“State-of-the-Art Clinical Lecture” · 2019. 5. 3. · The Miller Lab “State-of-the-Art...

The Miller Lab

“State-of-the-Art Clinical Lecture”

Advances in the Development of Universal

Influenza Virus Vaccines

Matthew S Miller, PhD

Michael G. DeGroote Institute for Infectious Diseases ResearchMcMaster Immunology Research Centre

Department of Biochemistry and Biomedical SciencesMcMaster University

AAMI Canada-CACMID Annual ConferenceOttawa, ONApril 5, 2019

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Disclosure/Conflict-of-interest

Research Contract: Medicago (Influenza virus vaccine responses)

Speaking Honorariums: All from universities (Under $500)

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Objectives

• List various strategies being used to develop universal influenza virus vaccines

• Describe the ways in which various vaccine platforms achieve protective immunity

• Identify current gaps in knowledge related to the successful development of a universal influenza virus vaccine

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IAV pandemics

Wantanabe et al., 2012

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1918/19 “Spanish Flu” Pandemic: 100 years later

Fort Riley, Kansas

Widely considered to be the greatest “natural disaster” in human history

3-5% of the global population died during the pandemic (this would now amount to the population of North America)

4 pandemics since 1918 – none as severe

VERY LIMITED improvements in pandemic preparedness over past 100 years!

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Seasonal influenza

https://www.canada.ca/en/public-health/services/publications/diseases-conditions/fluwatch/2018-2019/week12-march-17-march-23-2019.html

Canada: 12,200 hospitalizations; 3,500 deaths

International: 3-5 million severe cases; 290,000 – 650,000 deaths

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Influenza A virus (IAV)

Negative-sense ssRNA genome

8 segments

Enveloped

Hemagglutinin (HA) and neuraminidase (NA) are the major antigenic determinants

Nomenclature HxNx

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IAV host range

Modified from: Manz et al., 2013

H17-H18

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IAV diversity

~1 nucleotide/genome

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HA phylogeny YYang and Seong, Viruses, 2014 Mallajosyula, Front. Immunol., 2015

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HA phylogeny

H1 H2 H5 H3 H7 H10

Group 1 Group 2

Y Y Y Y Y YYang and Seong, Viruses, 2014

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Seasonal influenza vaccines: Canada

National Influenza Immunization Coverage Suvery, Canada, 2016-2017

Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2017–2018

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Limitations of current seasonal influenza vaccines

Limited breadth of protection• strain-specific responses• require annual reformulation (prediction-based)• low vaccine uptake• no protection against novel, pandemic strains

Suboptimal efficacy• especially in high-risk groups (e.g. very young, very old)

Production timeline• 6+ months between seed strain recommendations and vaccine administration• worst for egg-based platforms

Egg-based adaptations• Can have a profound and unexpected effect on efficacy

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Why not just make pandemic vaccines when the

need arises?

Source: CIDRAP

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Limitations of current seasonal influenza vaccines

Limited breadth of protection• strain-specific responses• require annual reformulation (prediction-based)• low vaccine uptake

Suboptimal efficacy• especially in high-risk groups (e.g. very young, very old)

Production timeline• 6+ months between seed strain recommendations and vaccine administration• worst for egg-based platforms

Egg-based adaptations• Can have a profound and unexpected effect on efficacy

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Qualities of a “universal” influenza virus vaccine

There is no universally accepted definition – means different things to different people/groups

NIH Bill and Melinda Gates Foundation

At least 75% effective At least 70% protection against moderate/severe disease in all age

groups

Protect against group 1 and group 2 influenza A viruses

All strains of influenza A and B viruses

At least 1 year of protection 3-5 years of protection

Suitable for all age groups 6 weeks and older

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Universal influenza virus vaccine strategies

All “universal” influenza virus vaccine strategies seek to generate immune responses against conserved viral epitopes

B cell/antibody vaccinesT cell vaccines

• Usually peptides, DNA, or viral-vectored

• Often target conserved, internal viral proteins

• Designed to generate high numbers of cytotoxic T lymphocytes to eliminate infected cells

• Usually inactivated virus, live-attenuated virus, recombinant protein, DNA, mRNA, VLPs

• Target viral surface proteins

• Designed to elicit high titers of broadly-neutralizing antibodies

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Universal influenza virus vaccine strategies

All “universal” influenza virus vaccine strategies seek to generate immune responses against conserved viral epitopes

B cell/antibody vaccinesT cell vaccines

• Usually peptides, DNA, or viral-vectored

• Often target conserved, internal viral proteins

• Designed to generate high numbers of cytotoxic T lymphocytes to eliminate infected cells

• Usually inactivated virus, live-attenuated virus, recombinant protein, DNA, mRNA, VLPs

• Target viral surface proteins

• Designed to elicit high titers of broadly-neutralizing antibodies

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BiondVax: M-001 (“Multimeric-001”)

• Peptide composed of 9 epitopes derived from HA, NP and M1 (produced in E. coli)

