UNIVERSAL INFLUENZA VACCINES

WHO PDVAC meeting

26 June 2018

Barney S. Graham, MD, PhD

Deputy Director

Vaccine Research Center, NIAID, NIH

Global Disease Burden

• 3-5 million annual cases of severe illness globally – 2017-18 cases in U.S. similar to 2009 pandemic year (~7.7%)

• 290,000 to 650,000 annual deaths globally

• HIC - most influenza deaths occur in elderly – Conventional vaccine has marginal efficacy

• LMIC – higher overall severity of disease – Mortality greatest in children under 5 (28,000 - 111,500 associated with ALRI)

Sources: Lancet 2017, Dec 14; MMWR 2018; 67:169; , WHO, CDC 2

Influenza A has been the cause of prior pandemics

3 Confidential to VRC/NIAID/NIH

Need For a Universal Influenza Vaccine

Current Influenza Vaccines:

• Use 1940’s technology - inactivated virus grown in

chicken eggs

• Only 50-60% effective in good years

• Need to be reformulated every year to match

circulating influenza strains

• Not effective against new pandemic strains and

response is too late

Future Influenza Vaccines:

• Will use mammalian and insect cell manufacturing of

recombinant proteins

• Apply new technologies and endpoints

20 nm

Major Biological Challenges for Universal Influenza Vaccine

5

• Antigenic and Genetic variation • Extensive zoonotic reservoir, reassortment, adaptive mutations

• Pre-existing immunity • Immunodominance of serotype-specific epitopes

• Immunodominance of antibody lineages with limited breadth

• Influence on B cell phenotypes

• Most severe disease at extremes of age and in vulnerable populations with compromised immunity

Slide Credit: Dr. Anthony Fauci, NIAID

Workshop Meeting Report

The Pathway to a Universal

Influenza Vaccine

Paules CI, Marston HD, Eisinger RW,

Baltimore D, Fauci AS

October 2017

Established definition for a universal

influenza vaccine to serve as a goal for

future research efforts

Identified current research tools and

discussed advantages and disadvantages

Coordination of the influenza research field

is critical for success

Identified key gaps in knowledge to guide

strategic planning

Slide Credit (adapted from): Dr. Anthony Fauci, NIAID

Protection: >75% against symptomatic influenza infection

Breadth: Protection against group 1 and group 2 influenza A

viruses

– Influenza B as a secondary target

Durability: >1 year

Population: Suitable for all age groups

Definition of a Universal Influenza Vaccine

Slide Credit: Dr. Anthony Fauci, NIAID

NIAID Universal Influenza Vaccine Strategic Plan

NIAID priority to develop a universal influenza vaccine that provides

durable protection against multiple influenza strains

Foundation for future investments in influenza research

NIAID Universal Influenza Vaccine Strategic Plan

Influenza Genome and Proteins

11

NEP and NS1

NA (neuraminidase)

PB1, PB2, PA (RNA polymerase)

M1 (matrix protein)

HA (hemagglutinin)

M2 (ion channel)

Lipid envelope

NP (nucleocapsid protein)

Segmented (-) strand RNA genome

• Orthomyxovirus with segmented, negative-sense, single-stranded RNA genome • 8 gene segments encoding 11 proteins • Sialic acid receptor-dependent tropism

Influenza Vaccine Strategies

Strategy Phase Theoretical Mechanism

Leading universal vaccine concepts

HA stem or head-stem chimera Phase I Broad NAb (no HAI) and ADCC

HA head chimera (COBRA) Pre-clinical Broad NAb (with HAI)

Additional concepts

M2 ectodomain I/II Broad cross-reactive Ab; ADCC (no NT)

Co-assembled HA or RBD on NP Pre-clinical Favors cross-reactive B cells

Improved seasonal vaccines

HA rosettes, individual full-length HA nanoparticles, VLP

I/II Potency from particle display, breadth from multiple strains mixed or sequential delivery

Add neuraminidase antigen Pre-clinical Additional antigen for NT breadth/potency

Live-attenuated or single-round virus or gene-based delivery

Pre-clinical Additional antigens, T cell responses, and mucosal immunity

Mammalian cells, high-dose, adjuvants, LAIV or DNA prime

Post-marketing

Improved manufacturing or immunogenicity of conventional vaccine

Approaches for Influenza HA-based Vaccine Delivery

13

Soluble HA Trimer

WT, chimeric, or engineered for consensus

Live

influenza

N, M, +/- NA

Gene-based

delivery

Virus-like

particles

Conventional

inactivated vaccine

Can we use technology to turn anti-viral vaccine

development into an engineering exercise?

