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

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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

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 ( : cases, deaths WHO) Transmition : Aerosol, through mucosal surfaces, biological fluid droplets, fomites.

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?

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

Study 1 Immune responses induced by the vaccination, in NHP

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 *

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

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

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.

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.

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.

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.

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.

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

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

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.

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

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

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

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

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

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.

Study 2 Protection conferred by aerosolized vaccine

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

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

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,

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

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