Document text
Principal Investigator: Magnus Adrian Gero Hoffmann
Organization: J. DAVID GLADSTONE INSTITUTES
Fiscal Year: 2024
Award: $472,500
Funding agency: NIH Office of the Director
Project Summary/Abstract
The COVID-19 pandemic represents the 3rd outbreak caused by zoonotic transmission of a beta-coronavirus
(beta-CoV) in the last 20 years. Hence there is an urgent need for new vaccine strategies to control the ongoing
pandemic and prevent future CoV outbreaks. mRNA vaccines have emerged as an ideal platform for the
development of rapid-response vaccines, but clinical studies have shown that neutralizing antibody titers elicited
by mRNA vaccines are ~10-fold lower than titers elicited by protein nanoparticle (NP) vaccines. This is a concern
with regards to the emergence of SARS-CoV-2 variants of concern (VOCs) that are less sensitive to vaccine-
induced antibodies. In addition, less than 25% of the world population is fully vaccinated. Thus, rapid-response
vaccine technologies are needed that elicit potent antibody responses with a single injection and/or lower doses,
to ensure lasting protection against VOCs, reduce costs, and accelerate global distribution. Moreover, prevention
of future CoV pandemics requires the development of a universal CoV vaccine that elicits cross-reactive immune
responses against a broad spectrum of CoV strains by focusing responses to conserved epitopes. The scope of
the proposed research is to design and evaluate new vaccine strategies to enhance the potency of mRNA-based
rapid-response vaccines and facilitate universal CoV vaccine development. The proposal is based on the EBR
NP technology, which modifies membrane proteins such as CoV spike (S) proteins to self-assemble into virus-
resembling NPs that bud from the cell surface. NP assembly is induced by inserting a short amino acid sequence
into the cytoplasmic tail designed to recruit proteins from the endosomal sorting complex required for transport
(ESCRT) pathway. Initial studies in mice showed that low-dose injections of EBR NPs presenting the SARS-
CoV-2 S protein elicited 10-fold higher neutralizing antibody titers than soluble S protein and protein-based NPs
that displayed the receptor-binding domain (RBD) of the S protein. The EBR NP technology will be applied to
accomplish three goals: i) Design a hybrid mRNA vaccine encoding the modified SARS-CoV-2 S-EBR construct
that would be expressed at the cell surface and self-assemble into virus-resembling NPs to elicit more potent
antibody responses than the approved Pfizer/Moderna vaccines, while retaining the manufacturing properties
and T-cell activation of mRNA vaccines. ii) Engineer S-EBR NPs to package and deliver S or S-EBR mRNA
vaccines as an alternative to lipid NPs. This delivery approach would enhance mRNA vaccine potency as S
proteins presented on S-EBR NPs induce potent antibody responses, facilitate efficient intracellular delivery, and
target mRNA vaccines to tissues that are naturally infected by SARS-CoV-2 to induce local immune responses.
iii) Design and evaluate mosaic S-EBR NP-based universal CoV vaccine candidates that present full-length
membrane-associated S proteins from multiple CoV strains to elicit cross-reactive immune responses against a
broad spectrum of CoVs and protect against future outbreaks. The proposed vaccine strategies could have direct
impact on the COVID-19 global health crisis and advance our emergency preparedness for the next pandemic.
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Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Sorting><Surface Proteins><System><T-Cell 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