COVID-19 Booster Comparison Shows Higher Antibody Levels With mRNA Vaccine

A randomized controlled trial conducted by the Murdoch Children's Research Institute (MCRI) in Melbourne, Australia, found that a fourth dose of a bivalent mRNA COVID-19 vaccine generated higher and more durable antibody responses than a protein-based vaccine over 12 months, though both vaccines conferred similar protection against SARS-CoV-2 infection. The findings, published in the Journal of Infection, are described by the study authors as the first direct comparison of long-term immunogenicity and efficacy between an mRNA and a protein COVID-19 vaccine given as a fourth dose.¹

"This research provides valuable evidence showing that smaller vaccine doses can still provide strong, long-lasting immunity, which is encouraging for countries looking for practical and affordable ways to deliver booster programs," Nadia Mazarakis, MCRI postdoctoral researcher of vaccine immunology, said in a news release.²

About The Study

Adults 18 years and older who had received a third COVID-19 vaccine dose at least 6 months earlier were randomized 1:1 to receive a bivalent mRNA vaccine (mRNA-1273.214/mRNA-1273.222, Moderna; n = 177) or a protein-based vaccine (NVX-CoV2373, Novavax; n = 176) as a fourth dose. A nonrandomized, age-matched control group that did not receive a fourth dose (n = 143) was also followed for comparison.¹

Participants were assessed at baseline, 28 days, 6 months, and 12 months post-vaccination (3 time points for the control group), with blood samples used to measure binding IgG antibodies, surrogate neutralizing antibodies, and interferon-gamma release assay (IGRA) responses as a proxy for T-cell immunity against the Ancestral strain and Omicron subvariants BA.1, BA.4/5, and JN.1.1 The trial ran from February 2023 through 12-month follow-up visits with the JN.1 infection wave circulating in Australia between November 2023 and June 2024, overlapping the study's 6- and 12-month assessments.¹

IgG levels against the Ancestral strain were higher in the Moderna group than the Novavax group at 6 months (geometric mean ratio [GMR], 1.59; 95% CI, 1.38-1.82) and 12 months (GMR, 1.34; 95% CI, 1.16-1.55), with similar patterns for the Omicron variants tested. Neutralizing antibody results followed the same pattern, ranging from a GMR of 1.35 to 2.22 favoring Moderna across timepoints and variants. Both vaccine groups showed higher IgG levels than the control group at 6 and 12 months, though for Novavax, this advantage over the control was observed mainly at the 6-month timepoint. Despite these antibody differences, IGRA responses were similar between the Moderna and Novavax groups at every timepoint, suggesting comparable T-cell immunity between the 2 vaccine types.¹

Over the 12-month follow-up, SARS-CoV-2 infection occurred in 68.1% (94 of 138) of participants in the control group, compared with 43.0% (74 of 172) in the Moderna group and 47.0% (77 of 164) in the Novavax group. Post-hoc vaccine efficacy against combined documented and undocumented infection was 33% (95% CI, 17%-46%) for Moderna and 29% (95% CI, 13%-42%) for Novavax over the full 12 months.¹

Efficacy was considerably higher in the first 6 months after vaccination, at 61% (95% CI, 38%-75%) for Moderna and 50% (95% CI, 23%-68%) for Novavax, before declining to 12% and 17%, respectively, between 6 and 12 months. All identified SARS-CoV-2 infections were mild and did not require hospitalization. Adverse events over the 12-month period were uncommon across both vaccine groups combined (5.4%; 19 of 353), with most classified as mild. There were 2 serious adverse events, supraventricular tachycardia and myocarditis, which were possibly related to vaccination.¹

"These trial results demonstrate that shaping effective public health policy requires monitoring long-term immune responses across diverse settings with variable infection rates and different primary vaccine schedules," Claire von Mollendorf, associate professor and MCRI team leader for new vaccines, said in a news release.²

Current COVID-19 Vaccination Landscape

These 12-month trial results land amid a shifting vaccination landscape. Interim data from the CDC-led Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), covering encounters from September through December 2025, found the 2025-2026 monovalent COVID-19 vaccines—updated to the Omicron JN.1 lineage and preferentially targeting the LP.8.1 strain—provided a vaccine effectiveness of 50% against emergency department/urgent care encounters and 55% against hospitalization among immunocompetent adults.³

Because JN.1 descendants, including LP.8.1, have remained the dominant global lineages since late 2023, the VISION findings and the MCRI trial's use of a JN.1-era infection wave to assess real-world protection are complementary: both indicate that Ancestral strain-primed immunity, whether reinforced with an updated JN.1-lineage vaccine or an older Ancestral/BA.1-BA.4/5 bivalent booster has continued to provide meaningful cross-protection against JN.1-descendant variants.^1,3

Vaccination policy has also changed since the MCRI trial's enrollment period. In September 2025, the Advisory Committee on Immunization Practices (ACIP) recommended that COVID-19 vaccination for people 6 months and older be based on individual or shared clinical decision-making rather than a universal recommendation, a shift the CDC adopted in October 2025. A federal court stayed certain other 2025 ACIP-driven schedule changes in March 2026, though the May 2025 COVID-19 vaccine recommendation itself was not affected by that stay.³

Pharmacists remain a primary point of access for COVID-19 vaccination and are often best positioned to discuss individualized risk-benefit considerations with patients under this shared decision-making framework, using effectiveness data such as the MCRI trial's findings and the current VISION estimates to guide those conversations.³

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;92:106727. doi:10.1016/j.jinf.2026.106727

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

3. Gallagher A. 2025-2026 COVID-19 vaccines cut risk of hospitalization nearly in half. Drug Topics. July 7, 2026. Accessed July 16, 2026. https://www.drugtopics.com/view/2025-2026-covid-19-vaccines-cut-risk-of-hospitalization-nearly-in-half