An Intranasal Vaccine Based on Outer Membrane Vesicles Against SARS-CoV-2

Abstract

The prevailing pandemic of SARS-CoV-2 highlights the desperate need of alternative vaccine-platforms, which are safe, effective, and can be modified to carry antigens of emerging pathogens. The current SARS-CoV-2 vaccines based on mRNA and adenoviral vector technology meet some of these criteria but still face limitations regarding administration route, mass production, stability, and storage. Herein, we introduce a novel SARS-CoV-2 vaccine candidate based on bacterial outer membrane vesicles (OMVs). Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) have been genetically modified to produce increased amounts of detoxified OMVs decorated with the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein. Intranasal immunization with RBD-decorated OMVs induced not only a robust immune response against the bacterial outer membrane components but also detectable antibody titers against the Spike protein. Cell culture infection assays using a Spike-pseudotyped lentivirus confirmed the presence of SARS-CoV-2 neutralizing antibodies. Highest titers against the SARS-CoV-2 Spike protein and most potent neutralization activity were observed for an alternating immunization regimen using RBD-decorated OMVs from ETEC and V. cholerae in turn. These results highlight the versatile vaccine applications offered by OMVs via expression of heterologous antigens in the donor bacterium.

Outer Membrane Vesicles: A Challenging Yet Promising Platform for COVID-19 Vaccines

“…Vibrio cholerae and E. coli OMVs were compared as adjuvants for intranasal RBD immunization [50]. Both preparations elicited a robust systemic and mucosal immune response, supported by neutralizing antibodies.…”

“…Both preparations elicited a robust systemic and mucosal immune response, supported by neutralizing antibodies. The most promising results were obtained when OMVs from each bacterium were administrated in turn, as a heterogeneous prime-booster approach [50].…”

Biological Nanoparticles in Vaccine Development

“…As mentioned, OMV-based vaccines currently exist for the prevention of Hib and MenB infections. Recent literature has focused on the development of OMV vaccines for influenza ( Rappazzo et al, 2016 ; Watkins et al, 2017b ), malaria ( Scaria et al, 2019 ), pertussis ( Raeven et al, 2020 ; Carriquiriborde et al, 2021 ), Lyme disease ( Klouwens et al, 2021 ), plague ( Carvalho et al, 2019 ; Wang X. et al, 2020 ), and SARS-Cov-2 ( Gaspar et al, 2021 ; Thapa et al, 2021 ; van der Ley et al, 2021 ). Due to the inherent flexibility and capability of the OMV platform, there is interest in expressing heterologous antigens from different pathogens on the same OMV to create novel combined vaccines ( König et al, 2021 ).…”

Potential Application of Bionanoparticles to Treat Severe Acute Respiratory Syndrome Coronavirus-2 Infection

“…This OMVs-based vaccine overcomes several limitations faced with an mRNA-based vaccine. An increased amount of detoxified OMVs was prepared from genetically modified Vibrio cholerae and enterotoxigenic E. coli (ETEC) (Thapa et al, 2021). Noninvasive intranasal immunization has confirmed a higher titer, induced protective, long-lasting antibody response in the murine model.…”