The Lancet. Microbe · 2026
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.
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Idoko Olubukola T, Vargas Sergio L, Bueso Agustin, Rivera Doris, Edward Henderson, Banooni Peyman, Berger Shaun, Janicot Stephane, Vercasson Camille, Pallardy Sophie, Nteene Rapi, Adhikarla Haritha, Gerchman Eric, Gasparotto Monica, Gallichan Scott, Rivas Enrique, Buchholz Ursula J, Sesay Sanie, Gurunathan Sanjay, De Bruijn Iris, Dhingra Mandeep S
Аннотация
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.
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.