Amid US ordeal, Moderna wins EU approval for flu/COVID-19 combo shot

Moderna's mCOMBRIAX Wins EU Approval Amid US Regulatory Hurdles

Moderna has secured the European Commission’s go-ahead for its combination flu and COVID-19 vaccine, mCOMBRIAX, for active immunization of people 50 years and up across all 27 EU member states, Iceland, Liechtenstein and Norway. This regulatory win comes despite its investigational flu component, mRNA-1010, not yet being approved as a standalone shot in the EU, though it received a positive opinion from the Committee for Medicinal Products for Human Use in February. In stark contrast, the vaccine has faced considerable struggle in the U.S. Moderna withdrew its approval application in May 2025 after discussions with the FDA and later received a refusal-to-file letter for mRNA-1010 in February, citing insufficient data. The FDA has since accepted mRNA-1010 for review, setting a decision date in August, but the timeline for the combo shot's resubmission remains uncertain.

• The European Commission granted approval for Moderna's mCOMBRIAX, a combination flu and COVID-19 vaccine, for individuals aged 50 and older. This approval extends across all 27 EU member states, Iceland, Liechtenstein, and Norway. The decision followed a positive opinion from the Committee for Medicinal Products for Human Use in February, indicating a favorable regulatory environment in Europe for this novel mRNA vaccine. This marks a significant milestone for Moderna in the European market.
• In contrast to its European success, Moderna's combo vaccine has faced substantial challenges with the U.S. FDA. The company voluntarily withdrew its approval application for the two-in-one shot in May 2025. Furthermore, the FDA issued a refusal-to-file letter for the standalone flu vaccine component, mRNA-1010, in February, citing an "inadequate and well-controlled" trial. While the FDA has since accepted mRNA-1010 for review with an August decision date, the path for the combination shot in the U.S. remains unclear.
• The mCOMBRIAX vaccine is a combination of Moderna's next-generation COVID-19 vaccine, mNEXSPIKE, and its investigational flu vaccine, mRNA-1010. A Phase 3 readout in June demonstrated that mRNA-1010 outperformed a current commercial flu shot, showing a 26.6% vaccine efficacy edge in adults aged 50 years and older. This efficacy data for the flu component was a key factor, even though the EU approval for the combo shot came before standalone approval for mRNA-1010.

Addressing Unmet Needs in Flu and COVID-19 for Older Adults

Cancer patients represent a critical vulnerable population facing significant unmet needs for both influenza and COVID-19 protection. Despite available effective vaccines for major respiratory pathogens, vaccination uptake remains suboptimal in this high-risk group, leading to preventable morbidity and mortality. Multiple systemic challenges continue to impede optimal protection strategies across various populations globally.

• Cancer patients face heightened vulnerability to severe outcomes from respiratory infections including influenza and COVID-19, with increased risk of hospitalization, ICU admission, and death even in the vaccination era, while respiratory infections can delay cancer therapy and negatively affect treatment outcomes

• Vaccine hesitancy and global inequity represent major barriers to protection, driven by misinformation, political issues, and inequitable distribution especially in low- and middle-income countries, with root causes including political will limitations and profit-driven patent protection systems

• Emerging viral variants and therapeutic limitations create ongoing unmet needs, as conventional treatments fall behind constant SARS-CoV-2 mutations due to long screening processes and high production costs, while vaccine efficacy wanes over time requiring booster considerations

• Regulatory and delivery system gaps hinder optimal vaccine deployment, with underfunded and fragmented regulatory systems perpetuating access inequities, while delivery strategies require optimization to increase value and accessibility of improved vaccines globally

• Marginalized populations encounter additional access barriers due to perceptions about system inefficiency and inflexibility, requiring vaccination systems that specifically consider vulnerable group needs and community engagement to co-create solutions for improved uptake

• Next-generation therapeutic approaches are being developed to address current limitations, including functional nucleic acid-based therapeutics, broadly neutralizing monoclonal antibodies, and AI-optimized combination therapies designed for rapid adaptation to viral variants

