Abstract
Background: Due to the highly variable nature of the antigenic properties of the influenza virus, many efforts have been made to develop broadly reactive influenza vaccines. Various vaccine platforms have been explored to deliver conserved viral antigens to the target cells to induce cross-reactive immune responses. Here, we assessed the feasibility of using Enterococcus faecium L3 as a bacterial vector for oral immunization against influenza virus. Methods: we generated two vaccine prototypes by inserting full-length HA2 (L3-HA2) protein or its long alpha helix (LAH) domain in combination with four M2e tandem repeats (L3-LAH+M2e) into genome of E.faecium L3 probiotic strain. The immunogenicity and protective potential of these oral vaccines were assessed in a lethal challenge model in BALB/c mice. Results: as expected, both vaccine prototypes induced HA stem-targeting antibodies, whereas only L3-LAH+4M2e vaccine induced M2e-specific antibody. The L3-HA2 vaccine partially protected mice against lethal challenge with two H1N1 heterologous viruses, while 100% of animals in the L3-LAH+4M2e vaccine group survived in both challenge experiments, and there was significant protection against weight loss in this group, compared to the L3 vector-immunized control mice. Conclusions: the recombinant enterococcal strain L3-LAH+4M2e can be considered as a promising live probiotic vaccine candidate for influenza prevention and warrants further evaluation in relevant pre-clinical models.
Highlights
The composition of influenza vaccines is updated almost every year to account for the high variability of influenza viruses
Great efforts have been made over the last decade to develop a universal influenza vaccine, that is, a vaccine with a broad spectrum of action capable of providing long-lasting protection, against drifted type A virus strains of one subtype, but from viruses belonging to different subtypes as well [6]
The two chimeric DNA constructs containing the HA2 or long alpha helix (LAH)+4M2e element were inserted into the d2 Enterococcus gene resulting in the exposure of the influenza virus antigens on the surface of bacteria as a part of their pili (Figure 2A,B)
Summary
The composition of influenza vaccines is updated almost every year to account for the high variability of influenza viruses. Licensed influenza vaccines typically induce neutralizing antibodies targeted at immunodominant, but highly variable sites in the globular head domain of the influenza hemagglutinin (HA), making it possible for the virus to escape these antibodies [4,5]. Great efforts have been made over the last decade to develop a universal influenza vaccine, that is, a vaccine with a broad spectrum of action capable of providing long-lasting protection, against drifted type A virus strains of one subtype, but from viruses belonging to different subtypes as well [6]. Due to the highly variable nature of the antigenic properties of the influenza virus, many efforts have been made to develop broadly reactive influenza vaccines.
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