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      The novel Lyme borreliosis vaccine VLA15 shows broad protection against Borrelia species expressing six different OspA serotypes

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          Abstract

          We have previously shown that the Outer surface protein A (OspA) based Lyme borreliosis vaccine VLA15 induces protective immunity in mice. Herein, we report the induction of protective immunity by VLA15 with mouse models using ticks infected with B. burgdorferi (OspA serotype 1), B. afzelii (OspA serotype 2) and B. bavariensis (OspA serotype 4) or with in vitro grown B. garinii (OspA serotype 5 and 6) for challenge. For B. garinii (OspA serotype 3), we have developed a growth inhibition assay using chicken complement and functional antibodies targeting B. garinii (OspA serotype 3) could be demonstrated after immunization with VLA15. Furthermore, following three priming immunizations, a booster dose was administered five months later and the induction of immunological memory could be confirmed. Thus, the antibody titers after the booster dose were increased considerably compared to those after primary immunization. In addition, the half-lives of anti-OspA serotype specific antibodies after administration of the booster immunization were longer than after primary immunization. Taken together, we could show that VLA15 induced protection in mice against challenge with four different clinically relevant Borrelia species ( B. burgdorferi, B. afzelii, B. garinii and B. bavariensis) expressing five of the six OspA serotypes included in the vaccine. The protection data is supported by functional assays showing efficacy against spirochetes expressing any of the six OspA serotypes (1 to 6). To our knowledge, this is the first time a Lyme borreliosis vaccine has been able to demonstrate such broad protection in preclinical studies. These new data provide further promise for the clinical development of VLA15 and supports our efforts to provide a new Lyme borreliosis vaccine available for global use.

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          Most cited references34

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          Lyme disease.

          A Steere (2001)
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            Host association of Borrelia burgdorferi sensu lato--the key role of host complement.

            Borrelia burgdorferi sensu lato (s.l.), the tick-borne agent of Lyme borreliosis, is a bacterial species complex comprising 11 genospecies. Here, we discuss whether the delineation of genospecies is ecologically relevant. We provide evidence that B. burgdorferi s.l. is structured ecologically into distinct clusters that are host specific. An immunological model for niche adaptation is proposed that suggests the operation of complement-mediated selection in the midgut of the feeding tick. We conclude that vertebrate hosts rather than tick species are the key to Lyme borreliosis spirochaete diversity.
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              Induction of an outer surface protein on Borrelia burgdorferi during tick feeding.

              Lyme disease spirochetes, Borrelia burgdorferi sensu lato, are maintained in zoonotic cycles involving ticks and small mammals. In unfed ticks, the spirochetes produce one outer surface protein, OspA, but not OspC. During infection in mammals, immunological data suggest that the spirochetes have changed their surface, now expressing OspC but little or no OspA. We find by in vitro growth experiments that this change is regulated in part by temperature; OspC is produced by spirochetes at 32-37 degrees C but not at 24 degrees C. Furthermore, spirochetes in the midgut of ticks that have fully engorged on mice now have OspC on their surface. Thus two environmental cues, an increase in temperature and tick feeding, trigger a major alteration of the spirochetal outer membrane. This rapid synthesis of OspC by spirochetes during tick feeding may play an essential role in the capacity of these bacteria to successfully infect mammalian hosts, including humans, when transmitted by ticks.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 September 2017
                2017
                : 12
                : 9
                : e0184357
                Affiliations
                [001]Valneva Austria GmbH, Vienna, Austria
                University of Kentucky College of Medicine, UNITED STATES
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: All authors are or were employed at Valneva Austria GmbH at the time of this work and are authors of patents describing the invention. Two patents (having the same name but different numbers, one international and one for United States of America) are relevant for the publication: ‘‘Mutant Fragments of OspA and Methods and Uses Relating Thereto’’ (WO 2014/006226 A1) and ‘‘Mutant Fragments of OspA and Methods and Uses Relating Thereto’’ (US20140010835A1). There are no further patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                [¤]

                Current address: Evaxion Biotech, Copenhagen, Denmark

                Author information
                http://orcid.org/0000-0001-9731-840X
                Article
                PONE-D-17-07049
                10.1371/journal.pone.0184357
                5581183
                28863166
                4de845f4-a670-4854-a12b-e9ec607a22d4
                © 2017 Comstedt et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 February 2017
                : 22 August 2017
                Page count
                Figures: 2, Tables: 2, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004955, Österreichische Forschungsförderungsgesellschaft;
                Award ID: 821824
                This work was funded by the Austrian Research Promotion Agency ( www.ffg.at/en), BorreliaVac; grant 821824 and ZIT13 plus Technologie- und Innovationsförderungen für Wien 2013–2016, Förderprogramm Forschung, Call From Science to Products 2013. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors are or were employed at Valneva Austria GmbH at the time of this work. Valneva Austria GmbH provided support in the form of salaries for authors PC, WS, AM and UL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”
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