Abstract
Background:
Although both maternal RSVpreF vaccination and infant nirsevimab immunization have been approved for the prevention of RSV LRTIs, the two have not been evaluated in a single study, nor has their sequential administration been studied systematically. products
Methods:
We performed a prospective, randomized, open-label, Phase 4 study at 8 US sites of mother-infant pairs randomized 1:1:1:1 during pregnancy: maternal RSVpreF vaccine alone; maternal RSVpreF vaccine/infant nirsevimab at birth; maternal RSVpreF vaccine/infant nirsevimab at 3 months; or infant nirsevimab alone at birth. We are following the mother-infant pairs for 12 months to ascertain safety, infant tolerability, and the magnitude and durability of RSV-A and -B neutralizing antibodies (nAbs). We report interim data from September 19, 2024, to May 15, 2025, including 4-month infant follow-up.
Results:
181 mothers were enrolled. Both products alone and in combination were safe. No related SAEs were observed in mothers or infants. Nirsevimab was well tolerated, all local and systemic reactogenicity was mild to moderate in severity. RSVpreF vaccination boosted maternal RSV-A nAb titers 17.35-fold at the time of delivery, and titers were durable through 3 months post-delivery. The geometric mean transfer ratio (GMR) of RSV-A nAbs was >1.3 and similar across groups. RSV nAbs were highly elevated in infants at 6 weeks and 3 months, irrespective of group with modest differences in waning.
Conclusions:
Maternal RSVpreF vaccine and infant nirsevimab administration, either alone or in combination, were safe and provided high RSV nAb titers in infants through interim follow-up.
Introduction
RSV is a leading cause of lower respiratory tract disease (LRTD) and hospitalization in infants [1]. In 2023, the FDA approved two products designed to prevent RSV LRTD in all infants: a bivalent, prefusion F protein-based RSV vaccine (RSVpreF, ABRYSVO, Pfizer) administered during pregnancy [2] and a long-acting monoclonal antibody (nirsevimab, BEYFORTUS, AstraZeneca) administered to infants at birth or at the beginning of their first RSV season [3]. In clinical trials, each product demonstrated high efficacy in preventing LRTD caused by RSV in infants [4, 5]. Real-world effectiveness data have also shown that both maternal RSV vaccination [6] and infant nirsevimab immunoprophylaxis [7, 8] are highly effective in preventing RSV LRTD associated with infant hospitalization and severe disease.
To prevent severe RSV disease in infants, the American Academy of Pediatrics (AAP) currently recommends either maternal RSV vaccination or infant immunization with nirsevimab or the recently approved clesrovimab (Enflonsia, Merck) [9, 10]. Most infants do not need protection via both maternal vaccine and infant immunization, although there are certain circumstances when the benefit of administering both products should be considered. These circumstances include infants born <14 days after maternal RSV vaccination; infants born to mothers who may have a suboptimal immune response to vaccination (e.g. persons living with HIV infection); infants with accelerated loss of maternal antibodies, such as infants undergoing cardiopulmonary bypass; and infants with increased risk for severe RSV disease [2]. Infants born to mothers with unknown maternal vaccination history or those who received maternal vaccination during a previous pregnancy should also receive RSV monoclonal antibody. Thus, there is a need to understand the safety and tolerability of exposure to both maternal RSV vaccination and infant monoclonal antibody and to characterize the magnitude and durability of immune responses following exposure to both products. The purpose of this study was to evaluate the safety and immunology of maternal RSV vaccination and infant nirsevimab immunization administered alone or sequentially in mothers and infants. We hypothesized that both products would be safe and that differences in immunogenicity would be observed.
