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N Engl J Med. Author manuscript; available in PMC 2020 Jul 30.
Published in final edited form as:
N Engl J Med. 2020 Jul 30; 383(5): 426–439.
Published online 2020 Jul 30. doi:10.1056/NEJMoa1908380
PMCID: PMC7299433
PMID: 32726529
Shabir A Madhi,
1,2 Fernando P Polack,3 Pedro A Piedra,4 Flor M Munoz,4 Adrian A Trenholme,5 Eric AF Simoes,6 Geeta K Swamy,7 Khatija Ahmed,8 Abdullah H Baqui,9 Anna Calvert,10 Mark F Cotton,11 Clare L Cutland,12 Janet A Englund,12 Bernard Gonik,13 Laura Hammitt,14 Paul T Heath,10 Joanne N de Jesus,15 Christine E Jones,16 Asma Khalil,17 David W Kimberlin,18 Romina Libster,19 Marilla Lucero,15 Conrado J Llapur,20 Gonzalo Pérez Marc,21 Helen S Marshall,22 Federico Martinón-Torres,23 Terry M Nolan,24 Ayman Osman,8 Kirsten P Perret,25 Peter C Richmond,26 Matthew D Snape,27 Julie H Shakib,28 Tanya Stoney,26 Alan T Tita,29 Michael W Varner,30 Manu Vatish,31 Keith Vrbicky,32 Khalequ Zaman,33 Heather J Zar,34 Jennifer K Meece,35 Joyce S Plested,36 Sapecksh*ta Agrawal,37 Iksung Cho,36 Janice Chen,36 D. Nigel Thomas,38 Judy Wen,38 Amy Fix,39 Allison August,40 Vivek Shinde,36 Gregory M. Glenn,36 and Louis F. Fries36
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Associated Data
- Supplementary Materials
Abstract
Summary of study
A multi-country randomized, placebo-controlled trial of the safety, immunogenicity andefficacy of respiratory syncytial virus (RSV) F-protein nanoparticle vaccine wasundertaken in 4,636 pregnant women and their infants. RSV F-protein vaccine was safe andimmunogenic in the pregnant women inducing anti-F IgG, palivizumab-competing antibodiesand RSV neutralizing antibodies that were transferred to the fetus. Although the primaryendpoint of prevention of RSV-specific medically-significant lower respiratory tractinfection (MS-LRTI) was not met per protocol criteria for efficacy (i.e. 97.52% lowerbound >30%), vaccine efficacy was 39.4% (97.52% CI: -1.0, 63.7%; p=0.0278) ininfants 0-90 days age. Furthermore, there was a 58.8% (95% CI 31.9, 75.0%) lower rate ofRSV LRTI with severe hypoxemia (secondary endpoint) through to 90 days of age in theexpanded intent-to-treat analysis. The number of women needed to be vaccinated toprevent RSV-specific MS-LRTI or LRTI with severe hypoxemia in their infants through to180 days of life were 88 and 82, respectively.
Background
RSV is the dominant cause of severe lower respiratory tract infection (LRTI) ininfants, with most severe disease concentrated in younger-age infants.
Methods
Healthy, pregnant women between 28 and 36 weeks gestation, with expected delivery nearthe start of the RSV season, were randomized to a single intramuscular dose ofnanoparticle RSV F-protein vaccine, or placebo in a 2:1 ratio. Their infants werefollowed for 180 days for medically-significant LRTI (MS-LRTI), LRTI with severehypoxemia and/or LRTI- hospitalization. RSV detection was performed centrally by PCR.Safety evaluation continued until 364 days age.
Results
4,636 women were randomized, with 4,579 live births. Over the first 90 days of life,efficacy against RSV-MS-LRTI was 39.4% (97.52%CI: -1.0, 63.7%; p=0.0278) and 41.4%(95%CI: 5.3, 61.2%) in the per protocol and expanded intent-to-treat (eITT) analyses,respectively. There was a lower rate (efficacy 58.8%; 95%CI 31.9, 75.0% in eITTanalysis; not adjusted for multiplicity) of RSV-LRTI with severe hypoxemia in infants ofvaccinees through 90 days age. Pneumonia reported as a serious adverse events was 49.4%less common in infants of vaccinees (2.6%) than placebo-recipients through 364 daysage.
Conclusions
Maternal vaccination with RSV F-nanoparticle vaccine was safe and immunogenic. Theprespecified primary endpoint success criterion (efficacy 97.5% lower bound ≥30%)was not achieved. However, maternal immunization was associated with reduced risk ofRSV-confirmed MS-LRTI and LRTI with severe hypoxemia in early infancy.
Trial Registration Number
ClinicalTrials.Gov: NCT02624947.
Funding statement
Funded by Novavax, with supporting grant from the Bill and Melinda GatesFoundation.
Keywords: respiratory syncytial virus, efficacy, pregnancy, pneumonia, newborns, infants, phase III trial, immunogenicity, safety, epidemiology, transplacental antibody transfer
Background
Respiratory syncytial virus (RSV) is the dominant cause of lower respiratory tractinfection (LRTI)-related infant hospitalizations. In 2015, an estimated 3.2 millionRSV-associated LRTI hospitalizations occurred worldwide, with 118,000 deaths in childrenunder-5 years of age; 44% and 50% respectively in infants <6 months old1. No licensed RSV vaccine exists, and timelyactive immunization against severe RSV disease in the first 3-6 months of life may bechallenging. Passive immunity via transfer of IgG antibodies from immunized pregnant womenoffers an alternative, and is endorsed by the World Health Organization for tetanus,influenza and pertussis prevention in infants2-4. Passive immunity conferredby palivizumab, a monoclonal antibody to RSV fusion (F) protein site-II epitope, reducesRSV-LRTI hospitalization in premature infants, and those with chronic lung disease orcongenital heart disease5. Similarly,motavizumab (an experimental higher-potency palivizumab-like monoclonal antibody) reducedthe risk for RSV LRTI hospitalization by 87% in Navajo infants born at term6.
Vaccination of pregnant women with recombinant RSV F-nanoparticle vaccine (RSV-F vaccine)was well-tolerated in a phase 2 trial, and elicited RSV A and B neutralizing antibodies,antibodies to RSV F-protein site-II epitope (palivizumab-competitive antibody, PCA), andother epitopes with broadly-neutralizing activity; and these were efficiently transferred tothe infants7.
We describe results of a Phase 3 trial evaluating the safety and immunogenicity of RSV-Fvaccine in pregnant women and vaccine efficacy (VE) against RSV-associated LRTI among theirinfants from birth through to 90-180 days of life.
