December 12, 2024
Good afternoon, I’m Dr. Saman Asad Siddiqui, a physician with a master’s degree in clinical Investigation from Harvard Medical School. I am speaking today on behalf of the National Center for Health Research. Our research center does not accept funding from any companies that have a financial interest in our work, so we have no conflicts of interest. Thank you for the opportunity to speak today.
For children under 5 years of age In the United States, RSV is associated with an estimated 58,000 to 80,000 hospitalizations and 100 to 300 deaths annually.
The recent RHYME Phase 1 mRNA-1365-P101 study of mRNA RSV vaccines conducted by Moderna in infants aged 5-8 months raised significant safety concerns. Among the 40 infants who received a 15 μg dose of the RSV vaccine, 19 (47.5%) developed symptomatic RSV disease, and of these, 5 (26%) progressed to severe or very severe lower respiratory tract infections. In contrast, among the 20 placebo recipients, 12 (60%) developed symptomatic RSV disease, but only 1 (5%) experienced severe or very severe lower respiratory tract infections. This means that, overall, 12.5% of all vaccine recipients (5 out of 40) experienced severe or very severe RSV LRTI compared to 5% of the placebo group.
Of the six severe cases identified in the study, five required hospitalization, and one infant needed mechanical ventilation. The median time to resolution of severe cases was 19.5 days (ranging from 8 to 31 days). While the small sample size limits the certainty of these findings, the higher rates of severe illness in vaccine recipients compared to placebo raise serious concerns about the vaccine’s safety for infants in this age group. These findings led to a study pause and discontinuation of the RSV program for seronegative children under 2 years old, which we can all agree indicates the challenges in developing safe and effective RSV vaccines for young children.
While established safeguards exist for RSV vaccine development, the recent Phase 1 study (mRNA-1365-P101) results suggest these may not be sufficient to prevent all potential safety issues, particularly in RSV-naïve infants.
To enhance the safety of RSV vaccine development for infants and toddlers, we urge that several actionable steps should be prioritized.
#1: First, we agree with the FDA scientists that there must be an immediate reassessment of clinical trial designs. This should include
- implementing stringent safety monitoring protocols with continuous real-time data analysis,
- considering lower initial vaccine doses for younger age groups, and
- increasing the frequency of interim analyses with predefined thresholds for study pauses.
#2: Enhanced immune profiling is essential as outlined in the WHO guidelines; this involves
- conducting comprehensive analyses of T cell responses,
- focusing on neutralizing antibody functionality, and
- evaluating mucosal immunity alongside systemic responses.
#3: We recommend accelerated biomarker research focusing on large-scale genomic and proteomic studies of infants with severe RSV disease post-vaccination and developing predictive in vitro assays to assess VAERD risk prior to human trials, ensuring safer and more effective vaccines.
#4: Additionally, animal models need to be improved to better replicate human RSV disease and VAERD, as suggested by the WHO guidelines by conducting comparative studies across multiple models.
Finally, we would like to highlight the need for a global RSV vaccine safety consortium to facilitate collaboration among researchers, clinicians, and regulators. This will help to ensure rapid data sharing and standardized safety assessments across trials while developing harmonized protocols for VAERD risk assessment and management. By prioritizing these steps, we can significantly improve the safety profile of RSV vaccines for pediatric populations.
In conclusion, while progress has been made in RSV vaccine development, the recent study underscores the need for continued vigilance in our approach. We must balance the urgent need for an effective RSV vaccine for children with the paramount importance of safety for children participating in clinical trials prior to approving a vaccine. By addressing these challenges head-on, we can work towards a safe and effective RSV vaccine that could significantly reduce the global burden of this disease in our most vulnerable population.