Methods
Trial design and participants
A prospective, randomized, open-label, Phase 4 study was conducted at 8 U.S. sites. Mother-infant pairs were randomized 1:1:1:1 during pregnancy into four groups: Group 1A - maternal RSVpreF vaccine alone; Group 1B - maternal RSVpreF vaccine/infant nirsevimab at birth; Group 1C - maternal RSVpreF vaccine/infant nirsevimab at 3 months; or Group 2 - infant nirsevimab alone at birth. Randomization was performed in blocks by site using the enrollment module of AdvantageEDC software managed by the EMMES Corporation (Rockville, MD, USA). Mothers with uncomplicated singleton pregnancies at 32 0/7 to 36 6/7 weeks gestational age, inclusive, were eligible to enroll. Full eligibility criteria are included in the Supplementary Material. Enrollments occurred from September 19, 2024, through March 28, 2025, and mother-infant pairs remain in follow-up for 12 months after delivery to ascertain safety, infant tolerability, and the magnitude and durability of RSV binding and neutralizing antibodies in mothers and infants. Study visit windows were defined per protocol (Supplementary Figure 1, Supplementary Table 1), and visits substantially out of window were excluded from analysis. The results presented in this report represent an interim analysis of data collected through May 15, 2025, which was the study’s only pre-planned interim analysis and included up to 4-month infant safety follow-up. All maternal participants provided written informed consent for themselves and their infant. This study was approved by Advarra Institutional Review Board and posted on clinicaltrials.gov (NCT06551506) on August 13, 2024.
Data collection
Following enrollment, maternal demographic, clinical, and obstetrical information, concomitant medications, and vaccines were collected through participant questionnaire and baseline blood was collected. Participant race and ethnicity were collected, given known disparities in access to care and outcomes [11, 12]. Eligible participants were randomized, and those in Group 1 received maternal RSVpreF vaccine (Abrysvo™), which was stored, handled, and administered according to the package insert. Upon delivery of the infant, cord blood (or infant blood if cord blood was not available), maternal blood, and optional breast milk samples were collected. Infant demographic information, medical history, pregnancy outcome, neonatal data, concomitant medications, and vaccinations administered within ±7 days of study product were collected through questionnaire or medical chart abstraction. A physical examination was performed, including measurement of infant weight, length, and head circumference. After confirming infant eligibility and maternal consent to continue in the study, infants randomized to groups 1B or 2 received nirsevimab (Beyfortus™) within 7 days of delivery. Infants randomized to Group 1C received nirsevimab on Day 91 (±7 days). Nirsevimab was stored according to the package insert, dosed per weight, and administered intramuscularly. Following nirsevimab administration, solicited local and systemic adverse reactions were collected through 7 days post-immunization. Mothers and infants were seen on Days 43 and 91. At these visits, blood was collected from mothers and infants, and optional breast milk was collected to ascertain antibody responses. Breast milk was not analyzed for this interim analysis but will be included in a future final study report. To limit the number of blood draws, mothers-infant pairs were randomized to have blood collection on either Day 43 or Day 91. Safety phone calls occurred on Days 31 and 121. Maternal serious adverse events (SAEs) were collected through Day 31. Infant medically attended adverse events (MAAEs) and unsolicited, Grade 3 or higher AEs were collected for 30 days following each potential nirsevimab administration (i.e., birth through Day 31 and Day 91 through Day 121). Infant SAEs are being collected through Day 181.
Validated RSV-A and -B microneutralization assays
Validated RSV-A and -B microneutralization assays were performed using collected sera. Heat-inactivated sera were analyzed for neutralizing antibody (nAb) activity against RSV/A/Tracy (GA1 genotype) and RSV/B/18537 (GB1 genotype) in HEp-2 cells as previously described [13, 14] (Supplementary Methods). All nAb titers were normalized based on an internal reference standard and the World Health Organization (WHO) International Standard. The internal reference standard had been benchmarked to the WHO 1st International Standard for Antiserum to RSV [15, 16]. The LLOD of nAb titer in IU/mL was 12.0 and 7.0 against RSV/A/Tracy and RSV/B/18537, respectively. While no threshold of protection against RSV disease has been established, infant nAb titers at delivery in the phase 2 study of RSVpreF vaccine were GMT 28051 IU/mL against RSV-A and 35326 IU/mL against RSV-B [17]. Similarly, infant nAb titers at delivery in the phase 3 trial of nirsevimab had GMT 19737 IU/mL against RSV-A at the earliest time point post-administration (Day 31) [18].
