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Evaluation of Host-Pathogen Responses and Vaccine Efficacy in Mice
Published on: February 22, 2019
Mutant lipooligosaccharide-based conjugate vaccine demonstrates a broad-spectrum effectiveness against Moraxella
Dabin Ren1, Shengqing Yu, Song Gao
1Vaccine Research Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, 5 Research Court, Rockville, MD 20850, USA.
Abstract:
There is no licensed vaccine available against Moraxella catarrhalis, an exclusive human pathogen responsible for otitis media in children and respiratory infections in adults. We previously developed conjugate vaccine candidates based on lipooligosaccharides (LOSs) of M. catarrhalis serotypes A, B, and C, each of which was shown to cover a portion of the clinical strains. To generate conserved LOS antigens and eliminate a potential autoimmune response to a similar epitope between M. catarrhalis LOS moiety Galα1-4Galβ1-4Glc and human P(k) antigen, two LOS mutants from strain O35E were constructed. Mutant O35Elgt5 or O35EgalE revealed a deletion of one or two terminal galactose residues of wild type O35E LOS. Each LOS molecule was purified, characterized, detoxified, and coupled to tetanus toxoid (TT) to form conjugates, namely dLOS-TT. Three subcutaneous immunizations using dLOS-TT from O35Elgt5 or O35EgalE elicited significant increases (a 729- or 1263-fold above the preimmune serum levels) of serum immunoglobulin (Ig)G against O35E LOS in rabbits with an adjuvant or without an adjuvant (an 140- or 140-fold above the preimmune serum levels). Rabbit antisera demonstrated elevated complement-mediated bactericidal activities against the wild type strain O35E. The rabbit sera elicited by O35Elgt5 dLOS-TT were further examined and showed cross bactericidal activity against all additional 19 M. catarrhalis strains and clinical isolates studied. Moreover, the rabbit sera displayed cross-reactivity not only among three serotype strains but also clinical isolates in a whole-cell enzyme-linked immunosorbent assay (ELISA), which was further confirmed under transmission electron microscopy. In conclusion, O35Elgt5 dLOS-TT may act as a vaccine against most M. catarrhalis strains and therefore can be used for further in vivo efficacy studies.
Insights
A new Moraxella catarrhalis vaccine candidate, O35Elgt5 dLOS-TT, shows broad protection. This conjugate vaccine elicits strong immune responses and bactericidal activity against multiple strains, paving the way for further efficacy studies.
Area of Science:
- Bacteriology and Immunology
- Vaccine Development
- Molecular Biology
Background:
- Moraxella catarrhalis is a significant human pathogen causing otitis media and respiratory infections.
- Current vaccines for M. catarrhalis are lacking, necessitating the development of effective preventative strategies.
- Previous conjugate vaccine candidates based on lipooligosaccharides (LOS) covered only a portion of clinical strains.
Purpose of the Study:
- To develop conserved lipooligosaccharide (LOS) antigens for a Moraxella catarrhalis vaccine.
- To eliminate potential autoimmune responses by modifying M. catarrhalis LOS.
- To create and evaluate novel conjugate vaccine candidates against M. catarrhalis.
Main Methods:
- Construction of two LOS mutants (O35Elgt5, O35EgalE) from M. catarrhalis strain O35E, deleting terminal galactose residues.
- Purification, characterization, and detoxification of LOS molecules.
- Coupling of detoxified LOS to tetanus toxoid (TT) to form dLOS-TT conjugates for immunization in rabbits.
Main Results:
- Subcutaneous immunization with O35Elgt5 or O35EgalE dLOS-TT elicited significant increases in serum IgG against O35E LOS in rabbits.
- Rabbit antisera demonstrated enhanced complement-mediated bactericidal activity against the wild type strain O35E.
- O35Elgt5 dLOS-TT elicited sera showed cross-bactericidal activity against 19 additional M. catarrhalis strains and clinical isolates, with broad cross-reactivity observed in ELISA and electron microscopy.
Conclusions:
- The O35Elgt5 dLOS-TT conjugate vaccine candidate demonstrates broad immunogenic and bactericidal activity against diverse Moraxella catarrhalis strains.
- This conjugate vaccine shows potential for protecting against a wide range of M. catarrhalis infections.
- Further in vivo efficacy studies are warranted for the O35Elgt5 dLOS-TT vaccine candidate.
