Nouveaux vaccins: tenez-vous bien et soyez prêts.

Le tsunami s’en vientColloque Bleu

Montréal - 2016

Brian J Ward Institût de recherche de centre universitaire de santé McGill

Centre des maladies tropicales JD MacLean

Conflit d’intérêts (les dernières 5 ans)

Position in Pharma Medical Officer for Medicago Inc. (Oct 2011 - present)

Consulting Pfizer, Merck, Novartis, GSK, Sanofi Pasteur

MSSS, US Dept of Justice (Vaccine Compensation Programs)

Contracts Vaccine trials for virtually all companies

Shared Awards

Shared CIHR Team grant (Laval U, GSK)

CIHR-Industry grant (Medicago, Aviex)

Shared CQDM grant (Medicago, Laval U)

Occasional

Speakers Honoraria

Pfizer, Sanofi Pasteur,Novartis

Investments (sadly) Nil

Le vaccinoduc

www.shutterstock.com

Milestones in Human Vaccine Development

China 14th-15th century Smallpox (powdered scabs, fleas)

Mid-East ?? Leishmania inoculation

Turkey 17th-18th century Smallpox (variolation)

England 1798 Smallpox (cowpox)

France 18th century Rabies

Europe 19th century Typhoid (1896)

Cholera (1896)

Plague (1897)

World Early 20th century Diphtheria (1923)

Pertussis (1926)

Tetanus (1927)

BCG (1927)

Yellow Fever (1935) - egg-based

Influenza (1936) - egg-based

Rickettsia (1938)

World Post-WWII

Viruses Bacteria

Polio (oral) Rabies Typhoid (oral) Cholera (oral)

Polio (injected) Adenovirus Typhoid (injected) Pneumococcus

Measles Japanese B Meningococcus H influenzae

Mumps Hepatitis A Tick encephalitis Lyme borreliosis

Rubella Hepatitis B

Rotavirus Varicella

Papillomavirus

Cross-species

protection

Animal Passage

of Defined Pathogen

Toxin Isolation

Egg as crude cell culture

Germ Theory

Broth Cultures

DNA/RNA

Attenuation of Organisms

Basic Immunology

Cell Culture

Molecular Biology

Milestones in Human Vaccine Development

World Post-WWII

Viruses Bacteria

Polio (oral) Rabies Typhoid (oral) Cholera (oral)

Polio (injected) Adenovirus Typhoid (injected) Pneumococcus

Measles Japanese B Meningococcus H influenzae

Mumps Hepatitis A Tick encephalitis Lyme borreliosis

Rubella Hepatitis B

Rotavirus Varicella

Papillomavirus

Cytokines

Innate IR modifiers

Immunology: Th1/Th2/Th17/Treg

Dendritic Cells

New Adjuvants: Toll-like receptors, others

New Routes, Vectors & Schedules

What’s Driving Development?

• New science- new tools

- new targets

• Interest from governments- healthier populations

- saving money

• Philanthropy (Bill & Melinda Gates Foundation)

• Inter-connected world- biothreats

- pandemics

• Profits

Vaccines for EVERYTHING

Infectious

Diseases

Preventative

Monophasic/typic Viruses

Toxin-Mediated Dz

Antibody-Preventable Dz

Preventative II

Multiple Sero/genotype Dz

Repeated Infections

Dz Needing Cellular Response

Modified/Curative

Chronic Viral Dz

(HBV, HCV, HIV, etc)

Auto-

Immunity

Preventative

HLA-Associated

Infection -Induced

Modified/Curative

Th1/Th2/Th17

Increased Treg

Cancer

Preventative

General (p53)

Specific Antigens

Curative

Adjunct Rx

‘Mop-Up’ Rx

Boutique Vaccines

Fertility

Irreversible

Reversible

Le vaccinoducD’un riusseau à une inondation

www.truthdig.com

C’est

Nous

Je veux

inventer

un

vaccin

cette

semaine

Il y a de l’argent

à gagner avec les

vaccins

Estimated Total Value

of Vaccine Market (2016)

$52 Billion

Vaccine Market Expanding

at 12-16% per Year

http://www.in-pharmatechnologist.com

Value of Cancer Vaccine Market (2019)

$4.3 Billion

Prevnar (2008) $2.7 billion

(2009) $4.4 billion

(2014)possible $6.0 billion

Gardasil (2007) $1.1 billion

(2008)projected $1.9 billion

(2012)possible $3-10 billion

Zostavax (2008) $300 million

Even

Influenza (2011) $2.9 billion

MMRV (2010) $1.4 billion(US)

Dtap±HBV-IPV (2010) $1.2 billion(US)

Vaccines as Blockbusters

M Davis. Price as a double-edged sword in the

golden era of vaccines. Human Vaccines 2010

Cancer VaccinesSipuleucel-T (Provenge™)

• Activated (GM-CSF), Prostatic Acid Phosphatase

(PAP)-primed, antigen presenting cells

• Extends median survival by ~4.1 months

• Cost $93,000

• 2013 World Vaccine Congress (Washington DC)

• Most Promising Vaccines- 1 targeting an infectious disease (H. pylori)

