Pediatric RSV vaccine trial enrollment on hold in US, VRBPAC says | Image Credit: © kitsawet - © kitsawet - stock.adobe.com.

The enrollment of children aged younger than 2 years and respiratory syncytial virus (RSV) -naïve children aged 2 through 5 years into clinical studies of RSV vaccine candidates is currently on hold in the United States, according to a briefing document by the FDA. The document was released ahead of a December 12, 2024, Vaccines and Related Biological Products Advisory Committee (VRBPAC) Meeting.

The halt follows a severe respiratory disease safety signal that resulted in the pause of the phase 1 mRNA-1365-P101 study in July of 2024. The study evaluated the safety, tolerability, and immunogenicity of a pair of Moderna RSV vaccine candidates, mRNA-1345 and mRNA-1365, in infants aged 5 months to <24 months.

Safety signal led to study pause

According to the briefing document, a study pause criteria was met after a potential safety signal for RSV severe lower respiratory tract illness (sLRTI) was identified. An imbalance in cases of RSV sLRTI was also observed, with more cases present among vaccine groups compared to control group counterparts, which raised concern for vaccine-associated enhanced respiratory disease.

"The protocol’s study pause criterion of any sLRTI with positive polymerase chain reaction (PCR) for RSV in ≥2 participants was met. Once the pause rule was met, the study was immediately put on hold by the Sponsor, and no participants were subsequently enrolled or received additional doses," stated the FDA in the briefing.

The study consisted of 3 parts; A, B, and C, with a description as follows, courtesy of the FDA briefing document:

• "Part A (Cohorts 1 and 2) is randomized, observer-blind, and placebo-controlled, and is designed to evaluate 30 µg mRNA-1345, 30 µg mRNA-1365, and placebo in approximately 90 participants 8 months to <24 months of age (randomized in a 1:1:1 ratio, respectively)."
• "Part B (Cohorts 3 through 6) is randomized, observer-blind, and placebo-controlled, and is designed to evaluate 2 dose levels of mRNA-1345 and mRNA-1365 and placebo in approximately 120 participants 5 months to <8 months of age (randomized in a 1:1:1 ratio, respectively)."
• "Part C (Cohorts 7 and 8) is open-label and began enrollment following the initiation of Part B Cohorts 3 and 4. It is designed to evaluate 3 doses of 30 µg mRNA-1345 administered to approximately 100 participants 8 months to <12 months of age who have (Cohort 7) or have not (Cohort 8) previously received nirsevimab."

Clinically significant severe/very severe (CS-severe/very severe) cases were defined as RSV LRTI cases that met the protocol-specified definition of severe or very severe and/or required hospitalization.

Among cohorts 3 and 4 in part B of the study, there was an imbalance in the number of cases of CS-severe/very severe LRTI in the vaccine groups, as there were 5 cases in the mRNA-1345/1365 15 µg groups compared to 1 case in the part B placebo group.

Of these 6 cases, 5 required hospitalization, including 1 infant who required mechanical ventilation.

In the video above, Robert Frenck, MD, Professor of Pediatrics, Division of Infectious Diseases; Director, Vaccine Research, Cincinnati Children’s Hospital, highlights the benefits of nirsevimab and a positive perspective on a study pause because of safety concerns.

Response of mRNA-1345 following nirsevimab

In part C of the study, individuals aged 8 months through <12 months who were previously exposed to nirsevimab (n = 9) or not previously exposed to the monoclonal antibody (n = 6) received 1 dose of 30 µg mRNA-1345.

According to the results listed in the table provided by the FDA briefing document below, a potential lack of response to a single dose of mRNA-1345 (30 µg) was observed for those who were previously exposed to nirsevimab. Responses for the 3-dose series were not available because of the study pause, which hindered the receipt of additional vaccine doses.

Image credit: FDA - Vaccines and Related Biological Products Advisory Committee Meeting December 12, 2024 - Briefing Document

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VRBPAC meeting and outlook

The briefing document states the VRBPAC discussion topics for the December 12, 2024 meeting will include the interpretation of the safety data revealed in the phase 1 clinical trial of both vaccines, finding implications for ongoing and future pediatric development of non-live attenuated RSV vaccines. Additionally, the discussion will likely focus on the "Sequential Administration of RSV Monoclonal Antibodies (mAbs) followed by RSV Vaccines in Infants and Toddlers," according to the FDA.

With the hold of all clinical studies of RSV vaccine candidates currently in place, and in light of the observed safety signal, VRBPAC stated the decision to re-initiate enrollment of at-risk populations for VAERD and allow future pediatric studies will need to consider the following 7 statements:

"1. Whether our current understanding of the pathophysiology of VAERD following administration of FI-RSV vaccine informs assessment of this potential risk across other vaccine technologies (e.g., live-attenuated chimeric respiratory viral, other viral vectored, mRNA, and recombinant particle/subunit vaccine candidates)"

2. "The need for additional clinical or other assessments to further characterize the nature of the potential VAERD safety signal"

3. "Whether and what data may be helpful to stratify potential risk based on vaccine technology and/or antigenic composition"

4. "The utility of nonclinical studies and data, additional nonclinical testing that may be necessary, and how and whether nonclinical studies can adequately predict or reassure against the risk of VAERD, and if this may vary across vaccine technologies and/or antigenic compositions"

5. "Additional risk mitigation or risk management approaches that would be sufficient to address the potential for VAERD in a clinical trial"

6. "A benefit-risk assessment approach that incorporates evidence of the benefit of a vaccine candidate in RSV-experienced children and uncertainties regarding the VAERD risk, all in the context of the available preventive landscape, including nirsevimab, other anti-RSV monoclonal antibodies in late phases of clinical development, and maternal immunization approaches"

7. "How potential RSV mAB – RSV vaccine interactions should be addressed in the design of clinical trials and the overall clinical development plan, including potential populations indicated for use."

To view the entire FDA briefing document, click here.

Reference:

Vaccines and Related Biological Products Advisory Committee Meeting December 12, 2024. FDA. Briefing document. Accessed December 12, 2024. https://www.fda.gov/media/184301/download