For patients aged 65 and older, which mRNA COVID-19 vaccine—Spikevax (mRNA‑1273) or Comirnaty (BNT162b2)—offers superior efficacy?

Spikevax (mRNA-1273) Demonstrates Superior Efficacy Over Comirnaty (BNT162b2) in Adults ≥65 Years

For patients aged 65 and older, Spikevax (mRNA-1273) is the preferred COVID-19 vaccine based on superior real-world effectiveness against symptomatic infection, hospitalization, and severe disease compared to Comirnaty (BNT162b2).

Regulatory Framework

Both vaccines are FDA-approved for adults ≥65 years 1, 2. The 2024-2025 ACIP guidelines recommend either mRNA vaccine for this population, requiring a single dose if previously vaccinated, administered ≥8 weeks after the last dose 3. While guidelines do not differentiate between the two vaccines, emerging evidence supports preferential use of mRNA-1273.

Comparative Effectiveness Evidence

Most Recent Real-World Data (2026)

The highest quality recent evidence comes from a large US retrospective study evaluating the 2025-2026 vaccine formulations 4. Among adults ≥65 years:

• mRNA-1283 (Spikevax): 59.3% effectiveness against COVID-19 hospitalization and 42.0% against medically attended COVID-19
• BNT162b2 (Comirnaty): 48.3% effectiveness against hospitalization and 41.2% against medically attended COVID-19

The advantage was even more pronounced in adults ≥75 years, where mRNA-1283 showed 66.9% effectiveness against hospitalization versus 45.9% for BNT162b2 4.

Systematic Review and Meta-Analysis

A 2024 systematic review and meta-analysis of 24 observational studies demonstrated that mRNA-1273 was associated with significantly lower risk across multiple outcomes in adults ≥50 years 5:

• SARS-CoV-2 infection: 28% relative risk reduction (RR 0.72)
• Symptomatic infection: 28% relative risk reduction (RR 0.72)
• Severe infection: 33% relative risk reduction (RR 0.67)
• COVID-19 hospitalization: 35% relative risk reduction (RR 0.65)

Durability of Protection

A 2022 Veterans Affairs study of 4.8 million veterans (mean age 64 years) revealed critical differences in durability 6. In adults ≥65 years:

• Month 7 effectiveness against symptomatic infection: mRNA-1273 maintained 36.2% effectiveness versus BNT162b2 at -23.3% (indicating negative protection)
• Month 7 effectiveness against hospitalization: mRNA-1273 maintained 64.7% versus BNT162b2 at 1.7%

This demonstrates that mRNA-1273 provides substantially more durable protection in older adults.

Immunogenicity Data

A 2025 head-to-head immunogenicity study in elderly individuals (n=129) showed Spikevax induced 7:

• Significantly higher percentages of IFNγ+CD8+ and CD4+ T cells against XBB.1.5 (p<0.001)
• Higher neutralizing antibody titers against XBB1.5, JN.1, and KP.2 variants
• Higher positive T cell response rates (64.3% CD8, 71.4% CD4) versus Comirnaty (42.4% CD8, 57.6% CD4)

Safety Considerations

Common Pitfall: Providers may hesitate to recommend mRNA-1273 due to concerns about reactogenicity.

The evidence shows:

• Fever is more common with Spikevax (p=0.006) 7
• All side effects are short-term and self-resolving 7
• Both vaccines have similar myocarditis/pericarditis rates in older adults (approximately 8 cases per million doses in adults 6 months-64 years) 2
• The myocarditis risk is predominantly in males 12-24 years, not the ≥65 population 2

The slightly higher fever rate should not deter use given the substantial efficacy advantage.

Clinical Algorithm for Vaccine Selection

For patients ≥65 years presenting for COVID-19 vaccination:

1. First-line recommendation: Spikevax (mRNA-1273)

   • Superior effectiveness against hospitalization and symptomatic disease
   • More durable protection over time
   • Stronger cellular and humoral immune responses

2. Alternative (Comirnaty/BNT162b2): Only if:

   • Patient specifically requests it after counseling
   • Spikevax unavailable
   • Previous severe allergic reaction to mRNA-1273 components

3. Timing: Administer ≥8 weeks after last COVID-19 vaccine dose 3

Cost-Effectiveness

Economic modeling demonstrates mRNA-1273 dominates BNT162b2 in high-risk populations ≥65 years, providing improved clinical outcomes at lower cost 8. The benefit-cost ratio ranges from 1.91-7.90, meaning every dollar spent on mRNA-1273 returns approximately $2-8 in societal savings 8.

Key Takeaway

The preponderance of evidence—including the most recent 2026 real-world effectiveness data, systematic reviews, and immunogenicity studies—consistently demonstrates superior protection with mRNA-1273 versus BNT162b2 in adults ≥65 years. While both vaccines are acceptable per guidelines 3, the evidence supports preferential use of Spikevax for this vulnerable population to maximize protection against hospitalization and severe disease.