Does a Maternal RSV Vaccine Make Sense? It May Be Too Early to Tell.
On May 3, the Food and Drug Administration (FDA) approved Arexvy (GlaxoSmithKline), the first respiratory syncytial virus (RSV) vaccine for use in the United States. Arexvy is indicated to prevent lower respiratory tract disease caused by RSV in adults 60 years and older. A second RSV vaccine, Abrysvo (Pfizer), was approved May 31, for the same indication.
The next big decision regarding RSV vaccines is in the pediatric space. RSV is associated with 1.5 million outpatient visits, 58,000 to 80,000 hospitalizations, and 100 to 300 deaths annually in U.S. children under 5 years of age. Sixty-eight percent of infants with RSV are infected during their first year of life, and 97% of children with RSV are infected by the age of 2. The highest risk of infant and child RSV hospitalization occurs during the first months of life, and for those children under 2 who are hospitalized due to RSV, 79% have no underlying medical conditions.
Two pediatric RSV approaches
There are two potential approaches to preventing RSV in pediatrics expected to receive FDA decisions this year.
The first is maternal vaccination. Pfizer is seeking approval to use Abrysvo during pregnancy to prevent RSV in infants. The regulatory decision is anticipated to come in August 2023.
The second approach is a new monoclonal antibody for use in infants and children. Approval for pipeline candidate nirsevimab (Sanofi and AstraZeneca), a long-acting monoclonal antibody for the prevention of RSV in infants and children, is anticipated this fall. In addition to its use in high-risk patients, nirsevimab may also receive approval to prevent RSV in healthy-term infants, making it the first FDA-approved drug for this indication.
The combined use of the maternal RSV vaccine and nirsevimab has not been studied. It seems unlikely that both options would be used together due to a lack of cost effectiveness, so it remains to be seen how this will be navigated from a therapeutic selection standpoint.
MATISSE Trial evaluates efficacy
On May 18, the FDA's Vaccines and Related Biological Advisory Committee (VRBPAC) met to consider the efficacy and safety of Abrysvo given during the second or third trimester of pregnancy to prevent RSV lower respiratory tract disease in infants from birth through 6 months of age. All 14 panelists voted that the totality of data, including data from the phase 3 trial MATISSE, supported the vaccine's effectiveness. But on the question of safety, four panelists voted against citing Pfizer's data wasn't adequate to demonstrate safety.
The MATISSE trial, conducted over four RSV seasons during the COVID pandemic, enrolled more than 7,300 maternal participants from 18 countries. The trial stopped early – and no longer enrolled participants — after a second interim analysis revealed the vaccine was superior to placebo for one of the two primary endpoints. At the second interim analysis, 80 cases of medically attended (MA) RSV-associated lower respiratory tract infections (LRTI), including 39 severe cases, had accrued within 90 days after birth. Vaccine efficacy against severe infections was 81.8% at 90 days and 69.4% at 180 days. While vaccine efficacy against any MA RSV-positive LRTI was not superior to placebo at 90 days after birth, with the accrual of additional cases, vaccine efficacy was 51.3% at 180 days and superior to placebo. While these results seem impressive, it is important to keep in mind that vaccine efficacy is presented as a relative change in RSV cases between vaccine and placebo, not the absolute difference. In the trial, an 81.8% vaccine efficacy at 90 days was an absolute difference of 0.7% in severe cases.
Overall, RSV hospitalization was low with less than 100 infants hospitalized during follow-up, which creates uncertainty in determining the vaccine effect on hospitalization, but at all time points, fewer infants in the vaccine group were hospitalized. Absolute reductions in hospitalization with the vaccine ranged from 0.6% at 90 days to 0.8% at 180 days. The vaccine did not have a significant effect against all-cause MA-LRTI within 90 to 360 days after birth. Its effect may have been reduced by pandemic-related changes in RSV occurrence and seasonality. During the trial, RSV accounted for just 22% of the all-cause MA-LRTIs.
VRBPAC members agreed the vaccine was effective but expressed concern about a potential increase in late preterm births (less than 37 weeks of gestation) with the vaccine (5.6% vs. 4.7% for placebo). This increase in premature births was also observed in the Abrysvo phase 2 trial and in the suspended clinical trial program of GlaxoSmithKline (GSK)'s maternal RSV vaccine candidate. Abrysvo was associated with an increased occurrence of low birth weight (5.1% vs. 4.4% for placebo), but not infant mortality.
Because the study enrolled low-risk participants, the rate of preterm birth in the trial was low and there were not enough preterm birth events to determine if the observed increase in risk is a true safety issue or a chance occurrence. With enrollment stopped at the second interim analysis, post-marketing studies will be necessary to determine if Abrysvo causes preterm birth; however, it is more difficult to establish cause and effect relationships in real-world studies.
Clear, decisive results remain to be seen
The Advisory Committee on Immunization Practices (ACIP) met June 22 to discuss the evidence to recommendation framework for the use of Pfizer's RSV vaccine for maternal use. Similar efficacy and safety data presented at VRBPAC also were discussed by the ACIP. The primary policy question addressed was whether Abrysvo should be recommended during pregnancy to prevent RSV disease in infants. The work group felt that the desirable effects from maternal vaccination were moderate to high, while the potential undesirable effects were predominantly described as low or uncertain. It is anticipated that the vote language put forth at the upcoming October 2023 ACIP meeting will be based on shared clinical decision making, similar to the recommendations made for the use of RSV vaccines in older adults.
While RSV is an important contributor to infant morbidity, understanding the totality of evidence for Abrysvo is necessary. Based on data from the MATISSE trial, it appears that Abrysvo reduces the severity of RSV-positive LRTIs and reduces – but does not eliminate – MA RSV-positive LRTI for up to six months after birth. For other important outcomes, including RSV hospitalization and reduction of overall MA LRTI, the vaccine efficacy was less precise, likely because the trial was conducted during the pandemic and enrollment was stopped after an interim analysis.
The increased occurrence of prematurity observed with Abrysvo cannot be dismissed outright since the same trend was seen in the phase 2 trial and with GSK's maternal RSV candidate. The MATISSE trial was conducted in a population at low risk for preterm birth; therefore, it is important study further before vaccinating women at higher risk for preterm birth for which the benefit to risk analysis may be more complicated.
While most preterm births were late preterm births, only 25% of participants were vaccinated at the gestational age of less than 28 weeks; vaccination may occur earlier in practice. Shared decision making, informed by accurate discussion about the expected benefits and the potential unknowns of this vaccine, is essential to restoring trust in public health and vaccines post-pandemic.