Statistical analyses
The Safety Analysis population included all mother-infant pairs who received either one or both study products. The Primary Immunogenicity population consisted of mother-infant pairs who received study product(s) and had at least one serum sample collected from the infant. Participants were analyzed as treated. This included participants who were treated as randomized, and those who received different treatments from their assigned randomization (Supplementary Methods). Descriptive summaries of the safety data are presented for the Safety Analysis population, while descriptive summaries of immunogenicity data are presented for the Primary Immunogenicity population. Geometric mean titers (GMTs) of serum RSV-A and -B neutralizing antibodies in IU/mL were calculated, along with 95% confidence intervals (CIs), by study group, at each timepoint. The study was not powered for formal statistical comparisons between groups or time points (Supplementary Methods).
Results
Study participants
At the time of interim analysis, 181 mothers had enrolled at 8 U.S. sites, and 180 mothers and 179 infants were included in the safety population (Supplementary Figure 2). The median age of mothers was 32.0 years (interquartile range [IQR] 7.0). years] and median gestational age was 33.3 weeks (IQR 2.0 weeks) at the time of enrollment (Table 1). The median gestational age at the time of delivery was 39.0 weeks (IQR 2.0 weeks) and nearly all infants in Group 1 were born ≥14 days after maternal vaccination (n=129/135, 96%) (Table 2). The baseline characteristics of mothers and infants were similar between groups.
Table 1.
Baseline maternal characteristics.
| Variable | Group 1A: Maternal RSV vaccine alone (n=43) |
Group
1B: Maternal RSV vaccine plus Infant nirsevimab at birth (n=49) |
Group
1C: Maternal RSV vaccine plus Infant nirsevimab at 3 months (n=44) |
Group
2: Infant nirsevimab alone at birth (n=44) |
All participants (n=180) |
|---|---|---|---|---|---|
| Maternal Age in years, Median (IQR) | 32.0 (7.0) | 33.0 (6.0) | 32.0 (6.0) | 34.0 (6.0) | 32.0 (7.0) |
| Gestational at Enrollment, Median (IQR) | 33.3 (2.1) | 33.6 (2.6) | 33.3 (1.4) | 33.2 (1.6) | 33.3 (2.0) |
| Ethnicity, n (%) | |||||
| Not Hispanic or Latino | 35 (81) | 45 (92) | 37 (84) | 40 (91) | 157 (87) |
| Hispanic or Latino | 8 (19) | 4 (8) | 7 (16) | 4 (9) | 23 (13) |
| Race, n (%) | |||||
| American Indian or Alaska Native | 0 (0) | 0 (0) | 1 (2) | 0 (0) | 1 (1) |
| Asian | 3 (7) | 8 (16) | 8 (18) | 7 (16) | 26 (14) |
| Black or African American | 5 (12) | 8 (16) | 6 (14) | 5 (11) | 24 (13) |
| White | 29 (67) | 30 (61) | 29 (66) | 26 (59) | 114 (63) |
| Multi-racial | 3 (7) | 2 (4) | 0 (0) | 6 (14) | 11 (6) |
| Unknown | 3 (7) | 1 (2) | 0 (0) | 0 (0) | 4 (2) |
IQR, interquartile range; RSV, respiratory syncytial virus.
Table 2.
