Induktion von Langzeitimmunität gegen das Maul- und Klauenseuche Virus

• Forschungsstelle: BLV
• Projektnummer: 1.13.05
• Projekttitel Englisch: Towards enhancing the longevity of vaccine-induced immunity against foot-and-mouth disease virus

Schlüsselwörter (Deutsch)

Maul-und-Klauenseuche, Langzeitimmunität, Schaftranskriptom, Impfstoffe, Prävention, Kontrolle,
Ausrottung

Schlüsselwörter (Englisch)

Foot-and-mouth disease, long-term immunity, sheep transcriptome, vaccines, prevention, control,
eradication

Kurzbeschreibung (Deutsch)

Existierende MKS Impfstoffe sind zwar effizient als für Notfallimpfstoffe,
da sie eine schnell eine schützende Immunantwort induzieren,
aber induzieren nur eine Immunität von wenigen Monaten.
Dies beeinträchtig signifikant deren Wirksamkeit zur Bekämpfung der MKS in endemischen Gebieten,
da häufig Revakzinierungen notwendig sind, die jeweils mit hohen Kosten
und grossen Aufwand verbunden sind.
Die Vergangenheit hat aber gezeigt,
dass ohne Bekämpfung der MKS in endemischen Gebieten mit regelmässigen Ausbrüchen
in Europa zu rechnen ist,
zuletzt im Jahr 2011 in Bulgarien.
Das Ziel dieses Projektes ist daher Vakzinierungsprogramme
durch die Entwicklung eines Impfstoffes der eine Langzeitimmunität induziert zu verstärken

Kurzbeschreibung (Englisch)

Current FMD vaccines are efficacious as emergency vaccines since they induce rapid
antibody-mediated protection against FMDV infection. However,
this immunity is of particular short duration and only lasts a few months.
While this is not a problem for emergency vaccination,
it significantly enhances the costs and reduces the efficiency
of vaccination programs in endemic areas.
It is evi-dent from past experience that without combating FMDV
in endemic areas the virus will regularly be re-introduced into Europe.
To re-enforce the power of vaccination campaigns our aim is
to translate current immunological knowledge obtained from basic research
in mouse models and from human vaccinology into large animals such as cattle,
sheep and pigs towards improving the duration of immunity against FMDV in these animals.
The approach taken will be based on im-provement of current vaccines
with the aim to enable a rapid development of an applicable vac-cine.
There are several models for long-term antibody persistence
and none of them can explain the findings from vaccination data perfectly.
While antigen persistence is an element promoting long-term antibody responses,
there are also protein-based vaccines which probably cannot persist but still are able
to induce long-lasting antibody responses such as the tetanus vaccine.
An emerging concept is that long-lasting antibody responses are dependent on plasma cell lifespan
(Amanna and Slifka, 2010). Plasma cells themselves cannot be restimulated
by antigen since they lack anti-gen receptors (in contrast to memory B cells).
The hypothesis in this area of research thus pro-poses that the trigger which a naive B cell receives
in the priming phase and during its develop-ment into an antibody producing plasma cell
will determine the longevity of this cell and thereby the duration of immunity (Kasturi et al., 2011).
Based on this concept we propose that enhancing sig-nals known
to promote long-lasting immune responses in mouse models will also improve FMD vaccines.
The focus will be based on (i) promoting T helper cell responses through enhanced stimulation
of dendritic cells by TLR ligands; (ii) providing innate signals to B cells
which promote their development into long-lived plasma cells;
(iii) ensure appropriate B-cell receptor triggering through presentation of repetitive epitopes to B cells.
To this end, a nanoparticles-based vaccine formulation for the delivery of both antigen
and Toll-like receptor ligands will be employed. Based on the hypothesis that early (innate) responses
dictate the quality and longevity of the antibody response,
we will determine the signature of such responses using
"whole transcriptome shotgun sequencing" also called RNA-Seq (RNA Sequencing).
Transcriptomics have been successfully employed to identify the activation of key genes associated
with strong and long-lasting antibodies induced by human vaccines.
We thus anticipate that this project will identify early biomarkers potent vaccines
which will boost the development of more effective vaccines promoting animal health.

Projektziele (Englisch)

As introduced above, fundamental advances have been made in understanding the functioning
of immune responses induced by vaccines in mouse models and this was complemented
by system biology and "omics" approaches in the field of human vaccines.
We will translate this knowledge to the field of FMD vaccines with the aim
to improve the duration of immunity. A minor aspect of the project will also be
to explore the applicability of replicon-based vaccine platforms available at the IVI for FMD vaccines.

