Building protection against infectious diseases with nanostructured vaccines
Wyss Institute’s DoriVac combined vaccine and adjuvant technology uses nanoscale precision enabled by DNA origami to induce broad immunity against infectious viruses
By Benjamin Boettner
(Boston) — The COVID-19 pandemic brought messenger RNA (mRNA) vaccines to the forefront of global health care. After their clinical trial stages, the first COVID-19 mRNA vaccine was administered on 8 December 2020 and mathematical models suggest that mRNA vaccines prevented at least 14.4 million deaths from COVID-19 in the first year alone. Their extraordinary effectiveness in having softened the blow of the disease, has led to the development of mRNA vaccines to also combat other infectious pathogens. Clinical trials for influenza virus, Respiratory Syncytial Virus (RSV), HIV, Zika, Epstein-Barr virus, and tuberculosis bacteria are all on the way. Importantly, however, COVID-19 research has revealed shortcomings of mRNA vaccines that highlight the need for different approaches.
The immune responses produced by the COVID-19 mRNA vaccines can vary considerably between people, and their duration is limited. This problem is exacerbated by the fact that the SARS-CoV-2 virus constantly evolves and produces new variants that can evade the immune system, and thus COVID-19 mRNA vaccines have to be updated regularly. They also have other disadvantages, including their complex and costly manufacturing, poor control over the numbers of mRNA molecules that are loaded into the delivering lipid nanoparticles, the need for cold-storage, and potential off-target effects. Solving these challenges would enable entirely new response, prevention, and preparedness strategies for multiple infectious diseases.
Now, a multi-disciplinary research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), and collaborating institutions leveraged a recently developed highly versatile DNA origami nanotechnology that is both vaccine and adjuvant, named DoriVac, as an alternative to current vaccine platforms. DoriVac vaccines that targeted a peptide region (HR2) conserved in the spike proteins of a range of infectious viruses, including SARS-CoV-2, HIV, and Ebola, produced desirable immune responses and, in the case of the SARS-CoV-2 HR2 vaccine, potent antigen-specific antibody-mediated (humoral) and T cell-mediated (cellular) responses in mice. In a forward-looking pre-clinical in vitro model of the human lymph node engineered using the Wyss Institute’s microfluidic human Organ Chip technology, the SARS-CoV-2 HR2 vaccine produced potent antigen-specific human immune responses as well. In a head-to-head comparison with SARS-CoV-2 mRNA vaccines that are encapsulated in lipid nanoparticles, DoriVac vaccine bearing copies of the same spike protein variant produced a similarly strong human immune activation, but is much more stable and easier to both store and manufacture. The findings are published in Nature Biomedical Engineering.
“With the DoriVac platform, we have developed an extremely flexible chassis with a number of critical advantages, including an unprecedented control over vaccine composition, and the ability to program immune recognition in targeted immune cells on a molecular level to achieve better responses,” said co-corresponding author and Wyss Institute Core Faculty member William Shih, Ph.D., whose group pioneered the new vaccine concept. “Our study demonstrates DoriVac’s versatility and potential by taking a close look at the immune changes that are required to fight infectious viruses.” Shih is also Professor at the Harvard Medical School and DFCI.
Bringing viral antigens into the fold
In 2024, Shih’s team at the Wyss Institute and Dana-Farber developed DoriVac as a DNA nanotechnology-enabled vaccine platform with broad applicability. Yang (Claire) Zeng, M.D., Ph.D., who spearheaded the project together with collaborating researchers, also showed that DoriVac vaccines, by presenting immune-boosting adjuvant molecules with nano-scale precision to cells, could elicit highly beneficial immune responses in tumor-bearing mice that exceeded those observed with the origami-free vaccine components. DoriVac DNA origami vaccines consist of tiny self-folding and assembling square block-shaped nanostructures that on one face present the adjuvant molecules with an optimized nanometer spacing between them and on the opposite face antigens of choice, such as tumor or pathogen-derived peptides and proteins.
“While we were developing the platform for cancer applications, the COVID-19 pandemic was still moving with full force. So, the question quickly arose whether DoriVac’s superior adjuvant activity could also be leveraged in infectious disease settings,” said Zeng as a first and co-corresponding author on the new study, and now cofounder and CEO/CTO of DoriNano, leading the translation of this technology into clinical applications. To test this, Zeng and co-first author Olivia Young, Ph.D., a former graduate student working with Shih, teamed up with Donald Ingber’s group at the Wyss Institute. Ingber’s team has had a strong interest in innovating antiviral therapies, using AI- and multiomics-driven approaches in combination with microfluidic human Organ Chip technology. Together with co-first author Longlong Si, Ph.D., a former postdoctoral researcher on Ingber’s team, the researchers designed SARS-CoV-2, HIV, and Ebola-specific DoriVac vaccines presenting so-called HR2 peptides, which function as highly conserved antigens within the so-called spike proteins from a number of viruses.