Baseline infant characteristics.
| Variable | Group 1A: Maternal RSV vaccine alone (n=43) |
Group
1B: Maternal RSV vaccine plus Infant nirsevimab at birth (n=48) |
Group
1C: Maternal RSV vaccine plus Infant nirsevimab at 3 months (n=44) |
Group
2: Infant nirsevimab alone at birth (n=44) |
All participants (n=179) |
|---|---|---|---|---|---|
| Gestational Age at Delivery in weeks, Median (IQR) | 39.0 (1.0) | 39.0 (1.0) | 39.0 (1.0) | 39.0 (2.0) | 39.0 (2.0) |
| Birth Weight in kg, Median (IQR) | 3.2200 (0.5950) | 3.3625 (0.6105) | 3.2975 (0.6375) | 3.3150 (0.7400) | 3.2900 (0.6500) |
| Sex, n (%) | |||||
| Male | 21 (49) | 27 (56) | 22 (50) | 21 (48) | 91 (51) |
| Female | 22 (51) | 21 (44) | 22 (50) | 23 (52) | 88 (49) |
| Ethnicity, n (%) | |||||
| Not Hispanic or Latino | 34 (79) | 44 (92) | 34 (77) | 38 (86) | 150 (84) |
| Hispanic or Latino | 8 (19) | 4 (8) | 7 (16) | 5 (11) | 24 (13) |
| Not reported/Unknown | 1 (2) | 0 (0) | 3 (7) | 1 (2) | 5 (3) |
| Race, n (%) | |||||
| Asian | 3 (7) | 7 (15) | 7 (16) | 5 (11) | 22 (12) |
| Black or African American | 6 (14) | 7 (15) | 5 (11) | 8 (18) | 26 (15) |
| White | 25 (58) | 29 (60) | 29 (66) | 22 (50) | 105 (59) |
| Multi-racial | 7 (16) | 4 (8) | 2 (5) | 9 (21) | 22 (12) |
| Unknown | 2 (5) | 1 (2) | 1 (2) | 0 (0) | 4 (2) |
| Days of Delivery Relative to Maternal Vaccination, n (%) | |||||
| < 14 Days | 0 (0) | 4 (8) | 1 (2) | N/A | N/A |
| ≥ 14 Days | 42 (98) | 44 (92) | 43 (98) | N/A | N/A |
| Gestational Age at Delivery, n (%) | |||||
| 32-34 weeks | 0 (0) | 1 (2) | 0 (0) | 2 (5) | 3 (2) |
| 35-37 weeks | 7 (16) | 7 (15) | 6 (14) | 6 (14) | 26 (15) |
| 38-40 weeks | 36 (84) | 39 (81) | 35 (80) | 34 (77) | 144 (80) |
| ≥41 weeks | 0 (0) | 1 (2) | 3 (7) | 2 (5) | 6 (3) |
IQR, interquartile range; kg, kilogram; RSV, respiratory syncytial virus.
Safety and reactogenicity
Overall, both study products were safe, whether administered alone or sequentially. There were no related maternal SAEs in either study group (Supplementary Table 2). For infants, solicited AEs following nirsevimab were mild to moderate and balanced across groups (Groups 1B, 1C, and 2) (Figure 2, Supplementary Table 3). Local adverse reactions occurred in 17% of infants who received nirsevimab, the most common of which were injection site pain/tenderness (13%) and erythema (5%) (Figure 2). Systemic adverse reactions occurred in 60% of infants who received nirsevimab, the most common of which were sleepiness/fatigue (43%) and irritability/crying (43%) (Figure 2). Both local and systemic reactogenicity peaked on Days 1-2 post-nirsevimab immunization. Local reactogenicity was resolved by Day 6 in all infants (Supplementary Figure 3). Mild systemic symptoms varied but appeared to be less common as the week progressed. Moderate solicited systemic symptoms declined in all groups over the 7-day collection period and resolved by Day 7 in all infants (Supplementary Figure 4). Among infants, there were no related unsolicited grade 3 or higher AEs, nor were there related MAAEs or SAEs (Supplementary Table 3, Supplementary Figure 5).
Figure 2.
RSV-A and -B neutralizing antibodies (nAbs) in mothers and infants, geometric mean titers (GMTs) with 95% confidence intervals (CIs) by time point and treatment group, primary immunogenicity population using RSV strains A/Tracy and B/18537. IU/mL, international units per milliliter. LLOD, lower limit of detection.
