Exploring hybrid mRNA vaccine technology for lasting immunity to COVID-19

Vaccine Insights 2024; 3(1), 13–16

DOI: 10.18609/vac.2024.004

Published: 2 February
Magnus Hoffmann

While COVID-19 vaccines have proven effective, the need for lasting immunity has prompted exploration beyond conventional approaches. Casey Nevins, Assistant Editor, Vaccine Insights, speaks with Magnus Hoffmann, Merkin Institute Fellow in the Merkin Institute for Translational Research at Caltech, about his work on developing a hybrid mRNA vaccine technology and its potential to address the limitations of current COVID-19 vaccines.

What influenced you to start working with vaccines?

MH: I was really fascinated by trying to understand how drugs work and how they affect the human body, so I ended up studying pharmacy at Bath University, UK. However, I became frustrated with how limited our treatment options were for a lot of conditions. I wanted to work on developing new and better drugs so I decided to do a PhD in Pamela Bjorkman’s lab at Caltech. Pamela’s group has a long-standing interest in the characterization of monoclonal antibodies against various infectious diseases such as HIV-1 and SARS-CoV-2. The lab also focuses on the design of immunogens to make more effective vaccines against those diseases.

During my PhD, we developed a new hybrid mRNA vaccine technology—ESCRT-and ALIX-binding region (EABR) technology. Based on that work, I received a National Institute of Health Director’s Early Independence Award to launch my own laboratory at Caltech as an independent postdoctoral fellow. My team is focused on continuing to develop this technology.

What current gaps or challenges in existing COVID-19 vaccine approaches led you to explore different vaccine technologies?

MH: The current COVID-19 vaccines are effective, but they do have two main problems. The first problem is that the antibody titers that get elicited by COVID-19 vaccines contract relatively quickly over time. You get your shot, and then a few months later, you might not be fully protected anymore.

The second problem is that viruses like SARS-CoV-2 rapidly evolve to escape from immune responses elicited by vaccination or previous infections. For instance, the initial prime/boost regimens of the COVID-19 mRNA vaccines did not elicit effective antibody responses against the omicron-based variants that emerged later in the pandemic. As a result, we need to get frequent and updated booster shots, which is expensive and inconvenient.

There is a great need for innovative vaccine technologies to be able to induce more lasting protection.

Does your vaccine prototype offer an enhanced antibody response compared with existing mRNA vaccines?

MH: In mouse studies, our hybrid mRNA vaccine approach elicited about fivefold higher neutralizing antibody titers against the original variant as well as the Delta variant. The binding titers were also higher. Furthermore, in some cases, this technology elicited over tenfold higher titers against some of the omicron-based variants.

That being said, against the BA.5 omicron variant and some of the variants that came after that, like BQ.1.1 and XBB.1, the titers dropped considerably. This was, however, just an initial prime/boost regimen. In the human population, BA.5 only appeared after we had already received three immunizations. Had we given a third immunization in our mouse study, we may have seen high titers against these variants. We are currently testing this theory, evaluating our technology as a booster shot in pre-immunized animals.

Overall, these are promising results, but these responses were elicited in mice. We will have to evaluate this technology in larger animals, and eventually in humans. It is challenging to evaluate durability in mouse studies, so one of the key questions we want to answer is whether the higher peak antibody titers that we are seeing will translate into more durable responses.

How does the hybrid vaccine technology combine features of mRNA and protein nanoparticle-based vaccines?

MH: The conventional mRNA vaccine leads to cellular expression of the SARS-CoV-2 spike protein, which activates the adaptive immune system in two ways: the spike protein is presented on the surface of the cell, which activates B-cells; and the spike protein gets cleaved into peptides that get presented at major histocompatibility complex molecules, which activates T cells. An mRNA vaccine essentially mimics an infected cell to stimulate the immune response.

Other vaccines, such as the Novavax vaccine, present dense arrays of spike protein on the surface of virus-like particles (VLPs). These vaccines are also very effective at activating B-cell responses, and they do so by mimicking the virus.

These two types of vaccines stimulate the immune response by either mimicking an infected cell or mimicking the virus. We are trying to develop a technology that does both in one. In practice, our technology looks very similar to a conventional mRNA vaccine, but we have engineered the spike protein so that when it gets to the cell surface, the cytoplasmic tail of the spike protein recruits host proteins from the ESCRT pathway. That induces the self-assembly and budding of VLPs that pinch off from the plasma membrane and circulate in the body, which could activate immune cells more effectively. In our initial published study, we found that this approach can elicit higher binding and neutralizing antibody titers.

We also saw a slight improvement in T helper 2 responses, but the T helper 1 responses were very similar to the conventional mRNA vaccine. We are in the process of doing more work to characterize potential differences between these vaccine approaches to understand exactly how the immune responses are different.

Beyond COVID-19, do you see potential applications of the EABR technology in the development of other vaccines? Are there specific challenges or considerations when applying this technology to different pathogens?

MH: There is great potential for this technology in the development of effective vaccines against various viral as well as non-viral pathogens. Any associated challenges are quite similar to those involved with a conventional mRNA vaccine. One of the key considerations is that the immunogen has to express well. If the immunogen expresses poorly, you are not going to make a lot of VLPs. Therefore, a lot of work needs to be put into immunogen selection, optimization, and design.

Looking to the future, what are your key goals or priorities for your research?

MH: In addition to continuing the optimization, evaluation, and application of the hybrid mRNA vaccine technology, we are very interested in characterizing the immune responses that are being elicited by different vaccine approaches. There is a lot of information out there that can help us to further improve our vaccine designs. In addition, we are very interested in engineering the EABR nanoparticles to package and deliver nucleic acid-based cargoes. That could be very interesting for drug delivery applications.


Magnus Hoffmann is the Merkin Institute Fellow at the Merkin Institute for Translational Research at the California Institute of Technology. Based on his graduate work in Pamela Bjorkman’s laboratory at Caltech, he received the Milton and Francis Clauser Prize for the best PhD thesis across all disciplines, and was awarded an NIH Director’s Early Independence Award to launch his own laboratory as an independent postdoctoral scholar at Caltech. Hoffmann’s research focuses on the development of innovative vaccine technologies and gaining a deeper understanding of the immunological mechanisms that shape vaccine-induced immune responses. He developed the EABR technology, an innovative approach to genetically encode nanoparticles for vaccine applications. This vaccine platform combines features of mRNA- and protein nanoparticle-based vaccines, resulting in superior neutralizing antibody responses against original and variant SARS-CoV-2 in mice. Ongoing and future research in his group focuses on the continued optimization, evaluation, and application of this technology.


Magnus Hoffmann PhD
Merkin Institute Fellow,
Merkin Institute for Translational Research,
California Institute of Technology

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: The work for this manuscript was supported by the NIH, the Bill & Melinda Gates Foundation, Wellcome Leap, George Mason University Fast Grants, and the Rothenberg Innovation Initiative.

Disclosure and potential conflicts of interest: A patent has been filed for the EABR technology.

Funding declaration: Travel to meetings to present this work was supported by the NIH and Bill & Melinda Gates Foundation.

Article & Copyright Information

Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2024 Hoffmann M. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited; externally peer reviewed.

Revised manuscript received: Jan 30, 2024; Publication date: Feb 2, 2024.

This article is part of the Respiratory Diseases spotlight