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Principal Investigator: Devdoot Majumdar
Organization: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
Fiscal Year: 2023
Award: $226,930
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY: Devdoot Majumdar, PhD, Research Project Leader (RPL)
The mRNA vaccines against SARS-CoV-2 proved unexpectedly efficacious, but also require a series of
booster immunizations to remain protective. Global deployment of these vaccines has been slow, particularly in
low- and middle-income countries (LMIC), in part due to the logistical complications associated with multiple
vaccinations. We therefore propose a new RNA vaccine design: a single-dose self-amplifying mRNA vaccine
based on the SARS-CoV-2 coronavirus. Our long-term goal is to develop of a novel vaccine modality that
consists of an RNA vaccine that feasibly delivers durable humoral and cellular immunity to SARS-CoV-2 in a
single dose. Our novel design, named iDMV-1.0, utilizes RNA encoding the coronavirus replication machinery
in order to produce Spike mRNA within double membrane vesicles (DMV). iDMV-1.0, a 20 kB RNA derived
from the SARS-CoV-2 genome, consists of NSP1-16 of SARS CoV-2, mutations to stabilize the prefusion
conformation of Spike protein (19), ORF6-10, M protein, and N protein, GFP and Luciferase for detection, and
all non-coding 5’ and 3’ sequences of the SARS-CoV-2 genome. Because iDMV-1.0 permits self-amplification
of Spike mRNA, this lipid nanoparticles-encapsulated RNA vaccine exhibits increased protein expression in
tissue culture systems as compared to single round mRNA controls.
The objective of this grant is to assess iDMV-1.0 in preclinical studies in mice. In Aim 1, the humoral immune
response to the vaccine will be studied by assessing epitope choice of iDMV-1.0 as compared to mRNA-1273
(Moderna SARS-CoV-2 mRNA vaccine) using deep mutational scanning and traditional serology. We will
assess durability of antigen expression and durability of humoral immune response for iDMV-1.0 as compared
to conventional mRNA vaccination in mice. In Aim 2, the cellular immune response will be compared between
both vaccine modalities to determine whether T cells specific to the SARS-CoV-2 proteome are generated by
iDMV-1.0. Together, these studies will provide the foundation to understand durability and specificity of a
potential single-shot SARS-CoV-2 mRNA vaccine, providing a paradigm that may facilitate greater vaccine
uptake, particularly in LMIC settings.
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