Methods
Study design
A randomized, observer-blind, placebo-controlled trial was undertaken at 87 sites inArgentina, Australia, Chile, Bangladesh, Mexico, New Zealand, Philippines, South Africa,Spain, United Kingdom and United States of America (USA). Healthy women 18 to 40 years oldwith singleton pregnancies were injected between 280/7 and 366/7 weeks gestational age (GA), prior to anticipated circulation of RSV intheir locale (see Supplementary text 1.1). Inclusion and exclusion criteria are summarizedin Supplementary text 1.2 and treatment randomization is detailed in Supplementary text1.3 (full protocol is available in Supplement 4).
Study-staff conducted weekly active surveillance with mothers/caregivers until 180 daysafter delivery (Supplementary text 1.4) for detection of LRTI symptoms. Evaluation for RSVillnesses could also be triggered by spontaneous medical-care seeking by the parent.Infant evaluation included physical examination, respiratory rate determination, and pulseoximetry using a sponsor-provided RAD-5® pulse oximeter (Masimo, Irvine,California, USA). Nasal swabs were obtained using a nasal FLOQSwab™ (CopanDiagnostics, Murrieta, California, USA), placed into Universal Transport Medium, stored at-70°C, and shipped to the Marshfield Clinic Research Institute (Wisconsin, USA),where the validated GenMark eSensor RVP multiplex assay (Carlsbad, California, USA) wasused for molecular viral diagnosis.
Immunogenicity and safety evaluations are detailed in Supplementary texts 1.5 and 1.6.RSV serology included serum anti-F IgG concentrations, antibodies competitive withpalivizumab (PCA), and RSV/A and B microneutralization titers reported in InternationalUnits (IU) (completed only in a subset to date) as described7.
Study objectives
The primary objective was demonstration of vaccine efficacy (VE) of maternal immunizationwith RSV F-protein vaccine in protecting infants against RSV medically-significant LRTI(RSV-MS-LRTI) through 90 days of life Secondary objectives were evaluation of VE againstRSV-LRTI with severe hypoxemia and RSV-LRTI with hospitalization through 90 days of life;endpoint definitions are detailed in Supplementary text 1.7. For the primary and secondaryobjectives, in the event that VE was demonstrated through the first 90 days of life, ahierarchical sequence of hypothesis tests was to be carried out to examine VE through to120, 150, and 180 days of life. Detail of other secondary (including safety andimmunogenicity), as well exploratory (e.g. differences in rates of all-cause LRTIendpoints) and post-hoc analysis (comparison of high income [HIC] and low-middle incomecountries [LMIC] for primary, secondary and exploratory LRTI endpoints) is available insupplementary text 1.8 and protocol (supplement 4). Participating countries wereclassified as LMIC and HIC per World Bank ranking8.
Ethics
The protocol was reviewed and approved by regulatory authorities in all countries; and byethical review committees for all sites. All participants provided written informedconsent. An independent Data and Safety Monitoring Board (DSMB) monitored safety in anunblinded manner throughout active enrolment.
Randomization and Conduct
Enrolment of up to 8,618 pregnant women was planned, based on a projected primaryendpoint attack rate of 4% and efficacy of approximately 60%. Randomization was at sitelevel, and stratified by age (18 to < 29, 29 to 40 years, Supplementary text 1.3).Women were randomized 1:1 to vaccine (120 μg RSV-F protein adsorbed to 0.4 mgaluminium)10 or placebo (formulation buffer without aluminium) in the firstglobal RSV season; and 2:1 thereafter. Enrolment proved slower than planned, and after twoyears the sponsor elected to perform an informational analysis via the externalstatistician supporting the DSMB. The informational analysis was, in effect, a stringentfutility analysis which determined whether the trial would go forward. This analysisindicated that efficacy was present at a pre-specified minimum level (≥40%), withno other information provided to the sponsor. Based on this, enrolment was continued for afurther Northern and Southern Hemisphere season. At that point, the sponsor terminatedenrolment because it was believed that sufficient cases had been captured to test thehypothesis. Endpoints accrued following the data-lock for the futility analysis wereincluded in the final VE analysis. Although the final VE results for RSV-MS-LRTI fell wellwithin the 95% confidence interval (95%CI) about the point estimate at the informationalanalysis, they did not eventually meet the success criterion of 97.52% CI of≥30%.
Statistical analysis
The trial was planned as a group-sequential design with up to two interim analyses. Thiswas superceded by the informational analysis above, then a final analysis triggered afterenrolment in the active group exceeded the 3,000 minimum requested by regulatoryauthorities.
Primary and secondary VE analyses used the Per-Protocol (PP) population, as agreed withregulatory authorities (Supplementary text 1.9 for rationale), and considered data fromobservations by trained site staff, pulse oximetry using the sponsor-provided device, andRSV diagnosis performed by the central laboratory. Analyses concerning the exploratoryendpoints used these same elements, supplemented with data extracted from records ofinfants hospitalized for respiratory or infectious diagnoses (“expandeddata”). All primary, secondary, and key exploratory endpoints were validated by anindependent adjudication committee of three pediatricians before unblinding. VE estimateswere based on the relative risk and its confidence interval (CI) obtained from Poissonregression with robust error variance.11 As agreed upon with the regulatoryauthorities, the reported VE confidence intervals for secondary, exploratory and post-hocanalyses were not adjusted for multiplicity; and hence cannot be used to robustly infereffects.
VE against the primary endpoint, RSV-MS-LRTI between 0-90 days of age, was analysed usinga one-sided Type I error rate of 0.0124 (i.e., lower bound of a two-sided 97.52%CI). ThisType I error rate originated from the original group sequential design, but was retainedto guard against Type I error inflation after the decision was made to stop the trial.Success in the primary objective required exclusion of VE <30% for the US Food andDrug Administration, and ≤0% for other authorities. All other analyses used a 95%CIand a success criterion of exclusion of lower-bound of ≤0% (without adjusting formultiplicity). These further analyses were to be performed in a hierarchical sequenceconsidering efficacy from delivery through 120, 150, and 180 days of life (with eachanalysis enabled by a significant result at the preceding interval). Supportive analyseswere based on the intent-to-treat (ITT) population involving all live births with anyefficacy data (i.e. expanded ITT analyses; eITT); including preterm births andirrespective of timing of birth in relation to maternal randomization.“All-cause’’ VE was evaluated in infants meetingthe exploratory endpoint criteria, irrespective of detection of a specific pathogen
RESULTS
Between 03 December 2015 and 02 May 2018, 4,636 women were enrolled, including 3,051(65.8%) randomized to RSV-F vaccine; Figure 1.Fifty-two percent were enrolled in South Africa and 23.3% in USA; Figure 1, Table S1. There were 4,579 live births; 4,195 (91.8%) and4,527 (99.0%) were included in the PP and ITT populations, respectively. The mean GA atbirth was 39.3 weeks, and 5.9% (n=271) of births occurred at <37 weeks GA. The meanbirth weight was 3.20 (S.D. 0.49) Kg (Table 1).There were no meaningful differences in demographic or baseline characteristics of women orinfants between treatment groups, including when stratified by HIC or LMIC settings; (Table 1, Tables S2, S3).