Immunogenicity
In mothers, bivalent RSVpreF vaccination boosted maternal RSV-A and -B neutralizing antibody titers 17.35-fold (95%CI 14.48, 20.79) and 23.98-fold (95%CI 19.46, 29.54) respectively above baseline enrollment titers at delivery (Figure 3A-3B; Supplementary Figures 6-7; Supplementary Tables 4-5). Maternal RSV-A and -B neutralizing antibody titers of 8547.0 (95%CI 7077.8, 10321.3) and 12185.6 (95%CI 9650.9, 15386.0) IU/mL, respectively, were observed at delivery and remained durable through 3 months. Unvaccinated mothers in group 2 had minimal increases in antibody titers from delivery to 3 months (Supplementary Tables 4-5).
In infants, maternal RSV vaccination resulted in highly elevated RSV-A and B neutralizing antibody titers at birth, with GMTs of 11791.0 (95%CI 9411.0, 14772.9) and 15552.8 (95%CI 11175.5, 21644.5) IU/mL, respectively, in combined groups 1A and 1C (Supplementary Tables 6-7). Antibodies in these infants modestly waned by 3 months of life, although GMTs remained high at 1857.2 (95%CI 1054.6, 3270.5) for RSV-A and 2224.1 (95%CI 1302.2, 3798.6) IU/mL (Figure 3, Supplementary Figures 8-9; Supplementary Tables 6-7).
Compared to infants of mothers who received prenatal vaccination (Group 1A and 1C), infants of mothers who did not receive maternal RSV vaccination (Group 2) had lower RSV-A and -B neutralizing antibody titers at birth (1109.0 (95%CI 823.1, 1494.3) and 1116.1 (95%CI 783.6, 1589.8) IU/mL, respectively. In Group 2, administration of nirsevimab at birth substantially increased RSV antibodies at Day 43, with a geometric mean fold rise (GMFR) of 25.12 (95%CI 13.34, 47.32) to a peak titer of 28980.6 IU/mL (95%CI 20360.1, 41251.0) for RSV-A and GMFR of 7.43 (95%CI 3.73, 14.78) to a peak titer of 7533.6 IU/mL (95%CI 5174.3, 10968.6) for RSV-B. These antibodies were durable through 3 months of life.
Infants in Group 1B, whose mothers received RSV vaccination and who were given nirsevimab at birth, had high RSV antibody titers at delivery that persisted through interim follow-up. At delivery, infants in Group 1B had RSV-A neutralizing antibody titers of 11597.6 IU/mL (95%CI 8550.1, 15731.5), which increased 3.53-fold (95%CI 2.29, 5.42) following nirsevimab administration to a peak of 41052.5 IU/mL (95%CI 33797.2, 47703.0) at 6 weeks of life. These same infants had RSV-B neutralizing antibody titers of 17507.7 IU/mL (95%CI 11348.0, 27010.7) at delivery, which did not substantially increase following nirsevimab administration at 6 weeks of life, with a peak titer of 21505.4 IU/mL (95%CI 13370.5, 34589.8).
The cord-to-maternal ratios (CMR) of RSV-A and -B neutralizing antibodies were similar, regardless of maternal RSV vaccination status or antigen specificity, reflecting efficient transplacental transfer of antibodies from mother to infant. Among those who received maternal RSV vaccination (Group 1), RSV-A and -B CMRs were 1.36 (95%CI 1.18, 1.57) and 1.37 (95%CI 1.15, 1.62). Among those who did not receive maternal RSV vaccination (Group 2), RSV-A and -B CMRs were 1.45 (95% CI 1.25, 1.70) and 1.48 (95%CI 1.23, 1.78) (Table 3).
Table 3.
