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Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses Alexandra Scalvini & Émilien Gimaret Michelle Meyer, Tania Garron,

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Presentation on theme: "Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses Alexandra Scalvini & Émilien Gimaret Michelle Meyer, Tania Garron,"— Presentation transcript:

1 Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses Alexandra Scalvini & Émilien Gimaret Michelle Meyer, Tania Garron, Ndongala M. Lubaki, Chad E. Mire, Karla A. Fenton, Curtis Klages, Gene G. Olinger, Thomas W. Geisbert,Peter L. Collins and Alexander Bukreyev

2 Ebola virus (EBOV) Mononegavirales Filoviridae Ebolavirus RNA (-) 19 kB 970 nm long 80 nm diameter Target : human and NHP (non human primate) Severe hemorrhagic fever. Fatality ranges from 50% to 90%. Last outbreak (2014-2015 : 28601 cases, 11300 deaths WHO) Transmition : Aerosol, through mucosal surfaces, biological fluid droplets, fomites.

3 Background Vaccine strategy with aerosolized EBOV has never been tested. Aerosolized vaccines have many advantages : needle free, do not require trained medical personal. Aerosolized vaccines create a different immune response that is poorly studied in human. Could aerosolized vaccine be protective against EBOV?

4 The aerosolized vaccine Human Parainfluenza virus type 3-vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) Delivered through nebulizer to the respiratory tract (site of replication of HPIV3) Nebulizer HPIV3

5 Study 1 Immune responses induced by the vaccination, in NHP

6 Experiment Aims: - Study of both mucosal and systemic antibody responses and cell- mediated responses induced by aerosolized vaccine. - Comparison to both liquid HPIV3/EbovGP and VRP vaccines. 2 injections  days 0 and 28 Lungs, blood and spleen samplings *BAL = Broncho-Alveolar Lavage *

7 Serum IgG, IgA and neutralizing antibody responses in NHP Dose 1Dose 2 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Dose 1Dose 2 Method: EBOV-specific serum IgG and IgA analysed by ELISA

8 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Serum IgG, IgA and neutralizing antibody responses in NHP  Both aerosolized and liquid vaccines induce EBOV- specific serum IgG and IgA responses. Dose 1Dose 2 Dose 1Dose 2

9 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Ebola virus Serum IgG, IgA and neutralizing antibody responses in NHP Method: Serum-neutralizing antibody responses against EBOV determined by plaque-reduction assays.

10 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Ebola virus Serum IgG, IgA and neutralizing antibody responses in NHP  Induction of a systemic antibody responses comparable to those with liquid vaccine.

11 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Bundibugyo virusEbola virusSudan virus Ability to cross-neutralize EBOV Bundibugyo (BDBV) and Sudan (SUDV) Method: Serum-neutralizing antibody responses against EBOV, BDBV and SUDV determined by plaque-reduction assays.

12 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Bundibugyo virusEbola virusSudan virus Ability to cross-neutralize EBOV Bundibugyo (BDBV) and Sudan (SUDV)  Antibody cross-neutralization is stronger after the second dose vaccine.  Considerable animal-to-animal variability.

13 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Mucosal antibody-responses in the respiratory tract Method: - EBOV-specific serum IgG and IgA analysed by ELISA - Serum-neutralizing antibody responses against EBOV determined by plaque-reduction assays.

14 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP Mucosal antibody-responses in the respiratory tract  Both aerosolized and liquid vaccines induce strong mucosal antibody responses in the respiratory tract

15 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP % of cells MFI Mucosal CD8Non-mucosal CD8CD4 Cell-mediated response Method: - Flow cytometry

16 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP % of cells MFI Cell-mediated response Mucosal CD8Non-mucosal CD8CD4  Strong T cell responses predominantly in the respiratory tract.  Limited, but detectable, systemic spread.  Mainly IFNγ- and TNFα-secreting T cells.

17 Rhesus macaque 1 marker (IFN-γ or TNF-α or IL-2 or CD107a) 2 markers (e.g. 25% of the cells expresse one marker and 75% expresse two markers). Polyfunctional CD8 and CD4 T cell responses 3 markers 4 markers

18 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP CD8 -Polyfunctional response higher in the lungs -Mainly polyfunctional for 3 or 4 markers -Polyfunctional response higher in the lungs -Mainly polyfunctional for 1 or 2 markers CD4 1 marker 2 markers 3 markers 4 markers Polyfunctional CD8 and CD4 T cell responses

19 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP CD8 CD4 Polyfunctional CD8 and CD4 T cell responses -Polyfunctional response higher in the lungs -Mainly polyfunctional for 3 or 4 markers -Polyfunctional response higher in the lungs -Mainly polyfunctional for 1 or 2 markers 1 marker 2 markers 3 markers 4 markers

20 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP CD8 CD4  Both aerosolized and liquid vaccines induce a greater activation of lung CD8 and CD4 T cells.  Stronger activation of the CD8 T cells. Polyfunctional CD8 and CD4 T cell responses 1 marker 2 markers 3 markers 4 markers

21 HIPV3/EboGP aerosolHIPV3/EboGP IN/ITHPIV3VRP CD8 CD4 IFNγ expression in polyfunctional CD8 and CD4 T cells  Greater level of activation of CD8 T cells is accompanied by a greated level of IFNγ secretion.  Same trend for CD4 T cells? 4markers3markers2markers1marker

22 STUDY 1: Conclusions Aerosolized vaccine induce strong systemic and mucosal antibody responses, comparable to those obtained with liquid vaccine. Induction of neutralizing antibodies able to cross- neutralize different types of EBOV. Greater activation of T cells in the lungs, by aerosolized vaccine, may be the consequence of a more efficient delivery to the pulmonary bronchiole.

23 Study 2 Protection conferred by aerosolized vaccine

24 Experiment Aims: - Determine the protection that aerosolized vaccine could confer against EBOV infection. 2 injections  days 0 and 28 Or 1 injection at day 28 (purple) EBOV infection at day 55 Blood sampling

25 HIPV3/EboGP aerosol (2D) HIPV3/EboGP aerosol (1D) HIPV3/EboGP IN/IT HPIV3 Serum and mucosal antibody responses  Results similar to the ones obtain in the study 1.  Lower responses with only 1 injection

26 HIPV3/EboGP aerosol (2D) HIPV3/EboGP aerosol (1D) HIPV3/EboGP IN/IT HPIV3 Markers of EBOV infection, clinical sickness scores, survival and viremia during EBOV infection  A single administration of aerosolized vaccine completely protects against EBOV infection. Liver, hemolysis, kidney,

27 Aerosolized vaccine induces strong systemic (high antibody and T cell responses) and mucosal responses that can be accelerated with a second dose. Aerosolized vaccine confered cross-protection and can protect against viral hemorrhagic fever. Aerosolized vaccine can be easly implemented in case of an outbreak, or during bioterrorism and warfare scenarios. Perspectives: Application to other heamorrhagic fevers. Improve the cross-proctection efficiency. Phase I clinical study. Take home messages

28 Thank you for your attention ! Micrograph from F. A. Murphy, University of Texas Medical Branch, Galveston, Texas.

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