EBNEO Commentary: Respiratory syncytial virus vaccine in pregnancy for infant protection

MANUSCRIPT CITATION

Kampmann B, Madhi SA, Munjal I, Simões EAF, Pahud BA, Llapur C, Baker J, Pérez Marc G, Radley D, Shittu E, Glanternik J, Snaggs H, Baber J, Zachariah P, Barnabas SL, Fausett M, Adam T, Perreras N, Van Houten MA, Kantele A, Huang LM, Bont LJ, Otsuki T, Vargas SL, Gullam J, Tapiero B, Stein RT, Polack FP, Zar HJ, Staerke NB, Duron Padilla M, Richmond PC, Koury K, Schneider K, Kalinina EV, Cooper D, Jansen KU, Anderson AS, Swanson KA, Gruber WC, Gurtman A; MATISSE Study Group. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023 Apr 20;388(16):1451-1464. doi: 10.1056/NEJMoa2216480. Epub 2023 Apr 5. PMID: 37018474.

REVIEWED BY

Alvaro Proaño, MD

Neonatal-Perinatal Medicine Fellow

Children’s Hospital of Philadelphia

Email: proanofala@chop.edu

Dustin Daniel Flannery, DO, MSCE

Assistant Professor of Pediatrics

Children’s Hospital of Philadelphia

Email: flanneryd@chop.edu

CORRESPONDING AUTHOR

Dustin Daniel Flannery, DO, MSCE

Assistant Professor of Pediatrics

Children’s Hospital of Philadelphia

Email: flanneryd@chop.edu

Phone: 215-829-5248

TYPE OF INVESTIGATION

Prevention/Treatment – Efficacy and Safety

QUESTION

In pregnant women at 24 to 36 weeks’ gestation (P) does a single intramuscular injection of 120 ug of bivalent RSV prefusion F-protein-based vaccine (I) compared with placebo (C) decrease medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants (O) at 90, 120, 150, and 180 days of life (T).

METHODS

Design: A phase 3, randomized, placebo-controlled trial

Allocation: Pregnant women were randomly assigned in 1:1 ratio to receive RSVpreF vaccine or placebo

Blinding: Double-blind; vaccine dispenser was unblinded but all study personnel, including the investigator, study team, and subject were blinded

Follow-up period: Surveillance data for infants were collected from 72 hours after birth through 12 months of age (24 months of age in those enrolled during the first trial year).

Setting: 18 countries over four RSV seasons (two in the Northern Hemisphere and two in the Southern Hemisphere)

Participants:

• Main inclusion criteria: Healthy women who were 49 years old or younger and pregnant between 24 0/7 and 36 0/7 weeks’ gestation on the day of injection with an uncomplicated, singleton pregnancy. Further detailed inclusion criteria are listed in the protocol.
• Main exclusion criteria: BMI >40 kg/m²; allergy to vaccine component, in vitro fertilization; current or prior pregnancy complications or abnormalities at the time of consent; major maternal illness or disorder (bleeding, immune, rheumatologic, psychiatric, substance use); previous RSV vaccination; exposure to blood or plasma products or immunoglobulin in last 60 days; exposure to immunosuppressants or monoclonal antibodies in the last year; exposure to systemic steroid course in the last 28 days. Further detailed exclusion criteria are listed in the protocol.

Intervention: A single intramuscular injection of 120 μg of RSVpreF vaccine (60 μg each of RSV A and RSV B antigens) or placebo

Outcomes:

• Primary: Medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth
• Secondary: Medically attended RSV-associated lower respiratory tract illness, RSV-associated hospitalization, and medically attended lower respiratory tract illness of any cause, all occurring within 360 days after birth
• Exploratory: medically attended RSV-associated respiratory tract illness and medically attended RSV-associated lower respiratory tract illness due to RSV A or RSV B
• Safety: For maternal participants, adverse event data were collected through 1 month after injection and serious adverse event data were collected through 6 months after delivery. For infant participants, adverse events data were collected from birth to 1 month of age. Additional safety end points were serious adverse events and newly diagnosed chronic medical conditions from birth through 12 months of age. Specific events of interest included preterm birth, low birth weight, developmental delay, and SARS-CoV-2 infection.