“Our analysis of the immune responses provoked by these first DoriVac vaccines in mice led to several encouraging observations, including significantly greater and broader activation of humoral and cellular immunity across a range of relevant immune cell types than what the origami-free antigens and adjuvants could produce,” said Zeng. “We found that the numbers of antibody-producing B cells, activated antigen-presenting dendritic cells (DCs), and antigen-specific memory and cytotoxic T cell types that are vital for long-term protection were all increased, especially in the case of the SARS-CoV-2 HR2,” explained Zeng.
From mice to humans
Immune responses to infectious pathogens in mice can differ considerably from those in humans, causing many treatments that only have been tested in mouse models to fail in human trials. To bring their DoriVac vaccine platform closer to human applications, the team therefore assessed the effects of DoriVac vaccines in an engineered human immune system in the form of a human lymph node-on-a-chip (human LN Chip) that enables the rapid pre-clinical prediction of immune responses in humans. Advanced by co-first author Min Wen Ku and co-corresponding author Girija Goyal, Ph.D., Director, Bioinspired Therapeutics at the Wyss Institute, who works in Ingber’s group, the team demonstrated that the SARS-CoV-2-HR2 DoriVac vaccine activated human DCs and increased their production of inflammatory cytokine molecules to much higher levels than the origami-free vaccine components. Also, the numbers of CD4+ and CD8+ T cells with multiple protective functions were increased in human LN Chips. This further validated the potential of DoriVac vaccines for human treatments.
“The predictive capabilities of human LN Chips gave us an ideal testing ground for DoriVac vaccines and the induced, antigen-specific immune cell profiles and activities very likely reflect those that would occur in human recipients of the vaccines. This convergence of technologies enabled us to dramatically raise the chances of success for a new class of vaccines and create a new testbed for future vaccine developments,” said co-corresponding author Ingber, M.D., Ph.D. who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences.
In the same vein, the research team investigated a DoriVac vaccine presenting the complete SARS-CoV-2 spike protein, led by Zeng and co-author Qiancheng Xiong, in a head-to-head comparison with current Moderna and Pfizer/BioNTech mRNA lipid nanoparticle (LNP) SARS-CoV-2 vaccines encoding an identical spike protein in mice, using a common booster protocol. The observed anti-viral T cell and antibody-producing B cell responses were comparable. “This underscored DoriVac’s potential as a DNA nanotechnology-enabled, self-adjuvanted vaccine platform. But DoriVac vaccines have a number of other advantages: they don’t have the same cold-chain requirements as mRNA-LNP vaccines do and thus could be distributed much more effectively, especially in under-resourced regions; and they could overcome some of the enormous manufacturing complexities of LNP-formulated vaccines, to name two major ones,” said Shih. Recent studies at DoriNano have also demonstrated that DoriVac exhibits a promising safety profile.
Other authors on the study are Sylvie Bernier, Hawa Dembele, Giorgia Isinelli, Tal Gilboa, Zoe Swank, Su Hyun Seok, Anjali Rajwar, Amanda Jiang, Yunhao Zhai, LaTonya Williams, Caleb Hellman, Chris Wintersinger, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Sarai Bardales, Georgia Tomaras, Ju Hee Ryu, and Ick Chan Kwon. The study has been funded by the Director’s Fund and Validation Project program of the Wyss Institute; Claudia Adams Barr Program at DFCI; National Institutes of Health (U54 grant CA244726-01); US-Japan CRDF global fund (grant R-202105-67765); National Research Foundation of Korea (grants MSIT, RS-2024-00463774, RS-2023-00275456); Intramural Research Program of the Korea Institute of Science and Technology (KIST); and Bill and Melinda Gates Foundation (INV-002274).
PRESS CONTACT
Wyss Institute for Biologically Inspired Engineering at Harvard University
Benjamin Boettner, benjamin.boettner@wyss.harvard.edu
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The Wyss Institute for Biologically Inspired Engineering at Harvard University
A force of nature solving the world’s toughest challenges through biologically inspired innovation.
The Wyss Institute at Harvard University is a nonprofit research and development organization dedicated to translating groundbreaking discoveries from the lab into real-world solutions for human and planetary health. Since its founding in 2009, the Wyss has created a powerful pipeline of breakthrough technologies - from new cancer therapies to sustainable materials - by leveraging nature’s genius to tackle urgent global challenges. Through a unique model of radical collaboration across disciplines and a relentless focus on impact, the Wyss brings together scientists, engineers, clinicians, and industry leaders to accelerate innovations that improve lives and our environment.
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