Live-attenuated Vaccines Prevent Respiratory Syncytial Virus-associated Illness in Young Children

Abstract

Rationale: Active immunization is needed to protect infants and young children against respiratory syncytial virus (RSV). Rationally designed live-attenuated RSV vaccines are in clinical development.Objectives: Develop preliminary estimates of vaccine efficacy, assess durability of antibody responses to vaccination and "booster" responses after natural RSV infection, and determine sample sizes needed for more precise estimates of vaccine efficacy.Methods: We analyzed data from seven phase 1 trials of live-attenuated RSV vaccines in 6- to 24-month-old children (n = 239).Measurements and Main Results: The five vaccine regimens that induced neutralizing antibody responses in ≥80% of vaccinees (defined post hoc as "more promising") protected against RSV-associated medically attended acute respiratory illness (RSV-MAARI) and medically attended acute lower respiratory illness (RSV-MAALRI) and primed for potent anamnestic responses upon natural exposure to wild-type RSV. Among recipients of "more promising" RSV vaccines, efficacy against RSV-MAARI was 67% (95% confidence interval [CI], 24 to 85; P = 0.008) and against RSV-MAALRI was 88% (95% CI, -9 to 99; P = 0.04). A greater than or equal to fourfold increase in RSV serum neutralizing antibody following vaccination was strongly associated with protection against RSV-MAARI (odds ratio, 0.26; 95% CI, 0.09 to 0.75; P = 0.014) and RSV-MAALRI; no child with a greater than or equal to fourfold increase developed RSV-MAALRI. Rates of RSV-MAARI and RSV-MAALRI in placebo recipients were 21% and 7%, respectively. Given these rates, a study of 540 RSV-naive children would have 90% power to demonstrate ≥55% efficacy against RSV-MAARI and ≥80% efficacy against RSV-MAALRI; if rates were 10% and 3%, a study of 1,300 RSV-naive children would be needed.Conclusions: Rapid development of a live-attenuated RSV vaccine could contribute substantially to reducing the global burden of RSV disease.

Keywords: RSV; efficacy; immunity; pediatric; vaccine.

Figure 1.

Allocation by study arm and distribution of vaccinees according to immune response. Two hundred forty-one children ages 6–24 months were randomized in seven separate studies of live-attenuated respiratory syncytial virus (RSV) vaccines to receive vaccine (161 children) or placebo (80 children), including RSV ΔNS2/Δ1313/I1314L, RSVcps2, LID/cp/ΔM2–2, MEDIΔM2–2, RSV LIDΔM2–2, RSV LIDΔM2–2/1030s, and D46/NS2/N/ΔM2–2-HindIII (registered in clinicaltrials.gov as NCT01893554, NCT01852266/NCT01968083, NCT02890381/NCT02948127, NCT01459198, NCT02040831/NCT02237209, NCT02794870/NCT02952339, and NCT03099291/NCT03102034; certain vaccines were evaluated in more than one clinical trial). Subset analyses and losses to follow-up are as described in results. RSV F IgG ELISA titers were determined by endpoint titration. *Two placebo recipients were missing one or more surveillance serum specimens. F = fusion; MAALRI = medically attended acute lower respiratory illness; MAARI = medically attended acute respiratory illness.

Figure 2.

Percentage of the placebo recipients in clinical trials of live-attenuated respiratory syncytial virus (RSV) vaccines who experienced RSV-MAARI (red bars) and percentage with greater than or equal to fourfold increase in RSV plaque reduction–neutralizing antibody titer (PRNT) when presurveillance season and postsurveillance season sera were compared (“RSV neutralizing Ab response,” blue bars). Data are from 2011 through 2018; enrollment varied by year. In all, 72 placebo recipients were included in this analysis. Eight placebo recipients were excluded: in addition to the one placebo recipient who was infected with vaccine virus (see methods), five placebo recipients had a rise in RSV antibody titer between Days 0 and 56 after receipt of study product, presumably reflecting natural infection with wild-type (wt) RSV, and two placebo recipients, although assessed for medically attended respiratory outcomes (and therefore still eligible for the analysis of vaccine efficacy), were missing one or more surveillance serum specimens (see Figure 1). Wt RSV infection was defined as occurring in any participant who had a greater than or equal to fourfold increase in RSV PRNT between the pre- and postsurveillance serum specimens, detection of wt RSV in a nasal wash specimen during surveillance, or both. Ab = antibody; MAARI = medically attended acute respiratory illness.