Table 1
Demographic characteristics of women randomized, and birth characteristics of theirinfants.
| Maternal Participants | Placebo N = 1582 | RSV F Vaccine N = 3047 | Overall N = 4629 |
|---|---|---|---|
| Maternal age [years], mean (SD) | 26 (5.2) | 26 (5.3) | 26 (5.2) |
| Race, White, n (%) | 489 (30.9) | 903 (29.6) | 1392 (30.1) |
| Black or African American, n (%) | 683 (43.2) | 1337 (43.9) | 2020 (43.6) |
| Asian, n (%) | 168 (10.6) | 320 (10.5) | 488 (10.5) |
| Other, n (%) | 204 (12.9) | 416 (13.7) | 620 ( 13.4) |
| Hispanic/Latina, n (%) | 212 (13.4) | 409 (13.4) | 621 (13.4) |
| BMI [kg/m2], mean (SD) | 28.5 (5.1) | 28.6 (5.0) | 28.5 (5.1) |
| Primigravida, n (%) | 525 (33.2) | 1060 (34.8) | 1585 (34.2) |
| ≤ 3 prior pregnancies, n (%) | 1516 (95.8) | 2918 (95.8) | 4434 (95.8) |
| Gestational age at treatment [weeks], mean (SD) | 32 (2.6) | 32 (2.6) | 32 (2.6) |
| Interval from treatment to delivery [days], mean (SD) | 51.3 (20.75) | 51.9 (20.38) | 51.7 (20.51) |
| < 14 days, n (%) | 36 (2.3) | 50 (1.7) | 86 (1.9) |
| 14 to < 30 days, n (%) | 216 (13.8) | 437 (14.5) | 653 (14.3) |
| ≥ 30 days, n (%) | 1310 (83.9) | 2523 (83.8) | 3833 (83.8) |
| Delivery1:vagin*l2, n (%) | 1133 (72.1) | 2203 (72.7) | 3336 (72.5) |
| Caesarean section3, n (%) | 423 (26.9) | 806 (26.6) | 1229 (26.7) |
| Infant Participants | N = 1562 | N = 3010 | N = 4572 |
| Male, n (%) | 799 (51.2) | 1557 (51.7) | 2356 (51.5) |
| Gestational age at delivery [weeks], mean (SD) | 39.3 (1.58) | 39.3 (1.49) | 39.3 (1.52) |
| ≥ 37 weeks, n (%) | 1459 (93.4) | 2813 (93.5) | 4272 (93.4) |
| < 37 weeks, n (%) | 96 (6.1) | 175 (5.8) | 271 (5.9) |
| Infant birth weight [kg], mean (SD) | 3.20 (1.5, 6.8) | 3.20 (1.4, 5.5) | 3.20 (1.4, 6.8) |
| Infant birth length [cm], mean (SD) | 50.16 (3.14) | 50.04 (2.92) | 50.08 (3.00) |
| Frontal-occipital circumference [cm], mean (SD) | 34.2 (1.77) | 34.2 (2.08) | 34.2 (1.98) |
| APGAR scores at 1 minute, median (IQR) | 9 (8, 9) | 9 (8, 9) | 9 (8, 9) |
| APGAR scores at 5 minutes, median (IQR) | 10 (9, 10) | 10 (9, 10) | 10 (9, 10) |
| Smoker in the home, n (%) | 414 (26.5) | 755 (25.1) | 1169 (25.6) |
| Children < 5 years of age in household at Day 180, n (5) | 600 (38.4) | 1167 (38.8) | 1767 (38.6) |
| Children < 5 years in household at group care ≥ 3days/week at Day 180, n (%) | 360 (23.0) | 689 (22.9) | 1049 (22.9) |
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BMI = body mass index; SD = standard deviation; IQR = interquartile range.
1Delivery type percentages are based on the count of subjects with deliverydata (approximately 99.5% of all subjects in both high and low/middleincome countries), and thus differ marginally from percentages based on the columnheader.
2vagin*l deliveries include spontaneous vagin*l deliveries or forceps or vacuumassisted deliveries.
3Caesarean deliveries include planned repeat and primary procedures, Caesarean sectionafter failed attempts at vagin*l delivery, and emergent procedures. Emergent Caesareandeliveries accounted for 6.5% of all deliveries in high income countries, but 14.5% inlow/middle countries, but with no vaccine treatment effect in either economicstratum.
Figure 1
Consort diagram on screening, enrolment and disposition of subjects.
The maternal safety population included all maternal subjects who received any testarticle. Infant safety population was all infants born live to maternal subjects whor*ceived any test article.
The per-protocol efficacy population for maternal subjects was all maternal subjectswho received the test article and regimen to which they were randomized and had at leastone post-treatment encounter documented during which active and/or passive surveillanceactivities for RSV-suspect illness could occur, and had no major protocol deviationsaffecting the primary efficacy outcomes as determined and documented by Novavax prior todatabase lock and unblinding.
The per-protocol efficacy population for infant subjects included all infant subjectswho: a) were ≥ 37 weeks gestational age at birth, b) were born to maternalsubjects who received a study injection as randomized and ≥ 2 weeks prior todelivery, c) had not received prophylactic treatment with palivizumab between birth andDay 180 after delivery, d) had at least one post-partum contact during which activeand/or passive surveillance activities for RSV-suspect illness could occur, and e) hadno major protocol deviations affecting the primary efficacy outcomes as determined anddocumented by Novavax prior to database lock and unblinding.
The intent-to-treat efficacy population included all maternal subjects and theirinfants in the Safety Population for whom at least one post-treatment and post-partum,respectively, efficacy measurement was available for both the mother and the infant asevidenced by collection of surveillance observations.
Safety
RSV-F vaccine was well-tolerated. Local reactogenicity, predominantly mild, was morefrequent among vaccine than placebo recipients (57.0% vs. 41.3%; p<0.0001);systemic reactogenicity was similar in the two groups; including rates of fever withinseven days of vaccination (1.2% in vaccinees; 1.6% in placebo recipients, p=0.346). Therewere no statistically-significant differences between treatment groups in prespecifiedadverse events of special interest, including delivery outcomes (Table 2).