Cord-to-maternal ratios (CMRs) with 95% confidence intervals (CIs) of RSV-A and -B neutralizing antibodies in mother-infant pairs, primary immunogenicity population.
| RSV/A/Tracy neutralizing antibodies | ||
|---|---|---|
| Statistic | Group 1: Maternal RSV Vaccine (n=114) |
Group 2: No Maternal Vaccine (n=38) |
| Cord Blood IU/mL (GMT) | 11272.5 | 1116.4 |
| (95% CI) | (9379.1, 13548.2) | (815.4, 1528.5) |
| Maternal Serum IU/mL (GMT) | 8283.9 | 767.9 |
| (95% CI) | (6747.0, 10170.9) | (533.5, 1105.3) |
| Transfer Ratio (GMR) | 1.36 | 1.45 |
| (95% CI) | (1.18, 1.57) | (1.25, 1.70) |
| RSV/B/18537 neutralizing antibodies | ||
| Statistic | Group 1: Maternal RSV Vaccine (n=114) |
Group 2: No Maternal Vaccine (n=38) |
| Cord Blood IU/mL (GMT) | 16221.6 | 1108.3 |
| (95% CI) | (12307.9, 21379.9) | (756.8, 1623.2) |
| Maternal Serum IU/mL (GMT) | 11874.1 | 746.8 |
| (95% CI) | (9265.1, 15217.6) | (522.3, 1067.9) |
| Transfer Ratio (GMR) | 1.37 | 1.48 |
| (95% CI) | (1.15, 1.62) | (1.23, 1.78) |
CI, confidence intervals; GMR, geometric mean transfer ratio; GMT, geometric mean titer
IU/mL, international units per milliliter; RSV, respiratory syncytial virus.
Discussion
We performed a prospective, phase 4, open-label, multi-center clinical trial at 8 U.S. sites of mother-infant pairs randomized to receive maternal RSV vaccination, infant nirsevimab immunization, or both products to evaluate safety, infant tolerability, and the magnitude and durability of maternal and infant RSV antibodies. In this interim analysis, we found that both products alone and in combination were safe with no related SAEs observed in mothers or infants. Infants tolerated nirsevimab well, irrespective of study group. All local and systemic reactogenicity events were mild to moderate in severity, with no related grade 3 or higher unsolicited AEs or related MAAEs.
RSV vaccination substantially boosted RSV-A and -B neutralizing antibody titers in mothers, which persisted through 3 months post-delivery. Transplacental transfer of RSV antibodies from mother to infant was high, with CMR >1 irrespective of maternal vaccination status or antigen specificity. Importantly, infant RSV-A and -B neutralizing antibodies were highly elevated following either maternal RSV vaccination, infant nirsevimab immunization, or sequential administration of both products. Following maternal vaccination alone, infants had peak RSV antibody titers at delivery, and these waned modestly by 3 months of life. In contrast, RSV antibody titers among infants in Group 2 substantially increased following nirsevimab administration and persisted through 3 months of life. Although no threshold of protection against RSV disease has been well established, RSV neutralizing and pre-fusion F antibodies are known to correlate with protection against RSV disease in infants and to wane over the first months of life [19-23]. While we observed subtle differences in RSV neutralization titers across groups and time points in our study, antibody titers following maternal vaccination and or infant nirsevimab were similar in magnitude to those observed in the clinical trials of RSVpreF and nirsevimab, which were highly efficacious [17, 18].
The AAP recommends that infants <8 months of age born during or entering their first respiratory virus season receive protection from RSV LRTD through either maternal vaccination or infant RSV monoclonal antibody (nirsevimab or clesrovimab) [3], though each has different advantages. Maternal RSV vaccination, which is bivalent, elicits a response to both RSV-A and RSV-B; may provide benefit both mother and child; offers protection immediately upon birth due to transplacental transfer of RSV antibodies; and may provide ongoing benefit through breast milk secretion of antibodies. Maternal vaccination avoids intramuscular injection in the infant and has been more accessible than RSV monoclonal antibodies to date. Disadvantages of maternal RSV vaccination include the limited timing (September through January) and the narrow gestational window of administration (32 0/7 through 36 6/7 weeks GA). Additionally, while maternal RSV vaccination is expected to confer protection to the infant through the first respiratory season, natural antibodies wane more quickly than monoclonal antibodies containing the stabilizing YTE substitutions [18]. This difference in waning was also observed in our study and may impact durability of protection.