Emerging

infections

Technology

• Structural biology

• Protein engineering

• High throughput sequencing

• Rapid isolation of human mAbs

• New understanding of immunology and assay capabilities

• Rapid diagnostic tools

• Advanced imaging

• Systems biology

• Platform manufacturing

• Increasing human mobility, poverty, refugees, and immunological vulnerability

• Rapidly changing ecology

• Threat of bioterrorism

Major technologies being proposed to answer

and solve the key questions

• Structure-based understanding of neutralization and cross-reactive antibody binding

• Atomic level protein engineering for antigen design and nanoparticle display

• B cell biology to identify effective antibody lineages, define B cell phenotypes that can

sustain responses, and understand the role of initial antigen priming

• Platform manufacturing for rapid response

Hemagglutinin Structure

Influenza virus HA – sites of vulnerability

Diversity of influenza A hemagglutinins

Group 1 -specific

Group 2 -specific

Joyce et al. Cell (2016) 7

Cross-group 1/2 broadly neutralizing antibodies

Cross-group 1/2

Diversity of influenza A hemagglutinins

Joyce et al. Cell (2016) 8

Can stem-specific antibodies access HA on influenza virus?

Harris AK et al. PNAS 2013

Relative scale of antibodies and virions

Isolating Cross-Reactive Influenza mAbs

Single-cell analysis of PBMCs from clinical trials of pandemic vaccine candidates

HA-specific probes

20

Specific Ig Sequences Associated with HA Stem Cross-reactivity

Joyce, et al. Cell 2016 Andrews, Graham, Mascola, McDermott, Cold Spring Harbor Press, 2017

Group 1 and 2 HA Stem Antigens Induce Different

Antibody Lineages

H7N9 H5N1

Andrews et al. Science Immunology 2017 Confidential to VRC/NIAID/NIH 22

Technology Focus of VRC Influenza Vaccine

Development Program

• Design - Structure-guided approach for antigens and probes

• Display – Natural and designer nanoparticles

• Delivery – Protein or nucleic acid

• Detection of specific immunological endpoints

– Define and target specific antibody lineages with cross-neutralizing activity

– Analysis of B cell phenotype and repertoire at single-cell level

– Development of high-throughput functional serological assays

VRC Universal Influenza Vaccine Development

Immunodominant

strain-specific epitope

Hea

d

Ste

m

HA RBD

HA head removal

Conserved

epitope

Full-length

HA

Mosaic

monomers,

trimers, or

dimers

Headless HA

stem

Kanekiyo, et al. Nature 2013 Yassine, Boyington, et al. Nature Medicine 2015 24

Avoiding immunodominant strain-specific

antibody responses allowing cross-reactive

antibodies to emerge (avidity advantage)

Targeting conserved antigenic

sites in stem to induce cross-

reactive antibodies

Combined or serial heterologous antigen

regimens to recruit and accumulate antibodies

to diverse antigen sites and strains

Structure-guided

antigen design

HA is primary

antigenic target

Nanoparticle

display

Strategy for achieving protective antibodies

against future drifted and pandemic strains

Summary

• New technologies (particularly structural biology, rapid isolation of human monoclonal antibodies,

high-throughput sequencing, protein engineering, single-cell analysis, and their derivatives) have

provided new development options for influenza vaccines

• Influenza HA has discreet structurally-defined sites of vulnerability, and specific antibody lineages

have been defined that can provide broad immunity

• Vaccine antigens displayed on self-assembling NPs elicit high magnitude antibody responses

• Influenza HA antigen designs

• full-length HA (recombinant soluble trimers, consensus and combinations, displayed on nanoparticles

• HA stem as chimeric full-length proteins, soluble trimers, displayed on nanoparticles

• HA RBD displayed on mosaic nanoparticles

• Improved seasonal vaccines in the meantime using cell-based manufacturing, dose-adjustments,

adjuvants, and added neuraminidase, synthetic vaccinology for rapid manufacturing

• WHO PDVAC could help define and facilitate acceptable regulatory and logistical pathways to

compare with conventional vaccines and replace current manufacturing technology

Viral Pathogenesis Laboratory in NIAID VRC

NIAID Anthony Fauci Hilary Marston Cat Paules Robert Eisinger Emily Erbelding

NIAID Vaccine Research Center John Mascola Mario Roederer Richard Koup Daniel Douek Jason Gall Robert Seder Peter Kwong Nancy Sullivan Adrian McDermott Judy Stein Abe Mittelman Marybeth Daucher Sarah Andrews Gordon Joyce Julie Ledgerwood & Clinical Trial Program Diane Scorpio & Animal Care Program Richard Schwartz &Vaccine Production Program David Lindsay & Vaccine Clinical Material Program

Top row, left-to-right: Man Chen, Masaru Kanekiyo Truck bed, back: Tracy Ruckwardt, Erez Bar-Haim, April Killikelly, Jie Liu Truck bed, front: Rebecca Gillespie, Seyhan Boyoglu-Barnum, Kizzmekia Corbett, Assanatou Bamogo, Michelle Crank Standing: Syed Moin, Brian Fisher, Azad Kumar, Joan Ngwuta, Deepika Nair, La Che Wiggins, Kaitlyn Morabito, Adrian Creanga, Monique Young Not Pictured: Leda Castilho, Emily Phung, Erez Bar-Haim, Julia Lederhofer, Rebecca Loomis, Geoffrey Hutchinson, Hadi Yassine