New England Journal of Medicine April 20, 2023

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants

Beate Kampmann, Shabir A. Madhi, Iona Munjal, et al.

Bottom Line

Maternal vaccination with a bivalent RSV prefusion F protein-based vaccine (RSVpreF) safely reduced the risk of medically attended severe RSV-associated lower respiratory tract illness in infants by 81.8% at 90 days and 69.4% at 180 days after birth.

Key Findings

1. Vaccine efficacy against medically attended severe RSV-associated lower respiratory tract illness was 81.8% (99.5% CI, 40.6 to 96.3) within 90 days after birth (6 cases in the vaccine group vs. 33 in placebo).

2. Within 180 days after birth, vaccine efficacy against severe RSV illness remained high at 69.4% (97.58% CI, 44.3 to 84.1), with 19 cases in the vaccine group compared to 62 cases in the placebo group.

3. Vaccine efficacy against medically attended RSV-associated lower respiratory tract illness (any severity) was 57.1% (99.5% CI, 14.7 to 79.8) at 90 days and 51.3% (97.58% CI, 29.4 to 66.8) at 180 days.

4. The trial met the prespecified success criterion for the severe illness endpoint, but the 99.5% CI lower bound of 14.7% for the any-severity endpoint at 90 days fell short of the >20% threshold required for statistical success.

5. The vaccine was well tolerated with no significant safety signals; the incidence of maternal and infant adverse events was similar between the vaccine and placebo groups.

Study Design

Design

RCT

Double-Blind

Sample

7,358

Patients

Duration

180 days

Median

Setting

18 countries

Population Healthy pregnant women at 24 through 36 weeks' gestation and their respective infants.

Intervention Single intramuscular injection of 120 μg of bivalent RSV prefusion F protein-based (RSVpreF) vaccine.

Comparator Placebo injection.

Outcome 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.

Study Limitations

• The study missed the stringent statistical success criterion for one of its two primary endpoints (medically attended RSV lower respiratory tract illness of any severity at 90 days), despite a strong positive trend.

• A non-significant numerical imbalance in preterm births was observed (5.7% in the vaccine group vs. 4.7% in the placebo group), a finding that, while lacking statistical significance, requires ongoing post-marketing surveillance.

• The trial focused on healthy pregnant women without high-risk obstetric conditions, limiting the generalizability of safety and efficacy to more vulnerable pregnancies.

• The primary outcome only tracked infants up to 180 days, leaving long-term durability of protection and efficacy across subsequent RSV seasons to be determined.

Clinical Significance

The MATISSE trial validated maternal RSVpreF vaccination as a highly effective and safe strategy to protect young infants against severe RSV infection during their most vulnerable first six months of life. By leveraging placental transfer of maternal neutralizing antibodies, this approach represents a paradigm shift in pediatric preventive medicine and offers a major public health tool to drastically reduce the global burden of infant RSV hospitalizations.

Historical Context

Respiratory syncytial virus (RSV) has historically been the leading cause of viral lower respiratory tract infections and hospitalizations in infants globally. Vaccine development was stalled for over 50 years following a disastrous 1960s trial of a formalin-inactivated RSV vaccine that caused vaccine-associated enhanced respiratory disease (VAERD) and infant fatalities. The field was revitalized in 2013 by the breakthrough discovery of the stabilized prefusion conformation of the RSV F protein, which elicits highly potent neutralizing antibodies. The MATISSE trial represents the clinical culmination of this structural biology triumph.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is the prefusion form of the RSV F protein a superior immunogen for this vaccine compared to the postfusion form, and how does maternal vaccination translate into infant protection?

Key Response

The prefusion F protein exposes highly conserved, neutralizing epitopes (such as site zero) that are lost when the protein undergoes structural rearrangement to the postfusion state. Protection occurs via the transplacental transfer of maternal IgG (passive immunity), which peaks during the third trimester and provides immediate systemic protection to the newborn.

Resident

Given the availability of both the maternal RSVpreF vaccine and the infant monoclonal antibody nirsevimab, how should a clinician counsel a pregnant patient at 34 weeks gestation during RSV season regarding the optimal strategy to protect her newborn?

Key Response

Both modalities are highly effective, but guidelines typically recommend utilizing only one to avoid redundancy. Maternal vaccination at 32-36 weeks provides immediate protection at birth without the infant needing an injection, but requires at least 14 days for optimal placental antibody transfer. If delivery is anticipated within 14 days or the mother declines the vaccine, nirsevimab administration directly to the infant is the preferred alternative.