Table 2
Safety profile among maternal and infant participants1
| Counts (%) of Maternal Participants with Adverse Events(AEs) – through 180 days post delivery | |||
|---|---|---|---|
| Event | Placebo (N = 1582) | RSV F Vaccine (N = 3047) | Total (N = 4629) |
| Any treatment-emergent AEs | 1204 (76.1) | 2501 (82.1) | 3706 (80.1) |
| Solicited AEs (reactogenicity w/i 7 days of dose) | 653 (41.3) | 1738 (57.0) | 2391 (51.7) |
| Local solicited AEs (injection site) | 157 (9.9) | 1241 (40.7) | 1398 (30.2) |
| Severe local solicited AEs | 3 (0.2) | 21 (0.7) | 24 (0.5) |
| Systemic solicited AEs | 611 (38.6) | 1256 (41.2) | 1867 (40.3) |
| Severe systemic solicited AEs | 42 (2.7) | 79 (2.6) | 121 (2.6) |
| Fever (any severity) | 25 (1.6) | 37 (1.2) | 62 (1.3) |
| Fever (severe, >38.9°C) | 10 (0.6) | 6 (0.2) | 16 (0.3) |
| Unsolicited AEs | 1022 (64.6) | 2005 (65.8) | 3027 (65.4) |
| Severe2 unsolicited AEs | 203 (12.8) | 382 (12.5) | 585 (12.6) |
| Severe-related3 unsolicited AEs | 4 (0.3) | 2 (< 0.1) | 6 (0.1) |
| Medically-attended AEs | 802 (50.7) | 1535 (50.4) | 2337 (50.5) |
| Serious4 AEs | 455 (28.8) | 904 (29.7) | 1359 (29.4) |
| Serious AEs with outcome of death (through day 180post-partum) | 0 (0) | 2 (<0.1) | 2 (<0.1) |
| Protocol-specified AESIs5 | 190 (12.0) | 377 (12.4) | 567 (12.2) |
| Pregnancy and delivery outcomes | |||
| New or worsened gestational diabetes | 5 (0.3) | 5 (0.2) | 10 (0.2) |
| Gestational hypertension | 65 (4.1) | 141 (4.6) | 206 (4.4) |
| Pre-eclampsia | 42 (2.7) | 72 (2.4) | 114 (2.5) |
| Eclampsia | 6 (0.4) | 6 (0.2) | 12 (0.3) |
| Hemolytic, elevated liver enzyme and low plateletsyndrome | 0 (0.0) | 1 (< 0.1) | 1 (< 0.1) |
| Premature rupture of membranes | 35 (2.2) | 75 (2.5) | 110 (2.4) |
| Premature delivery or premature baby | 90 (5.7) | 174 (5.7) | 264 (5.7) |
| Stillbirth or fetal death | 9 (0.6) | 15 (0.5) | 24 (0.5) |
| Third trimester hemorrhage, incl. placenta praevia | 8 (0.5) | 14 (0.5) | 22 (0.5) |
| Placental abruption | 7 (0.4) | 12 (0.4) | 19 (0.4) |
| Post-partum hemorrhage | 30 (1.9) | 49 (1.6) | 79 (1.7) |
| Maternal fever or infection | 17 (1.1) | 17 (0.6) | 34 (0.7) |
| Chorioamnionitis | 17 (1.1) | 25 (0.8) | 42 (0.9) |
| Counts (%) of Infant Participants with AdverseEvents (AEs) – through 364 days of life | |||
| Event | Placebo (N = 1562) | RSV F Vaccine (N = 3010) | Total (N = 4572) |
| All treatment-emergent AEs | 1291 (82.7) | 2468 (82.0) | 3759 (82.2) |
| Severe AEs | 130 (8.3) | 229 (7.6) | 359 (7.9) |
| Severe-related3 AEs | 0 (0) | 0 (0) | 0 (0) |
| Medically-attended AEs | 1088 (69.7) | 2043 (67.9) | 3131 (68.5) |
| Serious AEs4 | 724 (46.4) | 1332 (44.3) | 2056 (45.0) |
| Serious AEs with outcome of death (through day 364days oflife) | 12 (0.8) | 17 (0.6) | 29 (0.6) |
| Protocol-specified AESIs4 | 151 (9.7) | 274 (9.1) | 425 (9.3) |
| Low birth weight (<2500 grams) | 98 (6.3) | 149 (5.0) | 247 (5.4) |
| Small for gestational age (small for dates) | 72 (4.6) | 151 (5.0) | 223 (4.9) |
| Intrauterine growth restriction | 7 (0.4) | 16 (0.5) | 23 (0.5) |
| Neonatal asphyxia | 10 (0.6) | 15 (0.5) | 25 (0.5) |
| Hypoxic-ischemic/encephalopathy | 7 (0.4) | 12 (0.4) | 19 (0.4) |
| Neonatal encephalopathy | 1 (<0.1) | 7 (0.2) | 8 (0.2) |
| Sudden infant death syndrome | 1 (< 0.1) | 3 (< 0.1) | 4 (< 0.1) |
| Serious AEs coded as pneumonia (all-cause, 0-364 days of life) | 70 (4.5) | 64 (2.1) | 134 (2.9) |
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AE = adverse event after treatment; AESI = adverse event of special interest; n =number of participants with an event; N = total participants evaluated.
1Data in this table represent analyses through 180 day of post-partum follow-up formaternal subjects, and 364 days of life for infant subjects; with analyses generatedfrom data included in a database update as of 9 July 2019. The safety databaseremained open as of this tabulation. Therefore, some entries in this table mightchange in final analyses as presented in the final clinical study report.
2Severe AEs are those that substantially prevent normal daily activities.
3Severe and related AEs are severe AEs that the clinical investigators assess as atleast possibly related to test article.
4Serious AEs are those that are fatal, life threatening, cause or prolonghospitalization, lead to persistent disability, or are congenital anomalies or birthdefects. In this study, all congenital anomalies, regardless of how minor, weretreated as serious AEs.
5Protocol-defined AESIs were pregnancy and puerperium AEs reflecting the BrightonCollaboration taskforces recommendations on safety data collection for maternalimmunization. (Munoz FM et al. Vaccine. 2015;33:6441-52).
The overall rates of serious AEs were similar among infants of placebo (46.4%) and RSV-Fvaccine (44.3%) recipients; including low birth weight (6.3% vs. 5.0%), small for dates(4.6% vs. 5.0%), and intrauterine growth restriction (0.4% vs. 0.5%); Table 2. Infant SAEs occurring in ≥1% of theactive vaccine group or with imbalances yielding a p-value <0.1 are shown in TableS4. There was a 49.4% lower rate of serious adverse event reports coded as pneumonia ininfants born to RSV-F vaccine (2.6%) compared to placebo recipients (5.1%) through 364days; Table 2 and Supplementary Table S4.
Immunogenicity
Vaccination with RSV-F vaccine resulted in a geometric mean fold rise (GMFR) of 12.39(95%CI: 11.98, 12.81) for PCA and 18.59 (95%CI: 17.84, 19.36) for anti-F IgG 14 days afterinjection, the observed timing of peak levels in phase 27,9. RSV/A andRSV/B MN IU titer GMFRs were 2.35 (95% CI: 2.06, 2.68) and 3.00 (95% CI 2.56, 3.51) at thesame timepoint based on currently available preliminary data. RSV antibodies in womenshowed a transient decrease at delivery, rebounded at day 35 post-partum, then declined atday 180 post-partum; Table 3.
