Abstract
The development of more effective, accessible, and easy to administer COVID-19 vaccines next to the currently marketed mRNA, viral vector, and whole inactivated virus vaccines is essential to curtailing the SARS-CoV-2 pandemic. A major concern is reduced vaccine-induced immune protection to emerging variants, and therefore booster vaccinations to broaden and strengthen the immune response might be required. Currently, all registered COVID-19 vaccines and the majority of COVID-19 vaccines in development are intramuscularly administered, targeting the induction of systemic immunity. Intranasal vaccines have the capacity to induce local mucosal immunity as well, thereby targeting the primary route of viral entry of SARS-CoV-2 with the potential of blocking transmission. Furthermore, intranasal vaccines offer greater practicality in terms of cost and ease of administration. Currently, only eight out of 112 vaccines in clinical development are administered intranasally. We developed an intranasal COVID-19 subunit vaccine, based on a recombinant, six-proline-stabilized, D614G spike protein (mC-Spike) of SARS-CoV-2 linked via the LPS-binding peptide sequence mCramp (mC) to outer membrane vesicles (OMVs) from Neisseria meningitidis. The spike protein was produced in CHO cells, and after linking to the OMVs, the OMV-mC-Spike vaccine was administered to mice and Syrian hamsters via intranasal or intramuscular prime-boost vaccinations. In all animals that received OMV-mC-Spike, serum-neutralizing antibodies were induced upon vaccination. Importantly, high levels of spike-binding immunoglobulin G (IgG) and A (IgA) antibodies in the nose and lungs were only detected in intranasally vaccinated animals, whereas intramuscular vaccination only induced an IgG response in the serum. Two weeks after their second vaccination, hamsters challenged with SARS-CoV-2 were protected from weight loss and viral replication in the lungs compared to the control groups vaccinated with OMV or spike alone. Histopathology showed no lesions in lungs 7 days after challenge in OMV-mC-Spike-vaccinated hamsters, whereas the control groups did show pathological lesions in the lung. The OMV-mC-Spike candidate vaccine data are very promising and support further development of this novel non-replicating, needle-free, subunit vaccine concept for clinical testing.
Highlights
Since the outbreak of SARS-CoV-2 [1], development of a vaccine against this emerging pathogen has been given the highest priority globally
We developed an innovative subunit vaccine for COVID-19 in which a HexaPro spike protein containing the D614G mutation [28,29,30] is associated with OMV, which serves as a carrier and adjuvant for the spike molecule, using the short amphipathic peptide sequence mCRAMP fused to the C-terminus
We describe the assessment of safety, immunogenicity, and protective capacity of OMV-mC-Spike, a COVID-19 vaccine consisting of HexaPro spike that is associated with OMVs from N. meningitidis via a short amphipathic peptide sequence, mCRAMP, in mice and Syrian hamsters
Summary
Since the outbreak of SARS-CoV-2 [1], development of a vaccine against this emerging pathogen has been given the highest priority globally. The first vaccine, an mRNA vaccine [2], entered the market with unprecedented speed early December 2020 [3]. All COVID-19 vaccines on the market today and the majority of COVID-19 vaccines in development are intramuscularly administered, targeting the induction of systemic immunity. The current vaccines protect against emerging SARS-CoV-2 variants, efficacy wanes [4]. The development of additional vaccines aims to broaden and strengthen the immune response because of concerns about reduced vaccine-induced immune protection to emerging variants [5, 6], the fact that many people in large parts of the world do not have access to vaccines yet, and there is still limited knowledge on the longevity of current vaccine responses
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