Advantages of infant nirsevimab administration include the reliable delivery of high-titer, long half-life, RSV neutralizing antibodies [3, 18]. The timing of administration can also be optimized to achieve peak effectiveness during the period of maximum exposure, including to certain high-risk infants during their second RSV season. Since the product is administered to the infant, it circumvents the possibility of any complication during pregnancy. Disadvantages of nirsevimab include high cost, which can impede access; supply shortages, such as those encountered during the initial season [24]; potential delays in administration if not dosed in the immediate newborn period; and the small risk of adverse reactions, such as hypersensitivity reactions or development of anti-drug antibodies (ADA) [5, 25]. It is also possible that RSV escape mutants may arise naturally or under selective pressure from an RSV mAb. In studies performed to date, the number of resistant strains detected has been small [26], but viral surveillance is ongoing.
The indications for administering both maternal RSV vaccination and infant nirsevimab immunization are few. Prior studies have demonstrated that this approach is not cost-effective and is not likely needed to protect most infants. In our study, we found that either product alone or in combination provided high titers of neutralizing antibodies to RSV in infants through 3 months of life. The infant nAb titers observed in our study were comparable to those observed in clinical trials of the two products, which have since been found to be highly effective [27, 28]. While modest differences in infant antibody titers, antigen specificity, and waning kinetics were observed in our study, we do not expect these to correspond with substantial differences in protection during these early months of life when infants are at highest risk of severe RSV. Nevertheless, we know that some infants will be exposed to both products, either inadvertently or for one of the clinical indications specified above. Reassuringly, our study found this approach to be safe and well tolerated.
This study has certain limitations. The relatively small sample size limits the ability to detect rare safety outcomes or make formal comparisons between groups. This study enrolled participants who had healthy, singleton pregnancies; this sampling bias could limit applicability to real-world scenarios when both maternal vaccination and infant nirsevimab might be indicated. The study was not designed to ascertain differences in efficacy, and we did not perform surveillance for breakthrough clinical RSV infections. While seroconversion to RSV nucleoprotein will be included in planned analyses as a marker of RSV exposure, this was not included or adjusted for in this interim analysis. Finally, because there is not a universally accepted immune correlate of protection against RSV disease, interpretation of the serologic results limits our ability to extrapolate efficacy. Larger, population-based studies are needed to ascertain differences in real-world effectiveness. Nevertheless, strengths of this study include its prospective, randomized, multi-center study design that reduces bias and improves generalizability.
Conclusions
Maternal RSV vaccination and infant nirsevimab immunization, administered either alone or sequentially, were safe and provided high RSV-A and -B neutralizing antibody titers in infants that persisted through 3 months after delivery. While most infants will not need to receive both products to be protected, our results suggest that maternal RSV vaccination and infant nirsevimab immunization may be safely sequentially administered.
Supplementary Material
Figure 1.
Infant local and systemic reactogenicity following nirsevimab administration in Groups 1B, 1C, and 2 through interim follow-up. Maximum severity of solicited events per infant participant by symptom and treatment group. NR, no reaction.
Article Summary:
This interim analysis of a randomized trial demonstrates the safety and immunology of maternal RSV vaccination, infant nirsevimab immunization, or sequential administration of both products.
What’s Known on This Subject:
Although both maternal RSV vaccination and infant nirsevimab immunization have been approved for the prevention of infant RSV LRTIs, the two products have not been evaluated in a single study, nor has their sequential administration been studied systematically.
What This Article Adds:
Maternal RSVpreF vaccination and infant nirsevimab administration, either alone or in combination, were safe and provided high RSV-A and -B neutralizing antibody titers in both mothers and infants that persisted through 3 months of age.
Acknowledgments
We thank the mothers and infants who generously contributed their time and effort to participate.