Analysis and Sample Size:

• Allowing for 60% vaccine efficacy and 10% of enrolled participants being nonevaluable, enrollment of approximately 6900 total participants was planned. They calculated that 124 cases of medically attended RSV-associated lower respiratory tract illness occurring within 90 days of birth would provide 90% power to reject the null hypothesis, assuming a vaccine efficacy of 60%.
• For the primary endpoints a lower boundary of the confidence interval that was greater than 20% was considered to meet the success criterion for vaccine efficacy; for the secondary endpoints a lower boundary of 0% was considered to meet the success criterion for vaccine efficacy.
• From June 17, 2020, to October 2, 2022, there were 7,392 women randomized with 7,358 receiving either vaccine (3,682) or placebo (3,676)

Patient Follow-up:

• At the time of the interim analysis, 3578 women in the vaccine group and 3570 in the placebo group had given birth, and 2840 and 2843, respectively, had completed the trial.
• Overall, 3570 infants born to women in the vaccine group and 3558 born to women in the placebo group were evaluated.
• Data were available from 85% of participants for follow-up through 180 days.

 

MAIN RESULTS

Baseline Demographics: Maternal and infant demographic and clinical characteristics were similar between groups. Maternal participants were enrolled from 18 countries, with the United States having the highest enrollment (45%). Median maternal age was 29 years and median gestation at injection was 31.3 weeks. Two thirds of maternal participants were of White race. Most infants (94%) were born at term gestation and nearly all (99%) had a 5-minute Apgar score ≥7.

Efficacy: After interim analysis, the data monitoring committee recommended early trial termination as the success criterion was met for one of the two primary outcomes: medically attended severe RSV-associated lower respiratory tract illness within 90 and 180 days after birth (Table). A sensitivity analysis using imputation showed that missing data had no effect on this outcome. For the other primary outcome, medically attended RSV-associated lower respiratory tract illness, the statistical success criterion was not met (Table).

Table: Primary Outcomes

Primary outcome	RSVpreF (N)	Placebo (N)	Efficacy (%)	CI
Medically attended severe RSV-associated LRTI
90 days	6	33	81.8	40.6, 96.3*
180 days	19	62	69.4	44.3, 84.1**
Medically attended RSV-associated LRTI
90 days	24	56	57.1	14.7, 79.8*
180 days	57	117	51.3	29.4, 66.8**

LRTI: Lower respiratory tract illness; *99.5% CI; **97.58% CI

For secondary outcomes, the incidence of medically attended RSV-associated lower respiratory tract illness within cumulative intervals beyond 180 days was lower in the vaccine group than in the placebo group at all time points through 360 days after birth. With respect to RSV-associated hospitalization within 90 days after birth, vaccine efficacy was 67.7% (99.17% CI, 15.9 to 89.5) and within 180 days after birth efficacy was 56.8% (99.17% CI, 10.1 to 80.7). Vaccination did not prevent medically attended lower respiratory tract illness from any cause within 90 days after birth (vaccine efficacy, 7.0%; 99.17% CI, −22.3 to 29.3).

For exploratory outcomes, vaccine efficacy against medically attended RSV-associated respiratory tract illness was 39.1% (95% CI, 16.7 to 55.7) within 90 days after birth and 37.9% (95% CI, 24.0 to 49.5) within 180 days after birth. Vaccine efficacy against medically-attended lower respiratory tract illness due to RSV A was 26.9 (–37.2–61.8) and for RSV B was 56.3 (35.4–71.0); for severe illness it was 50.0 (–32.4–82.9) and 75.0 (50.8–88.4), respectively.

Safety: There were similar incidences of maternal adverse events within 1 month and 6 months after injection, and similar incidences of infant adverse events within 1 month and 24 months after birth, between both groups. Their data shows that 5.6% (201/3568) of births in the vaccine group vs 4.7% (169/3558) in the placebo group were preterm (<37 weeks’).

CONCLUSION

Investigators concluded that RSVpreF vaccine was efficacious against medically attended severe RSV-associated lower respiratory tract illness and RSV-associated hospitalization in infants through 6 months after birth, with a favorable safety profile.

COMMENTARY

Worldwide, respiratory syncytial virus (RSV) is the leading cause of infant hospitalization and an important cause of death in children.^1,2 RSV leads to 3.2 million annual hospitalizations and 100,000 deaths annually.² Maternal RSV vaccination during pregnancy is a strategy that could potentially provide protection during early infancy via placental antibody transfer, such as is recommended for influenza, pertussis, and more recently, SARS-CoV2. The aim of this phase 3, double-blinded, randomized, placebo-controlled, multi-national trial was to evaluate the efficacy and safety of an RSV prefusion F protein−based vaccine (RSVpreF) administered during the late second or third trimester of pregnancy to prevent severe RSV-associated infant lower respiratory tract illness.³

 

In this study, investigators enrolled more than 7,000 pregnant women and their offspring from 18 countries. Efficacy of RSVpreF in reducing severe illness in infants within 3 months after birth was 81.8%, and within 6 months after birth was 69.4%; these primary outcomes met a priori success criteria. The other primary outcomes, RSV-associated lower respiratory tract illness at 3 and 6 months, did not meet success criteria, though efficacy was 57.1% and 51.3%, respectively. Secondary and exploratory outcomes were overall supportive of vaccine benefit. Safety endpoints were similar between groups. There was a slightly higher percentage of preterm birth  in the vaccine group as compared to the placebo group (5.6% vs 4.7%).

