Safety and Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-Seronegative Children

Abstract

Background: Respiratory syncytial virus (RSV) is the leading global cause of severe pediatric acute respiratory tract illness, and a vaccine is needed. RSV/ΔNS2/Δ1313/I1314L contains 2 attenuating elements: (1) deletion of the interferon antagonist NS2 gene and (2) deletion of codon 1313 of the RSV polymerase gene and the stabilizing missense mutation I1314L. This live vaccine candidate was temperature-sensitive, genetically stable, replication restricted, and immunogenic in nonhuman primates.

Methods: A single intranasal dose of RSV/ΔNS2/Δ1313/I1314L was evaluated in a double-blind, placebo-controlled trial (vaccine-placebo ratio, 2:1) at 106 plaque-forming units (PFU) in 15 RSV-seropositive children and at 105 and 106 PFU in 21 and 30 RSV-seronegative children, respectively.

Results: In RSV-seronegative children, the 105 PFU dose was overattenuated, but the 106 PFU dose was well tolerated, infectious (RSV/ΔNS2/Δ1313/I1314L replication detected in 90% of vaccinees), and immunogenic (geometric mean serum RSV plaque-reduction neutralizing antibody titer, 1:64). After the RSV season, 9 of 20 vaccinees had increases in the RSV titer that were significantly greater than those in 8 of 10 placebo recipients (1:955 vs 1:69, respectively), indicating that the vaccine primed for anamnestic responses after natural RSV exposure.

Conclusion: Rational design yielded a genetically stable candidate RSV vaccine that is attenuated yet immunogenic in RSV-seronegative children, warranting further evaluation.

Clinical trials registration: NCT01893554.

Keywords: RSV; live-attenuated RSV vaccine; pediatric; vaccine.

Figure 1.

Screening, enrollment, and follow-up of RSV-seropositive children (panel A) and RSV-seronegative children (panels B and C) in the phase I clinical trial of the RSV/ΔNS2/Δ1313/I1314L vaccine. As described in Methods, enrollment in each of the cohorts depicted in A, B, and C occurred sequentially following a satisfactory safety review of data from the previous cohort.

Figure 2.

Proportions of RSV-seronegative vaccinees and placebo recipients with indicated illnesses in the 10⁵ PFU cohort (panel A) or the 10⁶ PFU cohort (panel B). Vaccinees are shown in black; placebo recipients are shown in gray.

Figure 3.

Peak titers of vaccine virus shed as detected by culture (A) and quantitative reverse-transcription polymerase chain reaction (RT-qPCR) (B) among RSV-seronegative recipients of 10⁵ or 10⁶ plaque-forming units (PFU) of vaccine. C, D, Individual daily titers by culture (C) and RT-qPCR (D) for RSV-seronegative recipients of the 10⁶ PFU dose. Triangles represent peak titers from individual vaccine recipients; continuous lines, mean values; and dotted lines, titers assigned for culture-negative (0.5 log₁₀ PFU/mL) (C) and RT-qPCR–negative (D) (1.7 log₁₀ copies/mL) nasal wash (NW) samples.

Figure 4.

Respiratory syncytial virus (RSV) plaque reduction neutralization antibody titers (PRNT) in RSV-seronegative recipients of 10⁶ plaque-forming units of vaccine (A) or placebo (B), measured before immunization (Pre), 56 days after immunization (Post), before the first RSV surveillance season (Pre–1st SS) and after the first RSV surveillance season (Post–1st SS). Triangles represent children with RSV-associated medically attended acute respiratory illness (RSV-MAARI); solid lines, means for the postinoculation, presurveillance, and postsurveillance time points; symbols enclosed by dotted line, titers from vaccinees with evidence of wild-type RSV infection during surveillance (≥4-fold increases in PRNT, RSV-MAARI, or both), with means from these subsets provided next to enclosed symbols.

Figure 5.

Respiratory syncytial virus (RSV) plaque reduction neutralization antibody titers (PRNT) in 20 RSV-seronegative recipients of 10⁶ plaque-forming units of vaccine (A) and 10 placebo recipients (B), by individual child. All 30 children were followed during the first surveillance season (SS); 16 of 20 vaccinees and 6 of 10 placebo recipients were followed through 2 RSV surveillance seasons. Dotted lines represent data from the 4 vaccinees and 4 placebo recipients who participated only in the first season; dashed lines, participants who experienced an episode of RSV-associated medically attended acute respiratory illness or lower respiratory illness during a surveillance season; triangles, occurrence of such illness. A, Vaccinees with a ≥4-fold increase in the first season (left), the second season (middle), or neither season (right). B, Placebo recipients with a ≥4-fold increase in 1 or both seasons. Only 1 placebo recipient did not have a detectable increase in RSV PRNT, and this child participated in only the first surveillance season. Abbreviations: Post, after; Pre, before.