Table 3
Immune response to RSV F-protein vaccine in pregnant women and kinetics of antibodiesamong maternal and infant participants, per-protocol immunogenicity population.
| Parameter: | Palivizumab competing antibody | Anti-F IgG | RSV/A micro-neutralization titer | RSV/B micro-neutralization titer | ||||
|---|---|---|---|---|---|---|---|---|
| Timepoint, Endpoint | Placebo | RSV F Vaccine | Placebo | RSV F Vaccine | Placebo | RSV F Vaccine | Placebo | RSV F Vaccine |
| Screening (-28 - 0) – mother, n | 1446 | 2776 | 1446 | 2776 | 489 | 879 | 489 | 878 |
| GMC/GMEU/GMT (95% CI) | 13 (13, 14) | 13 (13, 13) | 569 (545, 594) | 568 (551, 586) | 741 (691, 794) | 714 (677. 753) | 605 (552, 664) | 563 (525, 605) |
| Day 14 (± 2 days) – mother, n | 1370 | 2643 | 1370 | 2642 | 92 | 94 | 92 | 94 |
| GMC/GMEU/GMT (95% CI) | 13 (12, 13) | 162 (158, 167) | 563 (539, 587) | 10568 (10250, 10897) | 654 (565, 756) | 1622 (1384, 1900) | 845 (670,1066) | 2419 (1934, 3025) |
| GMFR (95%CI) | 0.94 (0.92, 0.96) | 12.39 (11.98, 12.81) | 0.99 (0.97, 1.02) | 18.59 (17.84, 19.36) | 0.98 (0.92, 1.05) | 2.35 (2.06, 2.68) | 0.96 (0.88, 1.04) | 3.00 (2.56, 3.51) |
| Delivery – mother, n | 1446 | 2776 | 1446 | 2776 | 489 | 879 | 489 | 879 |
| GMC/GMEU/GMT (95% CI) | 12 (12, 13) | 130 (127, 133) | 525 (504, 547) | 8165 (7945, 8391) | 663 (616, 713) | 1589 (1488, 1654) | 534 (487, 586) | 1213 (1138, 1293) |
| GMFR (95%CI) | 0.92 (0.90, 0.94) | 9.94 (9.64, 10.25) | 0.92 (0.90, 0.95) | 14.37 (13.86, 14.90) | 0.89 (0.86, 0.93) | 2.20 (2.10, 2.30) | 0.88 (0.84, 0.93) | 2.15 (2.06, 2.25) |
| CCord blood – infant, n | 1337 | 2547 | 1343 | 2557 | 424 | 759 | 423 | 758 |
| GMC/GMEU/GMT (95% CI) | 15 (14, 15) | 136 (132, 139) | 752 (719, 785) | 9501 (9224, 9787) | 732 (674, 796) | 1704 (1602, 1813) | 607 (544,678) | 1291 (1198, 1392) |
| Cord to maternal ratio, n | 1316 | 2508 | 1322 | 2517 | 421 | 752 | 420 | 751 |
| Cord to maternal ratio | 1.18 (1.15, 1.22) | 1.04 (1.02, 1.06) | 1.43 (1.38, 1.47) | 1.17 (1.14, 1.19) | 1.12 (1.07, 1.18) | 1.08 (1.04, 1.13) | 1.14 (1.08, 1.20) | 1.07 (1.03, 1.12) |
| Half-life in infants | 192.16 (150.85, 264.64) | 49.11 (47.94, 50.34) | 116.73 (97.28, 145.90) | 38.33 (37.47, 39.22) | 39.76 (37.50, 42.31) | 34.46 (33.28, 35.73) | 37.79 (32.48, 45.19) | 31.31 (27.87, 35.72) |
| R2 | 0.0615 | 0.5298 | 0.0854 | 0.5551 | 0.5213 | 0.6289 | 0.4370 | 0.5881 |
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CI = confidence interval; GMC = geometric mean concentration; GMEU = geometric meanELISA units; GMFR = geometric mean fold rise; GMT = geometric mean titer; n =participants analyzed per timepoint; PCA= palivizumab-competitive antibodies; SCR =seroconversion rate.
The per-protocol immunogenicity population (PP-IMM) was the primary population usedfor immunogenicity analyses.
The PP-IMM for maternal subjects was all maternal subjects who received the testarticle and regimen to which they were randomized, provided baseline and delivery(up to 72 hours post-delivery) serology data, and had no major protocol deviationsaffecting the primary immunogenicity outcomes as determined and documented byNovavax prior to database lock and unblinding.
The PP-IMM for infant subjects was all infant subjects who: a) were ≥ 37weeks gestational age at birth, b) were born to maternal subjects who received astudy injection as randomized and ≥ 2 weeks prior to delivery, c) hadprovided a cord blood specimen (or infant blood sample by venipuncture or heel stickwithin 72 hours of delivery as an acceptable substitute), d) had not receivedprophylactic treatment with palivizumab between birth and Day 180 after delivery,and e) had no major protocol deviations affecting the primary immunogenicityoutcomes as determined and documented by Novavax prior to database lock andunblinding.
PCA was measured in terms of GMC (μg/mL). Anti-F IgG was measured in termsof geometric means ELISA units. RSV microneutralization titers measured inInternational Units (IU).
Newborn infants of RSV F-protein vaccinees had higher RSV antibody levels than those ofplacebo-recipients. The cord blood to maternal antibody ratio at delivery in the RSV Fvaccine arm were 1.04 (95% CI: 1.02 to 1.06) for PCA and 1.17 (95% CI: 1.14 to 1.19) foranti-F IgG. The estimated half-life of antibody in infants born to RSV F vaccinerecipients were 49.1 and 38.3 for PCA and anti-F IgG, respectively; Table 3.
Transplacental antibody transfer was marginally lower in LMIC than HIC mother-infantdyads in the vaccinated group for PCA (1.02 vs 1.08) and anti-F IgG (1.12 vs. 1.23);although the mean antibody levels in the women were the same at delivery. This wascorrespondingly associated with slightly lower anti-F IgG geometric mean ELISA units(9,138 vs. 10,087) in infants of RSV-F vaccinees in LMIC than HIC for, whilst PCAgeometric mean concentration (133 vs. 139 µg/mL) were similar; Supplementary TableS5.
Efficacy against RSV illness outcomes
Efficacy is presented in Table 4 and Figure 2 a-c for the primary and secondary RSV LRTIendpoints. Exploratory endpoints based on the same definitions but using the ITTpopulation (Supplementary Table S6) and expanded datasets (eITT analyses) are provided inTable 4. The PP and eITT analyses weremutually supportive.
