Comparing mRNA and Protein-Based COVID-19 Vaccine Platforms at the Pharmacy Counter

Although COVID-19 is no longer a declared public health emergency, SARS-CoV-2 continues to circulate widely and remains a measurable burden on the US health care system. The CDC estimates that COVID-19 was responsible for roughly 43.6 million illnesses, 10 million outpatient visits, 1.1 million hospitalizations, and approximately 101,300 deaths during the October 2022 to September 2023 surveillance period; burden declined the following year but remained substantial, with an estimated 33 million illnesses and roughly 100,800 deaths between October 2023 and September 2024.¹ COVID-19 was the tenth leading cause of death in the United States in 2023; COVID-19 continues to account for hundreds of thousands of hospitalizations and tens of thousands of deaths each year.² These data are a reminder that, even as public attention has moved on from the pandemic, COVID-19 is still a concern for much of the population pharmacists serve.

Vaccination remains the most effective tool for reducing this burden. CDC data show that the 2023-2024 COVID-19 vaccines reduced the risk of critical illness by almost 70% in adults during the first 2 months after vaccination, with roughly 50% protection persisting through 10 months; hospitalization risk was reduced by about 50% in the first 2 months, tapering to about 30% by 10 months.² A similar level of protection was observed in adults 65 years and older, among whom updated vaccines reduced critical illness risk by about 67% shortly after vaccination, and in people with weakened immune systems, who saw hospitalization risk reduced by about 36% in the first 2 months following vaccination.² Vaccinated individuals who contract COVID-19 are also less likely to develop long COVID than those who are unvaccinated or not up to date.²

COVID-19 vaccination in the United States now relies on 2 distinct platforms, mRNA vaccines and the adjuvanted, protein-based vaccine, that differ in mechanism, reactogenicity, and how patients perceive their safety. Both platforms have demonstrated strong protection against symptomatic and severe COVID-19 in clinical trials and real-world use, but persistent hesitancy tied to the mRNA platforms’ novelty and adverse effect profiles continues to complicate counseling at the point of care.³

SARS-CoV-2 vaccines were developed across several platform types, including mRNA, protein subunit, viral vector, and inactivated virus vaccines, each using a different strategy to present the spike protein to the immune system.⁴ In the United States, the mRNA vaccines from Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) and the protein-based vaccine remain widely available, making the mechanistic distinction between these 2 platforms directly relevant to most COVID-19 vaccination encounters pharmacists will have with patients.

How the 2 Platforms Work

mRNA vaccines deliver synthetic mRNA into the cytoplasm where it ultimately produces the SARS-CoV-2 spike protein which is recognized by antigen-presenting cells to elicit immune protection.³ The process mimics natural infection without live or inactivated pathogens, achieving immunization by endogenous antigen production.³

Protein-based vaccines use a different strategy: A recombinant nanoparticle containing the full-length, stabilized spike protein is manufactured directly and administered alongside a saponin-based adjuvant, Matrix-M, which enhances the immune response.⁵ Because the antigen is delivered preformed rather than produced by host cells, this platform’s mechanism resembles established protein-subunit vaccines pharmacists may already be familiar with, such as inactivated influenza, shingles, or hepatitis B vaccines.

Efficacy data established for the 2 platforms are similar. Protein-based vaccines in a United Kingdom 2021 phase 3 trial (2020-004123-16) found 89.7% efficacy against symptomatic COVID-19 (95% CI, 80.2-94.6), including 86.3% efficacy against the B.1.1.7 (alpha) variant specifically.⁶ A companion US and Mexico trial (NCT04611802) reported 90.4% overall efficacy (95% CI, 82.9-94.6) and 100% efficacy against moderate to severe disease.⁷ In its 2022 interim recommendation, the CDC’s Advisory Committee on Immunization Practices (ACIP) cited a per-protocol vaccine efficacy of 89.6% (95% CI, 82.4%-93.8%) in adopting the protein-based vaccine for adults 18 years and older.⁵ An Israeli study in 2022 of the mRNA vaccine BNT162b found 96.8% efficacy for people 16-59 years old (95% CI, 96.0-97.5) and 93.1% efficacy for people aged 60 years or older (95% CI, 91.8-94.2) against infection and for reducing severe disease.⁸ The ACIP 2022 recommendation of Moderna’s mRNA-1273 cites the vaccine efficacy based on phase 3 trial (NCT04470427) results at 92.7% in adults without evidence of prior infection, and a 100% efficacy against COVID-19-associated deaths.⁹

