent assay against purified RSV F protein, respectively, for RSV/ΔNS2/Δ1313/I1314L vaccine (open circles), RSV/276 vaccine (filled circles), and placebo (×’s) recipients in serum samples collected before inoculation (screening), after inoculation (study day 56), before surveillance (October of the enrollment year), and after surveillance (usually April after the RSV season). Titers are expressed as the reciprocal log₂ values. Lines indicate median (solid lines) and mean (dashed lines) values. P values were determined by means of Wilcoxon rank sum test. Data for the presurveillance and postsurveillance visits are missing for 3 participants in each treatment group.