mRNA COVID-19 Booster Outperforms Protein-Based Shot on Antibodies, But Both Cut Infections Over 12 Months

A yearlong Australian trial found a bivalent mRNA fourth dose produced consistently higher antibody levels than a protein-based booster, yet the 2 vaccines reduced infections by a comparable margin through 12 months of follow-up.

Booster Uptake Remains Low Despite Ongoing Risk

COVID-19 vaccines continue to protect against severe illness and death, and updated boosters provide modest protection against symptomatic infection for up to about 3 months post-vaccination. The World Health Organization (WHO) recommends at least 1 additional dose per year—preferably every 6 months—for individuals at higher risk of severe disease, including older adults, pregnant individuals, immunocompromised patients, and frontline health care workers. Despite that guidance, global booster uptake has lagged; coverage of second or subsequent boosters among adults aged 60 and older remains at or below 31% in many settings, and overall uptake hovers around 23.6%. With supply and platform choice varying by country and pharmacy, data comparing mRNA and protein-based options head-to-head has been limited.^1-3

Comparing mRNA and Protein-Based Boosters Head-to-Head

Researchers at Murdoch Children's Research Institute (MCRI) randomly assigned 353 healthy adults aged 18 and older 1:1 to receive a bivalent mRNA booster (mRNA-1273.214/mRNA-1273.222, Moderna; n = 177) or a protein-based booster (NVX-CoV2373, Novavax; n = 176) as a fourth COVID-19 dose, each administered at least 6 months after a third dose. A self-selected control group of 143 adults who did not receive a fourth dose were also followed. Investigators measured geometric mean concentrations of anti-spike binding IgG and surrogate neutralizing antibodies against the ancestral strain and Omicron subvariants, along with interferon-gamma release assay (IGRA) results as a surrogate marker of T-cell response, at 6 and 12 months post-vaccination. The study authors describe it as the first direct, long-term comparison of immunogenicity and efficacy between an mRNA and a protein-based COVID-19 vaccine platform out to a full year.^1-3

mRNA Produced Higher Antibodies, But Similar Real-World Protection

IgG levels against the ancestral strain were about 59% higher in the Moderna group than the Novavax group at 6 months and 34% higher at 12 months. A similar pattern held against Omicron BA.1, BA.4/5, and JN.1 subvariants, with the Moderna advantage ranging from roughly 62% to 66% at 6 months and 33% to 43% at 12 months. Neutralizing antibody results tracked closely with the binding-antibody findings, but IGRA responses did not differ significantly between the 2 vaccine groups at either timepoint. Both boosted groups maintained higher antibody levels than the unboosted control group throughout follow-up.¹

Despite the antibody gap favoring mRNA, real-world protection converged in a post hoc analysis covering the period when the Omicron variant JN.1 subvariant was dominant in Australia (November 2023 to June 2024); 43.0% of the Moderna group (74 of 172) and 47.0% of the Novavax group (77 of 164) had a confirmed SARS-CoV-2 infection over 12 months, compared with 68.1% (94 of 138) of controls. Nearly all breakthrough infections in both vaccine groups were mild or asymptomatic, with no serious infections reported during the study period.^1,2

What This Means for Pharmacists Administering Boosters

For pharmacists counseling patients on a fourth or later dose, the findings suggest platform choice may matter less than simply staying up to date. Both mRNA and protein-based boosters produced meaningfully higher antibody levels than no fourth dose at all, and neither vaccine showed a clear real-world efficacy edge over the other through 12 months—even though the mRNA option generated a stronger antibody signal. For patients hesitant about a specific platform, or in settings where one vaccine is more readily available, the data offer reassurance that either option provides comparable protection over the first year.¹

Expert Insights

Pharmacy Times spoke with Paul V. Licciardi, BSc(Hons), PhD, vaccine immunology group leader at Murdoch Children's Research Institute and senior author of the study, about the immunogenicity findings, what's next for the cohort, and what pharmacists should know when counseling patients on booster choice.

Pharmacy Times: Your study found mRNA boosters produced higher antibody responses, but both vaccine types showed comparable protection against infection and similar durability over 12 months. What do you think explains that gap between antibody levels and actual clinical effectiveness?

Paul V. Licciardi, BSc(Hons), PhD: I think there are a couple of possible reasons for this. First, we do not know how much antibody is required to protect against infection, symptomatic or asymptomatic, so it is possible that the antibody levels observed in both vaccine groups were sufficient to protect over the period of our study. The other explanation is that when we measured T-cell responses, which are recognized as being important for protection against more severe disease, these were at a similar level between the 2 groups. It's important to note that infections in both groups were mostly asymptomatic or mild, with no serious infections detected during the study. I think it is likely a combination of those 2 aspects, but we can't exclude the possibility of other immunological factors that we did not measure in our study.

Pharmacy Times: You've now received funding to follow this cohort out to 30 months to study repeated mRNA vaccination specifically. What's the open question you're most hoping that longer follow-up answers?

Licciardi: Yes, we are pleased to receive funding from the Australian government to continue follow-up of this cohort in terms of the persistence of protective immunity. However, repeated mRNA vaccination is reported to skew responses toward antibodies with less function, though the clinical significance of this shift is unclear. Most of the evidence for this has come from smaller studies with short follow-up periods, so we have a real opportunity to determine whether such an effect occurs in our RCT, which is a gold-standard study design, and the duration of such an effect. This will be a very important contribution to our understanding of the long-term effects of repeated mRNA vaccination.

Pharmacy Times: For pharmacists administering fourth or later COVID-19 boosters, does this finding change how they should counsel patients choosing between an mRNA and a protein-based option, or is the takeaway that either is a reasonable choice?

Licciardi: From our data, we believe either vaccine provides a similar benefit, at least over the first 12 months. So, the recommendation to get vaccinated using whatever vaccine, mRNA or protein, is currently available is still valid. Our longer-term data may provide more insights into how these vaccines perform beyond 12 months.

REFERENCES

1. Mazarakis N, Toh ZQ, Neal E, et al. Immunogenicity and efficacy over 12 months following a fourth dose of a bivalent mRNA or protein-based COVID-19 vaccine: a randomised controlled trial in Australia. J Infect. 2026;92(4):106727. doi:10.1016/j.jinf.2026.106727

2. COVID-19 booster strategies provide lasting immunity. News release. Murdoch Children’s Research Institute; EurekAlert! Released July 16, 2026. Accessed July 20, 2026. https://www.eurekalert.org/news-releases/1136154

3. COVID-19 vaccines. World Health Organization. Updated May 15, 2026. Accessed July 20, 2026. https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-vaccines