What is the role of messenger RNA (mRNA) in Covid-19 vaccines, such as Pfizer-BioNTech (Comirnaty) and Moderna (mRNA-1273)?

Role of mRNA in COVID-19 Vaccines

mRNA in COVID-19 vaccines functions as a genetic blueprint that instructs human cells to produce the SARS-CoV-2 spike protein, triggering an immune response without using any live virus components, making it both effective and safe for preventing COVID-19 disease and its complications. 1

Mechanism of Action

• The Pfizer-BioNTech (Comirnaty) and Moderna (mRNA-1273) COVID-19 vaccines use messenger RNA (mRNA) technology that delivers genetic instructions to cells, resulting in temporary expression of the SARS-CoV-2 spike protein 1
• The mRNA is encapsulated within lipid nanoparticles that facilitate its entry into host cells, where cellular machinery translates the mRNA into the SARS-CoV-2 spike protein 1, 2
• Once produced, the spike protein appears on the cell surface where it is recognized by the immune system as a foreign antigen, triggering both antibody (humoral) and cellular immune responses 1
• Unlike traditional vaccines using weakened or inactivated viruses, mRNA vaccines do not contain any live virus components and therefore cannot cause COVID-19 infection 1
• The mRNA does not enter the cell nucleus or interact with DNA, and is degraded shortly after protein production, leaving no permanent genetic material in the body 1

Evolution of mRNA COVID-19 Vaccines

• The original monovalent mRNA vaccines contained genetic material coding for the spike protein from the ancestral (Wuhan-hu-1) strain of SARS-CoV-2 3
• As new variants emerged with the potential to evade immunity, bivalent booster formulations were developed 3, 4
• Bivalent boosters contain equal amounts of mRNA encoding spike proteins from both the original strain and the Omicron BA.4/BA.5 sublineages 3, 4, 5
• These bivalent formulations were designed to expand immune protection against currently circulating Omicron variants while maintaining protection against the original strain 3, 4

Clinical Effectiveness

• In clinical trials, the original Pfizer-BioNTech vaccine demonstrated 95% efficacy in preventing symptomatic COVID-19 infection 1, 2
• Effectiveness of monovalent COVID-19 vaccines was high after initial introduction but showed declining protection over time, particularly during the Omicron-predominant period 3
• During the BA.4/BA.5 period, monovalent vaccine effectiveness against COVID-19–associated hospitalization among immunocompetent adults was 49% at 14–149 days after dose 3 and declined to 34% ≥150 days after dose 3 3
• Bivalent boosters were developed specifically to address this waning immunity and improve protection against newer variants 3, 4

Safety Profile

• The most common adverse reactions to mRNA COVID-19 vaccines include injection site reactions (60.8%) and systemic reactions (54.8%) in the week after vaccination 5
• Serious adverse events are rare, with less than 1% of vaccine recipients requiring medical care after vaccination 5
• Myocarditis has been identified as a rare risk after mRNA COVID-19 vaccination, primarily affecting adolescent and young adult males 3
• The risk of myocarditis is higher after the second dose and is highest among male individuals between the ages of 16 and 19 years (risk difference of 137 per million) 3
• Despite this rare risk, benefit-risk assessments have consistently shown that the benefits of vaccination outweigh the risks across all age and sex groups, even in the highest risk subgroups 6

Current Recommendations

• The Advisory Committee on Immunization Practices (ACIP) recommends that all persons aged ≥5 years receive a bivalent mRNA COVID-19 vaccine booster dose to improve protection against COVID-19 3, 4
• The bivalent booster should be administered at least 2 months after completion of any FDA-approved or FDA-authorized primary series or monovalent booster doses 3, 4
• Persons who recently had a SARS-CoV-2 infection may consider delaying a booster dose by 3 months from symptom onset or positive test result 4

Important Considerations

• The mRNA technology allows for rapid adaptation of vaccines to address emerging variants, as demonstrated by the development of bivalent boosters targeting Omicron subvariants 7
• Unlike traditional vaccine platforms, mRNA vaccines do not require growing large amounts of virus, allowing for faster development and manufacturing 1
• The temporary nature of mRNA in the body (degraded within days) addresses safety concerns about long-term genetic effects 1
• Despite initial concerns about a novel vaccine platform, real-world evidence has confirmed both the safety and effectiveness of mRNA COVID-19 vaccines in preventing severe disease, hospitalization, and death 6