Table 4
Per-protocol and expanded intent-to-treat analyses of maternal vaccination efficacyagainst lower respiratory tract infection (LRTI) in infants born to pregnant womenvaccinated with RSV F vaccine or placebo.
| Per-Protocol Population Analyses* | Expanded Intent-to-Treat Population Analyses** | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Efficacy Endpoint: | Placebo | Vaccine | VE (%) | 95% CI† | Placebo | Vaccine | VE (%) | 95% CI† | NNV‡ |
| Medically-significant RSV LRTI ( see footnotesfor definition) | |||||||||
| Day 0 to 90, % (n/N) | 2.45 (35/1430) | 1.48 (41/2765) | 39.4 | 5.3 to 61.2† (97.52% CI: -1.0 to 63.7) | 4.01 (62/1547) | 2.35 (70/2980) | 41.4 | 18.0 to 58.1† (97.52% CI: 12.7 to 60.6) | 60 |
| Day 0 to 120, % (n/N) | 2.87 (41/1430) | 1.88 (52/2765) | 34.4 | 1.7 to 56.2 | 4.46 (69/1547) | 2.92 (87/2980) | 34.5 | 10.8 to 52.0 | 65 |
| Day 0 to 150, % (n/N) | 3.01 (43/1430) | 2.06 (57/2765) | 31.4 | -1.3 to 53.6 | 4.59 (71/1547) | 3.26 (97/2980) | 29.1 | 4.3 to 47.5 | 75 |
| Day 0 to 180, % (n/N) | 3.01 (43/1430) | 2.21 (61/2765) | 26.6 | -7.8 to 50.1 | 4.59 (71/1547) | 3.46 (103/2980) | 24.7 | -1.3 to 44.0 | 88 |
| RSV LRTI with hospitalization (see footnotes fordefinition) | |||||||||
| Day 0 to 90, % (n/N) | 3.71 (53/1430) | 2.06 (57/2765) | 44.4 | 19.6 to 61.5 | 4.07 (63/1547) | 2.18 (65/2980) | 46.4 | 24.7 to 61.9 | 53 |
| Day 0 to 120, % (n/N) | 3.92 (56/1430) | 2.31 (64/2765) | 40.9 | 15.9 to 58.5 | 4.33 (67/1547) | 2.52 (75/2980) | 41.9 | 19.7 to 58.0 | 55 |
| Day 0 to 150, % (n/N) | 3.99 (57/1430) | 2.42 (67/2765) | 39.2 | 14.0 to 57.7 | 4.40 (68/1547) | 2.68 (80/2980) | 38.9 | 16.1 to 55.5 | 58 |
| Day 0 to 180, % (n/N) | 4.13 (59/1430) | 2.46 (68/2765) | 40.4 | 16.0 to 57.7 | 4.52 (70/1547) | 2.79 (83/2980) | 38.4 | 15.9 to 54.9 | 58 |
| RSV LRTI with severe hypoxemia (see footnotesfor definition) | |||||||||
| Day 0 to 90, % (n/N) | 0.98 (14/1430) | 0.51 (14/2765) | 48.3 | -8.2 to 75.3 | 2.20 (34/1547) | 0.91 (27/2980) | 58.8 | 31.9 to 75.0 | 78 |
| Day 0 to 120, % (n/N) | 1.12 (16/1430) | 0.58 (16/2765) | 48.3 | -3.1 to 74.1 | 2.39 (37/1547) | 1.04 (31/2980) | 56.5 | 30.2 to 72.9 | 74 |
| Day 0 to 150, % (n/N) | 1.19 (17/1430) | 0.61 (17/2765) | 48.3 | -1.0 to 73.5 | 2.46 (38/1547) | 1.14 (34/2980) | 53.6 | 26.5 to 70.6 | 76 |
| Day 0 to 180, % (n/N) | 1.19 (17/1430) | 0.69 (19/2765) | 42.2 | -10.9 to 69.9 | 2.46 (38/1547) | 1.24 (37/2980) | 49.5 | 20.8 to 67.7 | 82 |
| All-cause medically-significant LRTI | |||||||||
| Day 0 to 90, episodes /100 infants (n/N) | 7.20 (103/1430) | 5.53 (153/2765) | 23.2 | 1.4 to 40.2 | 7.50 (116/1547) | 5.87 (175/2980) | 21.7 | 1.0 to 38.1 | 61 |
| Day 0 to 120, episodes /100 infants (n/N) | 9.58 (137/1430) | 7.34 (203/2765) | 23.4 | 4.8 to 38.3 | 9.76 (151/1547) | 7.82 (233/2980) | 19.9 | 1.7 to 34.7 | 52 |
| Day 0 to 150, episodes /100 infants (n/N) | 11.12 (159/1430) | 8.82 (244/2765) | 20.6 | 3.1 to 35.0 | 11.25 (174/1547) | 9.30 (277/2980) | 17.4 | 0.1 to 31.6 | 51 |
| Day 0 to 180, episodes /100 infants (n/N) | 12.24 (175/1430) | 9.76 (270/2765) | 20.2 | 3.5 to 34.0 | 12.41 (192/1547) | 10.20 (304/2980) | 17.8 | 1.5 to 31.4 | 45 |
| All-cause LRTI with hospitalization | |||||||||
| Day 0 to 90, episodes /100 infants (n/N) | 6.01 (86/1430) | 4.34 (120/2765) | 27.8 | 4.8 to 45.3 | 6.59 (102/1547) | 4.19 (125/2980) | 36.4 | 17.4 to 51.0 | 42 |
| Day 0 to 120, episodes /100 infants (n/N) | 6.85 (98/1430) | 4.99 (138/2765) | 27.2 | 5.7 to 43.8 | 7.50 (116/1547) | 4.87 (145/2980) | 35.1 | 17.2 to 49.2 | 38 |
| Day 0 to 150, episodes /100 infants (n/N) | 7.62 (109/1430) | 5.61 (155/2765) | 26.5 | 6.0 to 42.4 | 8.34 (129/1547) | 5.50 (164/2980) | 34.0 | 16.9 to 47.6 | 35 |
| Day 0 to 180, episodes /100 infants (n/N) | 8.18 (117/1430) | 6.11 (169/2765) | 25.3 | 5.4 to 41.0 | 8.86 (137/1547) | 6.01 (179/2980) | 32.2 | 15.3 to 45.7 | 35 |
| All-cause LRTI with severe hypoxemia | |||||||||
| Day 0 to 90, episodes /100 infants (n/N) | 3.15 (45/1430) | 1.70 (47/2765) | 46.0 | 18.7 to 64.1 | 3.23 (50/1547) | 1.71 (51/2980) | 47.0 | 21.8 to 64.2 | 66 |
| Day 0 to 120, episodes /100 infants (n/N) | 3.71 (53/1430) | 2.13 (59/2765) | 42.4 | 16.6 to 60.3 | 3.81 (59/1547) | 2.15 (64/2980) | 43.7 | 19.8 to 60.5 | 60 |
| Day 0 to 150, episodes /100 infants (n/N) | 3.92 (56/1430) | 2.39 (66/2765) | 39.0 | 13.0 to 57.3 | 4.01 (62/1547) | 2.38 (71/2980) | 40.6 | 16.4 to 57.7 | 61 |
| Day 0 to 180, episodes /100 infants (n/N) | 4.34 (62/1430) | 2.64 (73/2765) | 39.1 | 14.6 to 56.6 | 4.40 (68/1547) | 2.65 (79/2980) | 39.7 | 16.6 to 56.4 | 57 |
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n = number of participants with event; N = total participants evaluated; VE =vaccine efficacy; NNV = number need to vaccinate.