Comparing Reactogenicity and Safety

Where the platforms diverge most clearly is in reactogenicity, including injection-site pain, fatigue, and fever. In a real-world booster study, 84.3% of mRNA vaccine recipients reported at least 1 systemic reactogenicity event within 2 days of vaccination, compared with 60.5% of protein-based vaccine recipients; 61.4% of mRNA recipients reported 3 or more systemic symptoms, compared with 33.9% of protein-based vaccine recipients.¹⁰ Local reactogenicity followed a similar pattern, occurring in 91.7% of mRNA recipients vs 73.4% of protein-based vaccine recipients.¹⁰

A United Kingdom randomized phase 2 trial, COV-BOOST (ISRCTN73765130) that compared third-dose COVID-19 vaccines directly with a routine meningococcal conjugate vaccine (MenACWY) found that mRNA vaccines, particularly mRNA-1273, were associated with the greatest relative increase in adverse effects. In contrast, the protein-based vaccine elicited reactogenicity levels similar to those of MenACWY.¹¹ Newly reported data from the COMPARE trial (NCT07051031), a randomized, double-blind head-to-head study of protein-based and mRNA vaccines NVX-CoV2705 and mRNA-1283, found statistically significant lower systemic reactogenicity in the protein-based vaccine compared with the mRNA counterpart, with 91.6% of mRNA recipients experiencing at least 1 systemic reaction within 7 days of vaccination compared with 83.6% of protein-based recipients.¹² Moderate to severe systemic symptoms were also lower, with 43.1% of protein-based recipients experiencing grade 2 or 3 systemic symptoms compared with 61.3% of mRNA recipients.¹²

Serious adverse events remain rare across both platforms. The CDC notes that the COVID-19 vaccination minimally increases the risk of myocarditis and pericarditis, and recommends counseling patients on this risk while directing them to credible safety-monitoring resources such as the Vaccine Adverse Event Reporting System (VAERS) and V-Safe.¹³ Updated evidence published in the New England Journal of Medicine found myocarditis rates of 1.3 to 3.1 cases per 100,000 doses among male adolescents receiving mRNA vaccines, with a lower risk associated with longer intervals between doses.¹⁴

Addressing Vaccine Hesitancy at the Counter

Vaccine hesitancy in the United States stems from a complex, interconnected set of factors. A 2024 systematic review of 544 US-based studies published between 2022 and 2023 found that health concerns, such as fear of adverse effects and uncertainty about long-term effects, were the most commonly cited predictors of hesitancy, closely followed by concerns tied to the speed of vaccine development and the underlying technology itself, and by broader mistrust of the institutions involved in developing, authorizing, and distributing vaccines.¹⁵ Patients who experienced pronounced systemic symptoms after an mRNA dose may benefit from learning that a protein-based option exists and has demonstrated comparable protection with a milder reactogenicity profile in head-to-head comparisons.^10-12 Distinguishing expected and mild to moderate reactogenicity, such as pain, fatigue, or low-grade fever lasting 1 to 2 days, from rare but serious adverse events is central to this conversation, since unaddressed adverse effect concerns are a recognized driver of vaccine refusal and delayed booster uptake.¹⁵

Misinformation and systemic or institutional factors, such as inconsistent public messaging and inequitable access to care, were also recurring contributors, particularly among ethnic and racial minority populations and patients from lower socioeconomic backgrounds.¹⁵ For patients
whose hesitancy is rooted in institutional mistrust or exposure to misinformation, however, adverse effect counseling alone is unlikely to resolve the underlying concern; these conversations tend to benefit more from
transparent, nonjudgmental communication than from technical reassurance.¹⁵

Encouragingly, the same review found that trust and confidence in the vaccine and in the people recommending it were the single strongest drivers of vaccine uptake, and that a health care provider’s recommendation was among the top factors patients cited for getting vaccinated.¹⁵ A short, specific conversation at the counter, about whatever the patient is actually worried about, does more than a generic pitch.

What This Means for Pharmacists

Pharmacists administering COVID-19 vaccines can use platform-specific knowledge as a counseling tool rather than a technical footnote. For patients who report or fear strong reactogenicity, explaining that the protein-based vaccine has shown lower rates of systemic and local reactions than mRNA vaccines in real-world studies offers an evidence-based alternative rather than a reason to decline vaccination altogether.^10-12

For patients wary of mRNA technology specifically, pharmacists can explain in plain terms that mRNA is not incorporated into human DNA, is cleared within a few days, and has been evaluated across billions of doses administered without evidence of long-term genetic effects.³ This kind of mechanistic clarity, delivered briefly and without jargon, directly addresses one of the most commonly cited sources of mRNA-specific hesitancy.