Figure 3.

(A and B) Vaccine efficacy against respiratory syncytial virus (RSV)-associated medically attended acute respiratory illness (MAARI) (A) and RSV-associated medically attended acute lower respiratory illness (MAALRI) (B), with point estimates and 95% confidence intervals. In both panels, the black bars show the efficacy estimates for all 160 vaccinees (top black bars), and for the 122 vaccinees with RSV neutralizing antibody responses by Day 56 after vaccination “neut responders” (bottom black bars). Similarly, the blue bars in each grouping show the analyses for the 100 children who received the more promising vaccines (top blue bars), and further subset of 90 with neutralizing antibody responses to vaccine (bottom blue bars). Among all 160 vaccinees and 79 placebo recipients, there were 31 cases of RSV-MAARI (16 in vaccinees and 15 in placebo recipients) and 10 cases of RSV-MAALRI (5 in vaccinees and 5 in placebo recipients).

Figure 4.

Peak vaccine titers do not appear to be predictive of vaccine efficacy. Peak log₁₀ titers of vaccine virus shed among vaccinees who experienced respiratory syncytial virus (RSV)-associated medically attended acute respiratory illness (MAARI) (blue dots), vaccinees who did not experience RSV-MAARI but had serologic evidence of wild-type (wt) RSV exposure during the RSV season (orange dots), and vaccinees who did not experience RSV-MAARI and who also had no evidence of wt RSV exposure (black dots) during the subsequent RSV surveillance season. Means were calculated for RSV-MAARI+ (blue dots) and for RSV-MAARI− who had evidence of exposure to RSV during surveillance (orange dots). A shows all vaccinees and B shows recipients of the more promising vaccines.

Figure 5.

Comparisons of respiratory syncytial virus (RSV) plaque reduction–neutralizing antibody titer (PRNT) after immunization (Day 56) and after the surveillance period, with titers expressed as reciprocal log₂. Dots of the same color represent identical participants but at different time points. Open circles are postimmunization PRNTs; closed circles are postsurveillance PRNTs. Lines indicate the mean PRNT. Red scatterplots: anamnestic antibody responses following exposure to wild-type (wt) RSV in 36 vaccinees who developed a greater than or equal to fourfold PRNT response after immunization, and also had a greater than or equal to fourfold PRNT response during the surveillance period, indicating exposure to wt RSV. PRNTs after immunization (red open circles, mean 6.4 log₂, geometric mean titer = 84) are compared with PRNTs following surveillance (red closed circles, mean 10.2 log₂, 1,176). Blue scatterplots: durability of neutralizing antibody responses following vaccination in 83 vaccinees who developed a greater than or equal to fourfold PRNT response after immunization but did not have a greater than or equal to fourfold PRNT response during the surveillance period, indicating they were not exposed to wt RSV. PRNTs after immunization (open blue circles, mean 6.8 log₂, 111) are compared with PRNTs after surveillance (closed blue circles, mean 6.3 log₂, 79). Orange and black scatterplots: PRNTs induced by vaccination are comparable to those induced by wt RSV infection. The mean PRNT on Day 56 following vaccination among all 122 vaccinees was 6.7 log₂ (orange scatterplot), and the postsurveillance PRNT among 41 placebo recipients exposed to wt RSV during surveillance was 7.0 log₂ (black scatterplot).

Figure 6.

Power curves showing estimates of sample sizes needed to detect varying levels of vaccine efficacy against respiratory syncytial virus (RSV)-associated medically attended acute respiratory illness (MAARI) in RSV-seronegative children (red, 90% power; orange, 80% power) and against RSV-associated medically attended acute lower respiratory illness (MAALRI) (dark blue, 90% power; light blue, 80% power). In each case, the solid lines assume a 1:1 vaccine-to-placebo allocation, whereas dotted lines indicate a 2:1 allocation (note that these lines are very similar). The upper panel uses estimates of RSV-MAARI and -MAALRI attack rates derived from our study data (“current estimate”; 21% and 7%, respectively), whereas the lower panel assumes attack rates that are half as large (“conservative estimate”; 10% and 3%, respectively). Dotted lines indicate a sample size of (A) 540 and (B) 1,300; red circles, 55% efficacy against RSV-MAARI; blue circles, 80% efficacy against RSV-MAALRI.