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Whole-cell inactivated vaccines, also known as “ killed vaccines, ” are among the most traditionally used varieties of vaccines, having been developed against a wide range of pathogens, including cholera and E. coli.
In a new study, published as a preprint on the bioRxiv* server, a team of researchers inactivated whole cell E. coli with a reduced genome and used it to express coronavirus-specific fusion peptides, demonstrating a potent anamnestic response.
Vaccine design
Gram-negative bacteria carry transporter proteins, autotransporters, which allow the exchange of proteins expressed on the cell surface, and modern genetic engineering allows a protein of interest to express itself on the surface in this way. Up to 200,000 foreign proteins can be displayed on the surface of a single bacterium, and this technology has already been used to trigger an immune response. in vivo by displaying selected pathogenic antigens. However, the range of antigens that can be expressed by this method is limited in size, to less than about 50 kDa, and bacteria do not produce proteins with mammalian glycolysis, and therefore may not induce production of the proteins. appropriate antibodies.
No vaccine using this technology has yet been licensed, largely due to poor immunogenicity displayed due to improper glycolysis. In this article, the group hypothesized that removing foreign surface proteins from bacteria, in addition to the expressed antigen of interest, may elicit a stronger immune response. The set of SARS-CoV-2 spike protein used in the deployed vaccines is a 180 kDa large protein, and therefore could not be deployed using this method. Several families of viruses, including coronaviruses and SARS-CoV-2, carry the HIV-1 fusion peptide, which is involved in cell membrane penetration. As this region is highly conserved, it could potentially be a good vaccine candidate, and the authors further point out that the use of the entire spike protein has been implicated in an increased risk of rare inflammatory syndromes.
Testing the vaccine
The group used whole cells killed E. coli which have been genomically reduced in order to present less native cell surface proteins. A plasmid was inserted into the bacteria to express the SARS-CoV-2 specific HIV-1 fusion peptide, subsequently demonstrated by antibody binding assays. Alternative vaccines have also been prepared for porcine epidemic diarrhea virus (PEDV), expressing the correlated fusion peptide for this similar virus.
Pigs were vaccinated with one of the prepared vaccines and a control, given with a booster on day 21, then subjected to oral PEDV infection with the respective virus on day 35. Blood was drawn weekly and antibodies. circulating anti-fusion protein quantified, not being significantly higher after vaccination but before challenge. However, following viral challenge, anti-FP values were significantly higher among the vaccinated, suggesting that the vaccines prompted the pigs to respond. Serum interferon-γ levels were also higher in the vaccinees, and fewer of these pigs exhibited outward signs of PEDV-related symptoms.
As expected, the PEDV vaccine was found to be more effective in immunizing against PEDV than the SARS-CoV-2 vaccine. However, the similarity of the fusion proteins from each virus was such that a statistically significant response was always detected. Indeed, the 13 amino acid sequences surrounding the 6 core residues of each sequence are identical.
The group argues that these vaccines might be easier to produce and transport than currently deployed mRNA vaccines, especially given the need for a strong cold chain in the latter case, requiring constant temperatures of -20. ° C or colder. They concede, however, that the ability to elicit an immune response in hosts to the genome reduces E. coli carries a low but possible risk and requires further investigation.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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