We expect that our investigations will lead to novel and applicable FMD vaccines
including con-ventional vaccines and novel vaccines able to induced potent and long lasting immunity
through employment of novel adjuvants, appropriate immunostimulants and
Ag delivery systems. Through identification of the innate immune signature induced by such responses,
we will investigate early biomarker for potent and long lasting immunity of farm animals.

To achieve this, our specific aims are:

1. Reinforcing the T-cell help: Using in vitro experiments,
we will first test various TLR ligands for their activation of DC/T cell co-cultures to promote Th1 activation.

2. Identification of innate triggers for B-cells:
TLR ligands and combinations thereof will be tested for their ability to directly activate B cells.

3. Identification of optimal formulations for FMDV antigen to trigger the B-cell receptor:
To this end, we plan to evaluate an in vitro model in which live virus,
inactivated virus and experi-mental vaccine-formulated virus will be tested for its ability
to trigger FMDV-specific B-cell receptors.

4. Vaccination of sheep with conventional FMD vaccines supplemented with
TLR combina-tions know to promote long-term immune responses
(such as combinations of TLR4 and TLR7/8 ligands, identified in 2 and 3).
In addition specific novel vaccine formulations em-ploying polysaccharide particle-based delivery will be tested.

5. Evaluation of the suitability VSV replicon-based vaccine platform for FMD vaccines.

6. The gene expression profile from peripheral blood leukocytes from these animals
will be analysed by mRNA profiling using deep sequencing and by real-time
RT-PCR to identify genes expressions correlating to long-term immunity.
As outlined above, this approach has been shown to be feasible,
and has the potential of enabling a rapid testing of experimen-tal vaccines in animals.

Publikationen / Ergebnisse (Englisch)

Braun, R. O.; Brunner, L.; Auray, G.; Baumann, A.; Obdulio, G.-N.; Python, S.; Zumkehr,
B.; Collin, N.; Gaschen, V.; Stoffel, M.; Barnier-Quer, C.; Summerfield,
A. Development of a TLR-ligand adjuvanted liposome-based  vaccine to 
enhance the duration of immunity GCB Symposium, 04.02.2016, Bern, Switzerland (poster)

Braun, R. O.; Brunner, L.; Auray, G.; Baumann, A.; Obdulio, G.-N.; Python,
S.; Zumkehr, B.; Collin, N.; Gaschen, V.; Stoffel, M.; Barnier-Quer, C.; Summerfield,
A. Oral presentation: Development of liposome-based vaccine formulations
to enhance the longevity of vaccine-induced immunity against foot-and-mouth disease virus.
Wolfsberg Meeting, 10.02.2016, Ermatingen, Switzerland (oral presentation).

Braun, R. O.; Brunner, L.; Auray, G.; Baumann, A.; Obdulio, G.-N.; Python,
S.; Zumkehr, B.; Collin, N.; Gaschen, V.; Stoffel, M.; Barnier-Quer, C.; Summerfield,
A. Development of a TLR-ligand adjuvanted liposome-based  vaccine to  enhance the duration of immunity.
World Immune Regulation Meeting, 16.03.2016 - 19.03.2016, Davos, Switzerland (poster)

Braun, R. O.; Python, S.; Auray, G.; Summerfield, A. Response of porcine peripheral B cells to stimulation with 
Toll-like receptor ligands. International Veterinary Immunology Symposium,
16.08.2016 - 19.08.2016, Gold Coast, Australia (oral presentation).

Braun, R. O.; Wyler, K.; Brunner, L.; Auray, G.; Baumann, A.; Obdulio G.-N.; Python,
S.; Zumkehr, B.; Collin, N.; Keller, I.; Gaschen, V.; Stoffel, M.; Bruggmann, R.; Barnier-Quer,
C.; Summerfield, A. Application of systems immunology for veterinary vaccines.
International Veterinary Immunology Symposium, 16.08.2016 - 19.08.2016,
Gold Coast, Australia (oral presentation).

Braun, R.O.; Python, S.; Summerfield, A. Porcine B cell responses
to Toll-like receptor ligands. Frontiers in Immunology.

Braun R. O.; Application of systems vaccinology to the veterinary field using
a Toll-like receptor ligand adjuvanted liposomal vaccine targeting antigen presenting cells.
PhD Thesis, Graduate School for Cellular and Biomedical Sciences, University of Bern.

Zugehörige Dokumente

• 1.13.05_Summerfield_DB_MJB [PDF] 138 kB
• Braun_fimmu-08-01044 [PDF] 8'230 kB
• Braun_NPJ Vaccines [PDF] 2'267 kB
• fimmu-08-01044_r [PDF] 532 kB

URL-Adressen (Deutsch)

1.13.05 Summerfield Induktion von Langzeitimmunität gegen das Maul- und Klauenseuche Virus (063-505…