At the point of vaccination, pharmacists are well-positioned to set expectations proactively: describing the typical timeline and severity of adverse effects before the injection, distinguishing expected adverse effects from signs that warrant medical attention (such as chest pain or shortness of breath suggestive of myocarditis), and directing patients with additional questions to resources like VAERS or V-Safe.¹¹ Framing the choice between platforms, where clinically appropriate and available, as an opportunity to match a patient’s tolerance for reactogenicity with an equally protective option can convert a hesitant encounter into a completed vaccination. These conversations also offer pharmacists the opportunity to inform patients of other vaccines they may be due for, such as the flu vaccine. CDC guidance supports coadministration of flu and COVID-19 vaccines: Patients who are eligible and due for both can receive them at the same visit, and doing so is generally encouraged as a way to help patients stay up to date without requiring multiple visits.¹⁶

Conclusion

The choice between mRNA and protein-based vaccines matters less than getting patients vaccinated at all. Both offer strong, comparable protection against symptomatic and severe disease, and the differences between them are details pharmacists can use to meet patients where they are. Concerns about adverse effects can be addressed through platform choice. Mistrust and misinformation need a slower, more direct conversation. And with flu season bringing more patients through the door, coadministration is a practical way to close immunization gaps in a single visit.

References

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2. Centers for Disease Control. Benefits of getting vaccinated. June 10, 2025. Accessed September 1, 2026. https://www.cdc.gov/covid/vaccines/benefits.html

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6. Heath PT, Galiza EP, Baxter DN, et al. Safety and efficacy of NVX-COV2373 Covid-19 vaccine. N Engl J Med. 2021;385(13):1172-1183. doi:10.1056/NEJMoa2107659

7. Dunkle LM, Kotloff KL, Gay CL, et al. Efficacy and safety of NVX-COV2373 in adults in the United States and Mexico. N Engl J Med. 2022;386(6):531-543. doi:10.1056/NEJMoa2116185

8. Glatman-Freedman A, Bromberg M, Hershkovitz Y, et al. Effectiveness of BNT162b2 vaccine booster against SARS-CoV-2 infection and breakthrough complications, Israel. Emerg Infect Dis. 2022;28(5):948-956. doi:10.3201/eid2805.220141

9. Wallace M, Moulia D, Blain AE, et al. The Advisory Committee on Immunization Practices’ recommendation for use of Moderna COVID-19 vaccine in adults aged ≥18 years and considerations for extended intervals for administration of primary series doses of mRNA COVID-19 vaccines - United States, February 2022. MMWR Morb Mortal Wkly Rep. 2022;71:416-421. doi:10.15585/mmwr.mm7111a4

10. Rousculp MD, Hollis K, Ziemiecki R, et al. Reactogenicity differences between adjuvanted, protein-based, and messenger ribonucleic acid (mRNA)-based COVID-19 vaccines. Vaccines (Basel). 2024;12(7):802. doi:10.3390/vaccines12070802

11. Marchese AM, Beyhaghi H, Rousculp MD, et al. Local and systemic reactogenicity after mRNA and protein-based COVID-19 vaccines compared to meningococcal vaccine (MenACWY) in a UK blinded, randomized phase 2 trial (COV-BOOST). Vaccine. 2025;44:126569. doi:10.1016/j.vaccine.2024.126569

12. ESCMID: Sanofi’s Nuvaxovid COVID-19 vaccine showed better tolerability than mNEXSPIKE in a head-to-head study. News release. Sanofi. April 18, 2026. Accessed September 1, 2026. https://www.sanofi.com/en/media-room/press-releases/2026/2026-04-18-10-00-00-3276558

13. Centers for Disease Control. Safety considerations for COVID-19 vaccines. November 4, 2025. Accessed September 1, 2026. https://www.cdc.gov/covid/hcp/vaccine-considerations/safety-considerations.html

14. Scott J, Abers MS, Marwah HK, et al. Updated evidence for COVID-19, RSV, and influenza vaccines for 2025–2026. N Engl J Med. 2025;393:2221-2242. doi:10.1056/NEJMsa2514268

15. Nwachukwu G, Rihan A, Nwachukwu E, Uduma N, Elliott KS, Tiruneh YM. Understanding COVID-19 vaccine hesitancy in the United States: a systematic review. Vaccines (Basel). 2024;12(7):747. doi:10.3390/vaccines12070747

16. Centers for Disease Control. Getting a flu vaccine and other recommended vaccines at the same time. September 1, 2026. Accessed September 1, 2026. https://www.cdc.gov/flu/vaccines/coadministration.html