We thank the DMID 24-0003 Study Team, including our study staff, coordinators, laboratories, and analysts for their many contributions.
This study was supported by the Infectious Diseases Clinical Research Consortium (IDCRC) through the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH), under award numbers UM1AI148684, UM1AI148575, UM1AI148372, UM1AI148452, UM1AI148574, UM1AI148450, and UM1AI148689. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
The study product nirsevimab was provided by Sanofi & AstraZeneca.
Conflict of Interest Disclosures:
Rebecca C. Brady is the PI for studies sponsored by Pfizer. Funds to perform these studies are provided to her hospital.
James D. Campbell is the PI for studies sponsored by Pfizer, Merck, Sanofi, GSK, and Moderna. Funds to perform those studies are provided to his university.
C. Buddy Creech receives institutional research support from Moderna (completed work) and Pfizer; serves as a consultant to Pfizer, Moderna, GSK, Sanofi, AstraZeneca, Dianthus, Guidepoint Global, and TDCowen; serves as a DSMB member for studies sponsored by GSK and Bavarian Nordic; and receives royalties from UpToDate.
C. Mary Healy has received travel reimbursement from Hillevax and honorarium for a lecture from Healio.
Judith M. Martin is the PI for studies sponsored by Moderna and Vaxcyte. Funds to perform these studies are provided to her university.
Mark Mulligan has received personal fees for board service from Hillevax, Merck, Meissa Vaccines, Sanofi, Pfizer, and GSK.
Jennifer L. Nayak has received grant support for vaccine research awarded to University of Rochester from Pfizer, Moderna, Merck, and Sanofi Pasteur.
Lalitha Parameswaran has received contractual support from Pfizer, Sanofi, and Merck.
Pedro A. Piedra has received institutional research support from Eradivir, Fraizier Life Science, Icosavax, Mapp Biologics, Merck, Novavax, and consulted for Enanta, Gilead, Merck, Pfizer, and Sanofi-Pasteur.
Michael Quinn has received grant support for vaccine research awarded to University of Rochester from Pfizer and Sanofi.
Anne-Marie Rick has received institutional research support from Pfizer, Inc. and has consulted for Pfizer, Inc.
Christina A. Rostad has received institutional research support from Pfizer Inc., Sanofi Pasteur, Janssen, ModernaTX, Inc., Merck & Co., Inc., Novavax, and from the Centers for Disease Control and Prevention and the National Institutes of Health. She is coinventor of patented RSV vaccine technology which has been licensed to Meissa Vaccines, Inc.
The other authors have no conflicts of interest relevant to this article to disclose.
Role of Funder/Supporter:
The NIH participated in the design and conduct of the study and the decision to publish the results. Sanofi and AstraZeneca provided the study product nirsevimab.
Abbreviations:
- ADA
Anti-drug antibodies
- AE
adverse event
- CDC
Centers for Disease Control and Prevention
- CI
Confidence interval
- CPE
Cytopathic effect
- FDA
Food and Drug Administration
- GA
gestational age
- GMFR
Geometric mean fold rise
- GMT
Geometric mean titer
- LLOD
Lower limit of detection
- LRTD
lower respiratory tract disease
- LRTI
lower respiratory tract infectio
- MAAE
Medically attended adverse event
- nAbs
neutralizing antibodies
- NIBSC
National Institute for Biological Standards and Controls
- RSV
respiratory syncytial virus
- RSVpreF
respiratory syncytial virus pre-fusion F vaccination
- SAE
serious adverse events
- WHO
World Health Organization
Footnotes
ClinicalTrials.gov ID: NCT06551506. “The Immunology and Safety of Maternal RSV Vaccination (ABRYSVO), Infant Nirsevimab (BEYFORTUS) Immunization, or Both Products” First posted August 13, 2024.
Data Sharing Statement:
Deidentified individual participant data will not be made available.
References:
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Data Availability Statement
Deidentified individual participant data will not be made available.