Immunogenicity and shedding of live-attenuated intranasal respiratory syncytial virus vaccine in children aged 6-18 months by baseline serostatus: a multicentre, randomised, placebo-controlled, phase 1/2 trial.
Abstract
Background
Respiratory syncytial virus (RSV) causes acute respiratory illness in young children. The live-attenuated RSV vaccine candidate RSV/ΔNS2/Δ1313/I1314L (RSVt) has shown promising immunogenicity and safety in children aged 6-18 months. However, how baseline RSV serostatus influences immunogenicity and viral shedding after RSVt vaccination in young children remains largely unreported. In this phase 1/2 trial, we aimed to evaluate immunogenicity and virus shedding after RSVt vaccination in children aged 6-18 months stratified by baseline RSV serostatus.
Methods
In this multicentre, randomised, placebo-controlled, phase 1/2 trial, children in the USA (N=22 sites), Chile (N=2 sites), and Honduras (N=2 sites) were recruited as participants. Healthy children aged 6-18 months at enrolment who were born at or after 34 weeks of gestation (if age 1 year or older) or children younger than 1 year at enrolment who were born at or after 37 weeks of gestation were eligible for inclusion. Key exclusion criteria included previous administration of any RSV vaccine or anti-RSV products; administration of an influenza vaccine in the 7 days before enrolment; administration of inactivated vaccines or live-attenuated rotavirus vaccine in the 14 days before enrolment; or administration of any other live vaccines or investigational products in the 28 days before enrolment. Participants were assigned to four sequential cohorts to receive intranasal low-dose RSVt (RSVt-LD) or high-dose RSVt (RSVt-HD), administered once on day 0 or twice on day 0 and day 56, or placebo. Cohort 4 was the primary comparison cohort, and participants were randomly assigned (1:1:1) via a centralised interactive response system to receive two administrations of the treatment. Participants, investigators, and outcome assessors were masked to group allocation; only designated staff preparing and administering study interventions were unmasked. The primary outcomes reported were immunogenicity evaluated using serum RSV-neutralisation assays and anti-F IgG ELISA on days 0, 56, and 84 and vaccine virus shedding measured using quantitative RT-PCR on days 7 and 63 by baseline serostatus. Statistical analyses were descriptive and included all randomly assigned participants who received at least one dose of RSVt. Missing data were not imputed; 95% CI used the Clopper-Pearson method. This trial is registered with ClinicalTrials.gov (NCT04491877); the trial closed to enrolment on April 13, 2023.
Findings
Between Sept 10, 2020, and April 13, 2023, 180 participants in cohort 4 were randomly assigned to RSVt-LD (n=61; females, 31 [51%] of 61), RSVt-HD (n=58; females, 25 [43%] of 58), or placebo (n=61; females, 32 [52%] of 61). The mean age at enrolment was 10·4 months (SD 3·1) in the RSVt-LD, 10·6 months (SD 3·6) in the RSVt-HD, and 10·6 months (SD 3·8) in the placebo groups; most participants (>60%) were younger than 12 months in all three groups. The majority of participants (>65%) in all three groups were Hispanic or Latino. Participants were categorised as those with (RSV-experienced) or without (RSV-naive) previous RSV exposure. RSV-naive group was further classified as participants who were RSV-seronegative (no maternal antibody present) and RSV-passive-positive (having passive maternal RSV antibodies). Among the RSV-naive participants, on day 84, after the first or second vaccine administration, four-fold or higher increases in RSV-neutralising antibodies were observed in 19 of 28 (67·9%, 95% CI 47·6-84·1) participants in the RSVt-LD group, 13 of 21 (61·9%, 95% CI 38·4-81·9) participants in the RSVt-HD group, and two of 27 (7·4%, 95% CI 0·9-24·3) participants in the placebo group. Detectable shedding on day 7 occurred in 22 of 41 (53·7%, 95% CI 37·4-69·3) RSV-naive participants in the RSVt-LD group and 17 of 30 (56·7%, 95% CI 37·4-74·5) participants in the RSVt-HD group. Among RSV-naive participants who were RSV-seronegative, on day 84, four-fold or higher rises were observed in 15 of 20 (75·0%, 95% CI 50·9-91·3) participants in the RSVt-LD group, ten of 11 (90·9%, 95% CI 58·7-99·8) participants in the RSVt-HD group, and two of 15 (13·3%, 95% CI 1·7-40·5) participants in the placebo group; shedding on day 7 occurred in 17 of 28 (60·7%, 95% CI 40·6-78·5) participants in the RSVt-LD group and 11 of 18 (61·1%, 35·7-82·7) participants in the RSVt-HD group. Among RSV-naive participants who were RSV-passive-positive, on day 84, four-fold or higher rises were observed in four of eight (50·0%, 95% CI 15·7-84·3) participants in the RSVt-LD group, three of ten (30·0%, 95% CI 6·7-65·2) participants in the RSVt-HD group, and 0 of 12 (0, 95% CI 0·0-26·5) participants in the placebo group; shedding on day 7 occurred in five of 13 (38·5%, 95% CI 13·9-68·4) participants in the RSVt-LD group and six of 12 (50·0%, 95% CI 21·1-78·9) participants in the RSVt-HD group. Among RSV-experienced participants, on day 84, four-fold or higher rises were observed in two of 14 (14·3%, 95% CI 1·8-42·8) participants in the RSVt-LD group, one of 20 (5·0%, 95% CI 0·1-24·9) participants in the RSVt-HD group, and three of 23 (13·0%, 95% CI 2·8-33·6) participants in the placebo group; shedding on day 7 occurred in three of 14 (21·4%, 95% CI 4·7-50·8) RSV-experienced participants in the RSVt-LD group and three of 22 (13·6%, 95% CI 2·9-34·9) participants in the RSVt-HD group. No quantifiable shedding was observed in placebo recipients. No vaccine-related serious adverse events were reported.
Interpretation
RSVt induced immune responses and vaccine virus shedding, indicating viral replication and immune priming. RSVt induced greater neutralising antibody responses in RSV-naive participants than in RSV-experienced participants, indicating that baseline serostatus influences vaccine immunogenicity. The discordance between serum antibody responses and viral shedding suggests that serum measures alone might not fully capture vaccine-induced immunity. These findings support further evaluation of live-attenuated intranasal RSV vaccines and highlight the importance of baseline serostatus in interpreting immunogenicity outcomes.
Funding
Sanofi.