An intranasal OMV-based vaccine induces high mucosal and systemic protecting immunity against a SARS-CoV-2 infection

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 vaccines, is essential to curtain 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 seven 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.

A bacterial extracellular vesicle‐based intranasal vaccine against SARS‐CoV‐2 protects against disease and elicits neutralizing antibodies to wild‐type and Delta variants

“…These properties might recommend OMV vaccines for wider use, especially in geographical areas with limited access to low‐temperature refrigeration technologies. Indeed, since our preprint first appeared, we have become aware of two other OMV‐based SARS‐CoV‐2 vaccines in development (Van Der Ley et al., 2021 ; Yang et al., 2021 ).…”

A bacterial extracellular vesicle-based intranasal vaccine against SARS-CoV-2 protects against disease and elicits neutralizing antibodies to wild-type and Delta variants

“…These properties might recommend OMV vaccines for wider use, especially in geographical areas with limited access to low-temperature refrigeration technologies. Indeed, since our preprint first appeared, we have become aware of two other OMV-based SARS-CoV-2 vaccines in development 28,29 .…”

Trivalent outer membrane vesicles-based combination vaccine candidate induces protective immunity against Campylobacter and invasive non-typhoidal Salmonella in adult mice

“…Outer membrane vesicles (OMVs) are non-replicative membrane-derived spherical nanostructures that are released by gram-negative bacteria. These immunogenic facsimiles of secreting bacteria harbour a variety of bacteria-speci c antigens and different pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS), peptidoglycan and lipoproteins, which mimic the bacterial outer surface and can therefore serve as potential acellular vaccine candidate [23][24][25]. Along with strong immunogenicity, OMVs have intrinsic robust adjuvanticity due to presence of PAMPs, which activate various Toll-like receptors (TLRs) [23,26], eliminating the necessity for adding external adjuvants.…”