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Open Access | 
10.1172/JCI195933
When more isn’t better: the surprising superiority of glycoprotein-only Marburg vaccines
Pablo Penaloza-MacMaster
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Published September 2, 2025 - More info
J Clin Invest. 2025;135(17):e195933. https://doi.org/10.1172/JCI195933.
© 2025 Penaloza-MacMaster This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Although virus-like particle (VLP) vaccines were shown to be effective against several viruses, their advantage over vaccines that include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding the Marburg virus (MARV) full-length glycoprotein (GP) delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 were coexpressed. We vaccinated guinea pigs with a 2-component mRNA vaccine encoding GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than did the GP-only mRNA vaccine. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP vaccine conferred only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cell responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole-blood RNA-Seq revealed that the VLP vaccine downregulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated IFN signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection with a dose of as little as 1 μg in guinea pigs.
Authors
Chandru Subramani, Michelle Meyer, Matthew A. Hyde, Margaret E. Comeaux, Haiping Hao, James E. Crowe Jr., Vsevolod L. Popov, Harshwardhan Thaker, Sunny Himansu, Andrea Carfi, Alexander Bukreyev
Marburg virus (MARV) is classified by the WHO as a priority pathogen due to its high fatality rate and potential to cause outbreaks. Despite the evaluation of various MARV vaccine candidates, there is currently no licensed vaccine, and the optimal antigen formulation for achieving protective immunity remains unclear.
Virus-like particle–based (VLP-based) vaccines represent a versatile and effective platform that has been successfully implemented in several clinically approved vaccines, including those against human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis E virus (HEV). VLPs can self-assemble into nanostructures that mimic the morphology of authentic viruses but lack replicative genetic material, rendering them noninfectious. By recapitulating the structural features of native virions, VLPs can elicit antigenically relevant immune responses, including neutralizing antibodies that recognize conformational epitopes.
In addition to the surface glycoprotein (GP), VLPs can be engineered to include other structural viral antigens, with the aim of broadening immune responses and potentially enhancing protection beyond what is achieved with vaccines targeting only a single antigen. For example, studies conducted by my research group and others showed that SARS-CoV-2 vaccines expressing both spike and nucleoprotein are more protective than vaccines expressing either antigen alone (1, 2), suggesting that multiantigen formulations can potentiate vaccine efficacy. VLPs comprising multiple antigens are being explored for various pathogens like HIV (3) and filoviruses (4, 5), but whether inclusion of multiple antigens universally enhances vaccine efficacy remains an open question.
In this issue of the JCI, a study by Subramani and colleagues compared the protective efficacy of a MARV mRNA vaccine encoding only the GP with a vaccine encoding both the GP and the VP40 matrix protein, which self-assemble to form VLPs (6). At high vaccine doses, both vaccines conferred 100% protection against lethal MARV challenges. However, at low vaccine doses, the GP-only vaccine maintained full protection, whereas the VLP-based vaccine expressing both GP and VP40 conferred only partial protection. These findings demonstrate that under suboptimal dosing conditions, a multicomponent vaccine encoding both GP and VP40 is less effective than a monovalent GP-only vaccine.
This study also underscores the importance of empirically validating assumptions about antigenic breadth in multicomponent vaccine formulations. While VLPs offer structural and immunological advantages that can broaden immune responses to multiple epitopes, the inclusion of additional viral antigens beyond the surface GP does not universally improve protective immunity and, in some cases, may even interfere with other responses. These results warrant a reevaluation of VLP vaccine design for Marburg and other filoviruses and potentially for additional viruses for which similar assumptions about the superiority of VLPs have been made.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)