The FDA's Stance: Comparing mCOMBRIAX to Standard of Care

Recent studies demonstrate mixed efficacy for COVID-19 investigational therapies compared to standard care, with most failing to show significant clinical benefits. Nirmatrelvir-ritonavir (Paxlovid) showed no significant difference in 28-day mortality when added to standard treatment in hospitalized patients with severe COVID-19 and comorbidities (absolute risk difference 2.27; 95% CI -2.94 to 7.49). Similarly, atorvastatin effectively reduced inflammatory markers like C-reactive protein and IL-6 in critically ill patients but failed to influence clinical outcomes or disease severity. Other agents including IC14 (anti-CD14 monoclonal antibody), ruxolitinib, and fostamatinib also demonstrated no superior efficacy compared to standard care, with some trials stopped early for futility.

The landscape for established therapies shows more promising but variable results. Remdesivir represents the most successful intervention, with multiple randomized trials suggesting efficacy in hospitalized COVID-19 patients through decreased hospital length of stay, reduced progression to mechanical ventilation, and lower hospital resource utilization, though mortality benefits remain unclear. For influenza, oseltamivir demonstrated a 26% lower risk of clinical failure specifically in patients with laboratory-confirmed influenza infection (95% CI 3.2-48.0%), though this benefit was limited to confirmed cases rather than broader respiratory tract infections.

The evidence base reveals significant challenges in translating observational study benefits to randomized controlled trial outcomes. Hydroxychloroquine, ivermectin, aspirin, molnupiravir, and tenofovir all showed statistically significant benefits in observational studies that were subsequently not confirmed in RCTs. This pattern led to regulatory approvals during the pandemic based on non-randomized evidence due to urgent treatment needs, with the notable exception that most Emergency Use Authorizations were ultimately supported by well-powered randomized controlled trials demonstrating statistically significant efficacy.

Unpacking mCOMBRIAX: Efficacy Data Supporting EU Approval

Recent clinical data demonstrates significant advances in both COVID-19 and influenza interventions across various platforms. Multiple phase 2 and 3 studies have evaluated novel vaccine technologies, therapeutic compounds, and combination strategies with promising efficacy and safety profiles.

Moderna's Combo Vaccine: EU Breakthrough, US Regulatory Challenge

Moderna's recent European Commission approval for mCOMBRIAX, its combination flu and COVID-19 vaccine for individuals aged 50 and above, marks a pivotal moment for the company and the broader mRNA vaccine landscape. This regulatory success in the EU positions Moderna as an early leader in the emerging market for multi-pathogen respiratory vaccines, offering a streamlined solution for a vulnerable population. Studies have consistently demonstrated the high effectiveness of Moderna's COVID-19 vaccine in preventing severe outcomes, including hospitalization, among older adults, reinforcing the clinical value of this combined approach. This approval not only diversifies Moderna's product portfolio beyond its foundational COVID-19 vaccine but also leverages its innovative mRNA platform for broader applications in seasonal disease prevention.

However, the path to global market penetration is not without its complexities. The stark contrast with the US regulatory experience, where the investigational flu component faced a refusal-to-file and the combo shot's resubmission remains uncertain, highlights significant challenges. This divergence underscores the varied regulatory requirements and data interpretations across different health authorities. For Moderna, this means:

• Navigating distinct regulatory pathways: A tailored approach to clinical data presentation and regulatory engagement will be critical for securing US approval, potentially requiring additional studies or a revised submission strategy.

• Managing market access timelines: Delays in the US could impact overall revenue projections and allow competitors to gain ground in this lucrative market.

• Sustaining public and regulatory confidence: Transparent communication regarding the safety and efficacy of the combination vaccine, particularly concerning any rare adverse events associated with mRNA technology, will be paramount.

While the EU approval is a clear win, the company must meticulously address the US regulatory hurdles and prepare for an increasingly competitive landscape. The long-term success of mCOMBRIAX, and indeed the future of mRNA combination vaccines, will hinge on Moderna's ability to harmonize its global regulatory strategy and continue demonstrating robust safety and efficacy across diverse populations.