Fellow

Although the MATISSE trial enrolled pregnant individuals from 24 to 36 weeks gestation, the FDA approved RSVpreF only for administration between 32 and 36 weeks. What safety signal in the broader RSV vaccine landscape drove this discrepancy between the trial design and the final regulatory approval?

Key Response

A competing maternal RSV vaccine trial (by GSK) was halted due to a statistically significant increase in preterm births. While MATISSE did not show a statistically significant increase in preterm births, a slight numerical imbalance existed. Restricting administration to the 32-36 week window mitigates potential risks of extreme prematurity while still allowing sufficient time for transplacental antibody transfer.

Attending

With the implementation of the RSVpreF vaccine for pregnant patients, how does the seasonality of RSV infection complicate the timing of vaccine administration compared to year-round vaccines like Tdap, and what logistical challenges does this pose for obstetric practices?

Key Response

Unlike Tdap, which is given at 27-36 weeks year-round, RSVpreF is recommended by the CDC only during RSV season (e.g., September to January in most of the US) to maximize infant antibody titers during peak viral circulation. This requires obstetricians to implement complex seasonal screening protocols tied to specific gestational age windows, increasing the risk of missed administrations or inappropriate off-season dosing.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The MATISSE trial utilized two primary efficacy endpoints: medically attended severe RSV-associated LRTI and all medically attended RSV-associated LRTI. What is the methodological rationale for using dual primary endpoints with different severity thresholds, and how does this impact the statistical power and alpha allocation of the trial?

Key Response

Using dual endpoints allows researchers to capture both the most critical clinical outcome (severe LRTI, which strains healthcare capacity) and a broader, more frequent outcome to ensure sufficient event rates for early statistical powering. To control the family-wise error rate across both endpoints, the trial must utilize alpha-splitting or sequential testing procedures (e.g., the Hochberg procedure), which necessitates careful sample size estimation and event-driven analysis.

Journal Editor

In evaluating the robustness of the trial's safety data, particularly regarding the numerical imbalance in premature births, how should peer reviewers scrutinize the geographic variation in baseline prematurity rates across the participating countries, and could site-specific confounding influence the aggregate safety signal?

Key Response

Prematurity rates vary significantly on a global scale due to socioeconomic and healthcare system differences. A rigorous editorial review must examine whether the numerical increase in preterm births was evenly distributed or driven by specific regions, and whether differences in maternal baseline risks (such as prior preterm birth history) across trial sites were adequately controlled for in the safety analysis.

Guideline Committee

Based on the MATISSE trial outcomes and the concurrent availability of nirsevimab, how does the CDC ACIP currently position the maternal RSVpreF vaccine in their immunization schedules, and what specific clinical scenarios would prompt a guideline recommendation for nirsevimab over the maternal vaccine?

Key Response

ACIP recommends either maternal RSVpreF (administered at 32-36 weeks during RSV season) or infant nirsevimab, but explicitly states that both are rarely needed for the same infant. Nirsevimab is recommended if the mother did not receive the vaccine, if maternal vaccination occurred less than 14 days prior to delivery (resulting in insufficient transplacental antibody transfer), or for infants born prematurely before the maternal vaccination window could be reached.

Clinical Landscape

Noteworthy Related Trials

1998

IMpact-RSV Trial

n = 1,502 · Pediatrics

Tested

Palivizumab (monthly IM doses)

Population

Premature infants and infants with bronchopulmonary dysplasia

Comparator

Placebo

Endpoint

Hospitalization for RSV infection

Key result: Palivizumab prophylaxis resulted in a 55 percent reduction in RSV hospitalization rates among premature infants and those with bronchopulmonary dysplasia.

2020

Prepare Trial

n = 4,636 · NEJM

Tested

RSV F nanoparticle vaccine (ResVax)

Population

Healthy pregnant women at 28 to 36 weeks of gestation

Comparator

Placebo

Endpoint

Medically significant RSV lower respiratory tract infection in infants up to 90 days of life

Key result: The vaccine did not meet the prespecified success criterion for the primary endpoint but reduced the risk of severe hypoxemic RSV lower respiratory tract infection.

2022

MELODY Trial

n = 1,490 · NEJM

Tested

Nirsevimab (single IM dose)

Population

Healthy late-preterm and term infants

Comparator

Placebo

Endpoint

Medically attended RSV-associated lower respiratory tract infection

Key result: Nirsevimab reduced the incidence of medically attended RSV-associated lower respiratory tract infection by 74.5 percent compared to placebo.

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