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In a global phase III trial, an investigational vaccine given to mothers during pregnancy slashed infants' risk of severe respiratory syncytial virus (RSV) illness through 6 months of age.

One dose of the bivalent RSV prefusion F protein-based (RSVpreF) vaccine administered in the third trimester demonstrated a vaccine efficacy of 81.8% against severe RSV cases in infants within 90 days of birth (99.5% CI 40.6-96.3) and 69.4% within 180 days of birth (97.58% CI 44.3-84.1).

Through 6 months in the MATISSE study, which involved over 7,000 pregnancies, these severe cases occurred in 0.5% of infants born to mothers who received the vaccine and 1.8% of those in the placebo group, according to researchers led by Beate Kampmann, MD, PhD, of the London School of Hygiene and Tropical Medicine in Fajara, Gambia.

But the study's second co-primary endpoint -- any medically attended RSV-associated lower respiratory tract illness -- did not meet statistical criteria for success through 90 days, with a vaccine efficacy of 57.1% (99.5% CI 14.7-79.8), with cases occurring in 0.7% and 1.6% of infants in the two groups, respectively, the researchers wrote in the .

Still, the largely positive findings, published alongside of nirsevimab for RSV prophylaxis -- in this case, the vaccine-like antibody given directly to young babies -- bring the prospect of infant RSV protection one step closer to clinic.

Both products are currently at the FDA, with approval decisions expected later this year.

First discovered 66 years ago in young children hospitalized in Baltimore, "RSV infection has since emerged as the most frequent cause of hospitalization among infants in the United States and as the leading cause of pneumonia in young children worldwide," noted Ruth Karron, MD, of Johns Hopkins University in Baltimore, writing in an .

In kids under 5, infections from RSV globally are associated with over 3 million hospitalizations and 100,000 deaths per year, with infants under 6 months carrying the highest burden.

But, Karron pointed out, complex policy decisions await high-income countries should these interventions become available. For instance, substantial effort in the U.S. would be needed to push uptake beyond the 57% to 61% vaccination rates seen with maternal influenza or Tdap (tetanus, diphtheria, and acellular pertussis) vaccines.

And would both be needed?

"If both the RSVpreF vaccine for pregnant women and RSV monoclonal antibodies for infants are available, enhanced communication between obstetrical and pediatric care providers will be necessary to ensure appropriate use of each product," she wrote. "Doubly protecting healthy term infants with the use of RSVpreF vaccine antenatally and an RSV monoclonal antibody postnatally while leaving many of the infants in the world unimmunized would waste valuable products and exacerbate worldwide inequities in child health."

MATISSE Trial

The phase III (Maternal Immunization Study for Safety and Efficacy) trial was conducted in 18 countries, randomizing 7,392 women in their third trimester of pregnancy -- and with an uncomplicated single pregnancy and not at high-risk for complications -- to either the single intramuscular injection of RSVpreF vaccine (120 μg) or placebo.

A little less than half (45%) were from the U.S., with other top enrolling countries including South Africa (13%), Argentina (12%), and Japan (6%).

Mothers had a median age of 29 years (average gestational age 30.8 weeks at enrollment), 65% were white, 20% were Black, and 13% were Asian, with 29% being Hispanic.

For the co-primary endpoints, a lower bound confidence interval greater than 20% was considered success. Vaccine efficacy for any medically attended RSV case or severe medically attended RSV illness through 180 days after birth were as follows:

• 90 days: 57.1% (99.5% 14.7-79.8) and 81.8% (99.5% CI 40.6-96.3), respectively
• 180 days: 51.3% (97.58% CI 29.4-66.8) and 69.4% (97.58% CI 44.3-84.1)

Against RSV-associated hospitalization, vaccine efficacy was 67.7% and 56.8% within 90 and 180 days after birth, respectively, though with wide confidence intervals.

Noting the successful results of nirsevimab in RSV prevention, Kampmann and co-authors argued that "vaccination offers the possibility of an immune response to multiple neutralizing epitopes, thus reducing the risk of immune escape observed with some monoclonal antibodies," adding that "passive transfer of maternal antibodies can protect the youngest and most vulnerable infants immediately after birth, before effective immune responses can be elicited from active vaccination in infants."

No serious safety signals were reported in mothers or infants receiving the vaccine, "with mostly mild-to-moderate reactogenicity" and the adverse event (AE) profile was similar to placebo, the researchers reported.

Maternal AEs were reported in 13.8% of the vaccine group and 13.1% of placebo group, with infant AEs occurring at rates of 37.1% and 34.1%.

Serious maternal AEs through 6 months were similar between groups as well, with the most frequent being preeclampsia (1.8% and 1.4% of vaccine and placebo participants, respectively) and fetal distress syndrome (1.8% vs 1.6%). No serious adverse events in infants were deemed related to the RSVpreF vaccine.

One patient in the vaccine group died from postpartum hemorrhage and hypovolemic shock. Stillbirth occurred in 10 vaccinated women and eight placebo, while spontaneous abortion during a subsequent pregnancy occurred in one patient in the vaccine group and two in the placebo group. Through 2 years, five infants died in the vaccine group and twelve died in the placebo group (one from RSV infection).

"It is reassuring that no safety concerns were detected in the infants or mothers in this trial, although the number of participants was small," wrote Kampmann and co-authors.

Limitation of the results, they noted, included the exclusion of high-risk pregnancies and the limited data from lower-income countries, where young infants are at the greatest risk for severe outcomes from RSV.

Karron said that "additional information about the use of RSVpreF vaccine in low-resource settings, including the effect of the vaccine on lower respiratory tract illness of any cause, will help to ensure funding and guide decision making."

In the study, RSVpreF vaccination showed no evidence of protection against a lower respiratory tract illness of any kind requiring medical care within 90 days of birth (70%, 99.17% CI -22.3 to 29.3).

MELODY

Updated results of the now fully enrolled MELODY trial confirmed nirsevimab's protection against RSV. Efficacy of a single injection of the long-acting monoclonal antibody administered to infants reached 76.4% (95% CI 62.3-85.2) against RSV-associated lower respiratory tract infections requiring medical care, reported William Muller, MD, PhD, of Northwestern University in Chicago, and colleagues.

And the larger study population allowed for sufficient numbers to assess for more severe cases, where the monoclonal antibody showed similar protection against:

• Hospitalization for RSV: 76.8% (95% CI 49.4-89.4)
• Very severe medically attended RSV: 78.6% (95% CI 48.8-91.0)

"In term and late-preterm infants, a single dose of nirsevimab provided a consistent level of protection against hospitalization for RSV-associated lower respiratory tract infection and very severe medically attended RSV-associated lower respiratory tract infection during an RSV season," Muller and colleagues wrote, adding that "an estimated 57 days of hospitalization for lower respiratory tract infection of any cause were averted for every 1,000 infants who received nirsevimab."

The trial included 3,012 infants that underwent randomization 2:1 from 2019 to 2021 at 211 trial sites in 31 countries. Infants received either a single dose of nirsevimab (50 mg if under 5 kg or 100 mg if 5 kg or above). AEs related to the injection were reported in 1.3% of nirsevimab recipients and 1.5% of the placebo recipients.

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