 

The results of this Pfizer-sponsored trial suggest that maternal RSV vaccination could be a game changer in prevention of severe pediatric RSV disease. In May 2023, a US Food and Drug Administration (FDA) Advisory Committee voted in support of approval for Pfizer’s RSVpreF during pregnancy to provide infant protection, and the vaccine is currently under review by the FDA.^4,5 The reality that a maternal RSV vaccine may soon be licensed, after more than a half century of research, a is particularly remarkable in context of a disappointing and troublesome RSV vaccine history.⁶

 

Despite convincing efficacy data and reassuring maternal and infant safety data from this trial, the higher proportion of preterm births in the vaccine group has caused concern among some FDA advisers.⁷ Although this trial was not powered to detect a difference in preterm birth, a similar signal regarding increased incidence of preterm birth was reported in a GlaxoSmithKline RSV vaccine trial published in February 2022.³ Notably, the proportions of preterm birth in both arms of the current study were markedly lower than the overall U.S. preterm rate in 2021 (10.5%), likely reflecting the highly selected nature of the study participants.⁸ Analyses of the complete and final trial data, as well as post-market surveillance, will allow for continued evaluation of the vaccine’s safety and efficacy profiles.

 

While the trial results are promising, there are several limitations that must be considered. This trial was conducted during the COVID-19 pandemic when the incidence of RSV and other respiratory pathogens did not follow typical annual patterns. The majority of enrolled women were white and from high-income countries; RSV morbidity is higher in low- and middle-income countries where access to monoclonal antibodies is limited. Women with high-risk pregnancies, who may have increased risk of preterm delivery at baseline, were excluded.

 

Another important issue to resolve is optimal timing of vaccine administration during pregnancy. Infants born at the lowest gestational ages are at highest risk for severe RSV disease but will not benefit from maternal vaccination if routinely given late in the third trimester. Further, there is a paucity of data on the dynamics of placental transfer of RSV-F-specific antibodies at preterm gestations, particularly very preterm gestation (<28 weeks). A recent study suggested that coadministration of RSVpreF and Tdap led to a reduction in the pertussis component antibody response when compared to Tdap alone.^7,9

REFERENCES

1. Acosta PL, Caballero MT, Polack FP. Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease. Clin Vaccine Immunol. Dec 16 2015;23(3):189-95. doi:10.1128/CVI.00609-15

2. Shi T, McAllister DA, O’Brien KL, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. Sep 2 2017;390(10098):946-958. doi:10.1016/S0140-6736(17)30938-8

3. Kampmann B, Madhi SA, Munjal I, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. Apr 20 2023;388(16):1451-1464. doi:10.1056/NEJMoa2216480

4. Jewett C. F.D.A. Panel Recommends R.S.V. Vaccine to Protect Young Infants. New York Times. May 18, 2023. https://www.nytimes.com/2023/05/18/health/rsv-vaccine-infants-fda.html

5. Pfizer Inc. FDA Advisory Committee Votes in Support of Approval for Pfizer’s Vaccine Candidate to Help Prevent RSV in Infants Through Maternal Immunization. Accessed June 12, 2023, https://www.pfizer.com/news/press-release/press-release-detail/fda-advisory-committee-votes-support-approval-pfizers

6. Hurwitz JL. Respiratory syncytial virus vaccine development. Expert Rev Vaccines. Oct 2011;10(10):1415-33. doi:10.1586/erv.11.120

7. Wadman M. FDA advisers agree maternal RSV vaccine protects infants, but are divided on its safety. Science. 19 May 2023. https://www.science.org/content/article/fda-advisers-agree-maternal-rsv-vaccine-protects-infants-divided-safety

8. Centers for Disease Control and Prevention. Preterm Birth. Updated November 1, 2022. Accessed July 7, 2023, https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm

9. Peterson JT, Zareba AM, Fitz-Patrick D, et al. Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F Vaccine When Coadministered With a Tetanus, Diphtheria, and Acellular Pertussis Vaccine. J Infect Dis. Jun 15 2022;225(12):2077-2086. doi:10.1093/infdis/jiab505.