*Per-protocol population analyses of primary and secondary endpoints use dataderived from trained clinical site personnel observations only and protocol-mandatedtechnology (pulse oximeter and RT-PCR by central laboratory) only.
**ITT population analyses and any all-cause analyses use data from trained clinicalsite personnel observations and protocol mandated technology (pulse oximeter andRT-PCR by central laboratory) supplemented by data abstracted from hospital recordsof admitted subjects. The ITT of primary and secondary endpoints which was limitedto endpoints evaluated by protocol dictated standards is reported in SupplementaryTable S8.
†Report on 95% confidence interval (95%CI), unless otherwise indicated.
‡Number (of women) needed to vaccinate (NNV) to prevent one infant case over 180days = 1/(placebo incidence rate – vaccine incidence rate)
Medically-significant RSV LRTI (primary endpoint) was defined as the presence ofRSV infection confirmed by detection of the RSV genome by RT-PCR on respiratorysecretions (obtained within the continuous illness episode which fulfilled the othercriteria listed below); AND at least one manifestation of LRTI from among thefollowing: cough, nasal flaring, lower chest wall indrawing, subcostal retractions,stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea; ANDevidence of medical significance as defined by the presence of: EITHER hypoxemia(peripheral oxygen saturation [SpO2] < 95% at sea level or< 92% at altitudes > 1800 meters) OR tachypnea (≥ 70 breathsper minute [bpm] in infants 0 to 59 days of age and ≥ 60 bpm in infants≥ 60 days of age).
An event was considered RSV LRTI with severe hypoxemia (secondary endpoint) if allfollowing parameters were present during a continuous symptomatic illness episode:RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND at leastone manifestation of lower respiratory tract infection (LRTI) from among thefollowing: cough, nasal flaring, lower chest wall indrawing, subcostal retractions,stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea, ANDevidence of severe hypoxemia or the requirement for respiratory support as definedby the presence of: EITHER severe hypoxemia (peripheral oxygen saturation [SpO2]< 92% at sea level or < 87% at altitudes > 1800 meters) OR thedocumented use of oxygen by high flow nasal cannula OR continuous positive airwaypressure (CPAP) OR bilevel positive airway pressure (BiPAP) OR bubble CPAP ORbag-mask ventilation OR intubation with subsequent mechanical (or manual)ventilation OR extracorporeal membrane oxygenation (ECMO).
An event was considered RSV LRTI hospitalization (secondary endpoint) if allfollowing parameters were present during a continuous symptomatic illness episode:RSV infection as confirmed by detection of the RSV genome by RT-PCR, AND at leastone manifestation of lower respiratory tract infection (LRTI) from among thefollowing: cough, nasal flaring, lower chest wall indrawing, subcostal retractions,stridor, rales, rhonchi, wheezing, crackles/crepitations, or observed apnea, ANDdocumented hospitalization.
Data elements supporting the 3 criteria for a primary endpoint case and secondaryendpoints were present within the start and stop dates of a continuous illnessepisode and derived from clinical observations made by qualified clinical trial sitestaff, pulse oximetry performed by site personnel using a Masimo RAD-5 pulseoximeter supplied by the sponsor, and RSV detection based on study-specified RT-PCRperformed by the validated GenMark eSensor assay in place at the central laboratory(Marshfield Clinic Research Institute, Marshfield, Wisconsin). Evidence ofhospitalization and/or in-hospital use of high-flow nasal cannula, CPAP, BiPAP,bubble CPAP, intubation, or mechanical/manual ventilation or ECMO will be supportedby hospital records obtained by the clinical site staff. Only endpoints confirmed byan independent clinical adjudication committee (CEAC) were used for the primary andsecondary endpoints.
All-cause medically-significant LRTI, all-cause LRTI with severe hypoxemia, andall-cause LRTI with hospitalization follow the definitions of respective primary andsecondary endpoints, with no requirement for confirmation of RSV infection or CEACconfirmation. Data are derived from an expanded dataset which includes both of theobservations of the clinical site staff using sponsor-supplied devices anddiagnostic tests and/or review and abstraction of medical records for infantsundergoing hospitalization for a respiratory SAE.
Note: The reported vaccine efficacy confidence intervals were not adjusted formultiplicity and hence cannot be used to infer effects.
Figure 2 a-c
Kaplan-Meier Plots for the Primary and Secondary Efficacy Endpoints in thePer-Protocol Population
Panel 2a: Time to RSV Medically-significant Lower Respiratory Tract Infection
Panel 2b: Time to RSV Lower Respiratory Tract Infection with Severe Hypoxemia
Panel 2c: Time to RSV Lower Respiratory Tract Infection with Hospitalization
The rates of the primary-endpoint, RSV-MS-LRTI, through 0-90 days in infants of placeboand vaccine recipients were 2.45% and 1.48%, respectively; with a VE of 39.4%(97.5%CI:-1.0 to 63.7; 95%CI: 5.3 to 61.2; p=0.0278). The eITT population provided 66additional RSV-MS-LRTI endpoint cases and very similar VE with improved precision (41.4%,95%CI 18.0 to 58.1) for 0-90 days; Table 4.
The rates of RSV-LRTI with hospitalization in the PP population through 0-90 days were3.7% for placebo and 2.1% for vaccine group, with a VE of 44.4% (95%CI: 19.6 to 61.5%);again the eITT analysis was supportive. Finally, the rates of RSV-LRTI with severehypoxemia among PP infants of placebo and vaccine recipients through 0-90 days were 0.98%and 0.51%, respectively; VE was 48.3% (95%CI: -8.2 to 75.3). The larger number of cases inthe eITT dataset generated both a greater VE (58.8%) and greater precision (95% CI 31.9 to75.0); Table 4. Vaccine efficacy point estimatesthrough to 180 days age (relative to 0-90 days age) was lower for RSV-MS-LRTI, butremained similar throughout for RSV-LRTI hospitalization and RSV-LRTI with severehypoxemia endpoints in both PP and eITT.