• Designed to elicit cell-mediated immunity (T cells)

• Potential to be used as a “primer” prior to seasonal influenza vaccination

• Currently in Phase III clinical trials (Europe)

- Standalone- Adults aged 50+

Gottlieb and Ben-Yedidia. J Autoimmun., 2014Adar et al. Vaccine, 2009

H5N1 challenge (LD80)

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Oxford-Jenner Institute/Vaccitech: MVA-NP-M1

Lillie et al., Clin Infect Dis, 2012

• “MVA” = modified vaccinia Ankara

• Viral vector for expression of NP and M1

• Designed to elicit cell-mediated immunity (T cells)

• Currently in Phase IIb clinical trials- Administered in conjunction with seasonal IIV

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Universal influenza virus vaccine strategies

All “universal” influenza virus vaccine strategies seek to generate immune responses against conserved viral epitopes

B cell/antibody vaccinesT cell vaccines

• Usually peptides, DNA, or viral-vectored

• Often target conserved, internal viral proteins

• Designed to generate high numbers of cytotoxic T lymphocytes to eliminate infected cells

• Usually inactivated virus, live-attenuated virus, recombinant protein, DNA, mRNA, VLPs

• Target viral surface proteins

• Designed to elicit high titers of broadly-neutralizing antibodies

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Ted Ross/Sanofi Pasteur: Computationally

optimized broadly-reactive antigen “COBRA”

Carter et al., JVirol, 2016

• Similar to a recombinant “consensus HA”

• Designed to elicit broadly-reactive antibodies that bind to the HA head domain

• Effect at eliciting broad heterologous protection (ie. pan-H1, pan-H3)

• Could be particularly useful as a “supra-seasonal” vaccine

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Humoral immunity against IAV

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“Headless”/Mini-HA

Yassine et al., Nature, 2015; Impagliazzo et al., Science, 2015Steel et al., mBio, 2010

NIH

Entering Phase I

Clinical Trials

1x 20 mcgOR

2x 40 mcg

Crucell(Janssen)Palese Laboratory

(Icahn School of Medicine at Mount Sinai, New York,

NY)

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Peter Palese/GSK: Chimeric HA

Krammer et al. J. Virol. 2013

• Can be produced as recombinant proteins, or incorporated into current inactivated and live-attenuated vaccine platforms

• Designed to elicit bnAbs that target the HA stalk

• Flexibility to strategically incorporate relevant head domains (e.g. H5, H7)

• Currently in Phase I clinical trails- I.M. prime-boost of IIV (GSK)- LAIV + IIV prime-boost (PATH)

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HA stalk-binding bnAb-mediated protection:

Defying convention

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Mechanisms of stalk-binding bnAb-mediated

neutralization

Head Binding Ab

Stalk Binding Ab

Attachment ADCC (Fc-FcR)

Modified Modified from: Krammer, F., Palese, P. Curr. Opin. Virol., 2013

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HA stalk-binding bnAbs are relatively weak

neutralizers

He et al., J Virol, 2015

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The immune response to IAV is POLYCLONAL

Adapted from Mouquet, 2015

1. Specificity2. Isotype

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Isotype matters…a LOT!

Dilillo et al. Nature Med, 2014

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Isotype + specificity regulate Fc-FcR interactions

He et al., Proc Natl Acad Sci USA, 2016

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Isotype + specificity regulate Fc-FcR interactions

He et al., Proc Natl Acad Sci USA, 2016

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Isotype + specificity regulate Fc-FcR interactions

He et al., Proc Natl Acad Sci USA, 2016

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Leon et al., Proc Natl Acad Sci USA, 2016

Efficient FcR signaling by HA stalk-binding bnAbs

requires two points of contact

Alveolar Macrophages

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Alveolar macrophages are critical for protection mediated by IgG bnAb

He et al., Nat Communications, 2017

NK cells

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Remaining questions/barriers

• New “correlates of protection” need to be established

- Interpretation of Phase I/II clinical trials will be difficult since it is unclear what levels of bnAbs/T cells are needed to confer protection

• Novel platforms/strategies needed for vaccinating children (and the elderly)?

- bnAbs only need boosting in adults – but need to be established in children (ditto for T cells)

• Most efficient/effective strategy for performing Phase III (efficacy) trials?

- Universal vaccine vs. placebo not possible in all jurisdictions- Universal vaccine + seasonal vaccine?- Human challenge model?

• How do we measure vaccine efficacy?

- Prevention of PCR-confirmed infection?- Prevention of “moderate/severe disease?”

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Acknowledgements

The Boris Family Fund for

Excellence in Health Research

Dr. Peter PaleseDr. Florian Krammer

Dr. Gene Tan

Dr. Nicholas Heaton

Dr. Mark LoebDr. Dawn BowdishDr. Ali AshkarDr. Charu Kaushic

Dr. Wenqian He

Dr. Neda BarjestehDr. Alain Gagnon

Dr. Brian Ward