Efficacy against all-cause LRTI
All-cause MS-LRTI rates through 90 days age in the PP population were 7.2% and 5.5% amonginfants of placebo and vaccine recipients, respectively, yielding a VE of 23.2% (95%CI:1.4 to 40.2); Table 4. The PP all-cause LRTIhospitalization rates through 0-90 days were 6.0% and 4.3% among infants of placebo andvaccine recipients respectively, yielding a VE of 27.8% (95%CI: 4.8 to 45.3). The PP VEagainst all-cause LRTI with severe hypoxemia through 90 days age was 46.0% (95%CI: 21.8 to64.2); eITT analysis results were supportive; Table4.
All-cause effects appeared durable, and every point estimate from birth through to 90,120, 150, or 180 days of life remained positive. The number needed to vaccinate (NNV) inthe eITT analysis for RSV-confirmed versus all-cause endpoints through 180 days was 88 vs.45 for MS-LRTI, 58 vs. 35 for LRTI with hospitalization, and 82 vs. 57 for LRTI withsevere hypoxemia, Table 4.
Efficacy by LMIC and HIC
Supplementary Table S7 provides VE estimates against the various endpoints, in both PPand eITT analyses, in LMIC and HIC. In LMIC, VE through 180 days was uniformly positive(95%CI >0) in the eITT analyses for RSV-MS-LRTI (42.2%; 95%CI: 16.2 to 20.1),RSV-LRTI hospitalization (53.0%; 95%CI: 31.6 to 67.8) and RSV-LRTI with severe hypoxemia(68.5%; 95%CI: 43.6 to 82.4). In contrast, VE estimates were not significant (with wide95%CI margins) for the corresponding RSV-specific LRTI endpoints in HIC.
Efficacy by RSV subtype
The eITT placebo rate (0-90 days) for RSV-MS-LRTI was 1.55% for RSV/A and 2.46% forRSV/B. The eITT VE (0-90 days) for RSV-MS-LRTI for RSV/A was 20% (-33.3-51.9) and RSV/Bwas 53.6% (26.5-70.6). The related VE for RSV-LRTI with severe hypoxemia for RSV/A was48.1% (-8.6-75.2) and for RSV/B was 63.7% (28.3-81.6), and for RSV-LRTI withhospitalization was 42.7% (5.7-65.2) for RSV/A and 48.1% (16.8-67.6) for RSV/B(Supplementary Table S8).
RSV infection in the women
RSV associated symptomatic respiratory tract infection incidence was similar in RSVF-protein vaccinees (4.9%; 148/3004) and placebo recipients (4.8%;76/1569) through 180days post-partum.
DISCUSSION
This was the first large scale efficacy trial of an investigational vaccine in pregnancy,and provided evidence that maternal RSV vaccination can prevent RSV-LRTI in infants. Whilethe pre-specified target for success against RSV-MS-LRTI was not attained, PP and eITTanalyses showed the primary endpoint VE to be approximately 40% over the first 90 days oflife, wherein 73-76% of all cases occurred. The VE estimates against the secondary endpointsof RSV-LRTI with hospitalization and/or severe hypoxemia were 44% and 48%, respectively, andwere similarly confirmed in eITT analyses. Finally, a VE of 35% and 47% against all-causeLRTI-associated hospitalization or severe hypoxemia respectively was observed in the first90 days of life, and positive point estimates of efficacy against all-cause LRTI endpointspersisted as cases accrued through 180 days. Another notable observation was that infantsborn to RSV-F vaccinees were approximately 50% less likely to have all-cause pneumoniareported as a serious adverse event through 180 days, as well as through 364 days ofa*ge.
Although the trial was not powered to evaluate VE by country (or stratified by nationaleconomic status), efficacy against RSV-MS-LRTI, LRTI hospitalization and LRTI with severehypoxemia were higher in LMIC than the overall population. In contrast, there was generallylower VE in HIC for RSV-LRTI endpoints, with fewer cases and consequent wide uncertaintybounds. Future studies will be needed to elucidate possible heterogeneity in VE between HICand LMIC settings. The lower VE point-estimates (and imprecision thereof) in HIC may be acumulative result of several factors, including hospitalization of less severe RSV cases,lower frequency of breast feeding, and lower background rates of RSV-LRTI in HIC than LMIC.Lower RSV-LRTI attack rates in HIC infants could have been due to variability of RSVexposure across multiple geographies due to variations in temporal alignment with the localRSV season, as well as risk modifiers such as indoor smoke exposure and crowded livingconditions.
Although this study bridged broad geographies, it was limited by overestimation of theprimary endpoint attack rate, for which no applicable antecedent data existed, and thetrial’s early termination. Nevertheless, these data indicate that further developmentof this and other maternal RSV vaccine candidates should focus on reduction of LRTI withmore severe hypoxemia, both RSV-specific and all-cause, as appropriate targets. Additionaleffectiveness studies are also warranted to address the uncertainties of VE in HIC as wellas evaluation of the effectiveness of maternal RSV vaccination in prevention of RSV-LRTI ininfants born pre-term, which the current study was not designed or powered to evaluate withany meaningful accuracy.
Future analyses will aim to establish a correlate of protection against RSV-LRTI of varyingseverity, which could inform immunogenicity-bridging studies, including for exampleextrapolation of the applicability of our findings to women living with HIV infection. Alimitation of the current dataset is that testing of cord-blood for RSV/A and RSV/Bneutralization antibodies is not yet completed. This will be required to fully elucidate theassociation of RSV neutralization antibody, anti-F IgG and PCA levels to the risk of infantRSV-LRTI.
In conclusion RSV-F vaccine administered during pregnancy was safe. Although the study didnot meet its primary vaccine-efficacy endpoint (target of >30% for 97.52% CI lowerbound), this is nevertheless the first study to show that maternal RSV vaccination couldprevent RSV-specific and all-cause LRTI hospitalization and LRTI with severe hypoxemiathrough to 180 days. The modest number of women needed to vaccinate (57–82) toprevent one case of LRTI with severe hypoxemia, support the potential of this vaccine toreduce severe LRTI in young infants globally.
Supplementary Material
Click here for additional data file.(816K, pdf)
Acknowledgements
The authors wish to recognize the Clinical Immunology laboratory staff at Novavax,Gaithersburg, MD, USA, for performing RSV-F ELISA and palivizumab competing antibody assays;the staff at Department of Pediatrics and Molecular Virology and Microbiology, BaylorCollege of Medicine, Houston, TX, USA, for performing the RSV/A and RSV/Bmicroneutralization assays, and the staff of the molecular diagnostics laboratory of theMarshfield Clinic Research Institute, Marshfield, WI, USA, for performing moleculardetection of RSV. In addition, we wish to recognize the contributions of clinical andadministrative staff at all the participating study sites.
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