- 2 targeting autoimmune conditions

- 7 targeting cancers

Mergers & Acquisitions(1996-2012)

www.cepton.net/CEPTON_M&A_DINA4_150413.pdf

$68 billion acquisition of Wyeth by Pfizer

$47 billion acquisition of Genetech by Roche

Vaccine Landscape

Reuters

$1,500/copy

MOZ

$1,495/copy

Estimate of

$100B in Mergers

& Acquisitions

2014

colourbox.com

Vaccines used to be the ‘Nice’

Part of the Pharma Sector

http://neatorama.cachefly.net/images/2007-08/sumo-kid.jpg

They

Are Starting to

Throw Their

Weight Around

Je sais déja ce

que je vais faire

avec mon

bonus 2016

CAPEX$ 10 M > $ 200 M

Staff100 1000

From strain to vaccine 6 months6 weeks

COGS / dose$ 0.10 $ 1.00

Capacity20 mio doses 55 mio doses

Time to double capacity12-18 months 36-48 months

Surge capacity limitationVirtually

unlimited

Eggs supply

shortage

Bring on the ‘Little Guys’

Medicago

Egg-based

Landscape - 2013

Antisense (30)

Cell therapy (69)

Gene Therapy (46)

Monoclonal Antibodies (308)

Recombinant Proteins (93)

Vaccines (250)

Other (81)

http://www.phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf

Global Vaccine Market Features &

Future Trends (Miloud Kaddar - 2012)

• 10-15% growth rate (vs industry <2%)

• Total market potential $>100 billion by 2025

who.int/influenza_vaccines_plan/resources/session_10_kaddar.pdf

The Next Travel Vaccines?

• Attenuated Japanese Encephalitis vaccine

• Entervirus 71 vaccine(s)

• Ebola vaccine(s)

- Ebola monoclonal antibodies

• Dengue vaccine

• Chikungunya, Zika & MERS vaccines

• malaria vaccine(s)

• Many old vaccines in in new formats

- subunit + adjuvant

- attenuated vector vaccines (Adenovirus, Salmonella)

Je veux

inventer

un

vaccin

cette

semaine

I Think I’ll Make a Vaccine

this Week

Idea

Pre-Clinical

Phase I

Phase II

Phase III

Phase IV

http://seattletimes.nwsource.com/ABPub/2007/11/13/2004011858.jpg

www.inmagine.com

I Think I’ll Make a Vaccine this Week - II

Idea

Pre-ClinicalCan you make target (culture, molecular biology)?

Is there an animal model?

Are the correlates of immunity established?

Toxicity studies

Phase I

Phase II

Phase III

Phase IV

abee12.blogspot.com

Cost

~$1 million

I Think I’ll Make a Vaccine this Week - III

Idea

Pre-Clinical

Phase I First in humans

Focus on safety (sneak some

immunogenicity in)

15-50 adult subjects

Intensive monitoring

Phase II

Phase III

Phase IV

Cost

~$1-2 million

flickr.com

I Think I’ll Make a Vaccine this Week - IV

Idea

Pre-Clinical

Phase I

Phase IILarger numbers (300-3000)

Dose escalation (immunogenicity)

First look at efficacy (sometimes)

Studies in special populations

(kids, elderly, etc)

Phase III

Phase IV

Cost

~$10-50 million

www.caption-this.com

A billion here, a billion there and pretty

soon we’re talking real money

I Think I’ll Make a Vaccine this Week - V

Idea

Pre-Clinical

Phase I

Phase II

Phase IIIThe ‘pivotal’ study(ies)

Field efficacy trials

Numbers up to 60,000

Challenge studies

Expanded populations

Phase IV

Cost

~$100’s of millions

www.wunderground.com

Quoi?!?

Le vaccin

n’est pas

disponible?

Vaccine Supply IssuesChronic Shortages

• rabies vaccine and RIG

• zoster vaccine

Periodic Manufacturing Problems• polio vaccines

• conjugate pneumococcal & H. influenza vaccines

• yellow fever vaccine

Crisis Shortages• pandemic influenza vaccines

• meningococcal vaccines

• cholera vaccines

2012

5 companies

controlled 90% of

global vaccine sales

http://www.fiercevaccines.com/special-report/top-5-vaccine-companies-by-revenue-2012

Little International Coordination

Sanofi Pasteur’s IPV

• 2 versions exist (legacy)

• MRC-5 cells vs. Vero cells

• 2 different licensed production processes

• 16 stand-alone or combination formulations

• 32 different filled products

• 64 different package presentations

• Labelled for specific country requirements

300 different final products

distributed to different parts of the world

Vaccine Quantity & Quality• Vaccine are biological agents – stability & expiry dates

- Cold chain major issue for some (some live vaccines 1/2 log per hour)

- Storage & shipping (too hot and too cold both problematic)

- Most companies work on ‘just-in-time’ manufacturing

• Many products made in ‘purpose-built’ facilities- GSK’s influenza vaccine facility in Canada (2014-15)

- Sanofi’s new dengue facility in France (300M euros)

• Vaccines represented 50% of the FDA product

shortages list in 2012

• Non-Government suppliers often unreliable, even in

rich countries (eg: on-line pharmacies in USA)

Liang BA, Mackey TK. Vaccine shortages and suspect online pharmacy sellers. Vaccine. 2012 Jan 5;30(2):105-8.

Yen C et al. The development of global vaccine stockpiles. Lancet Infect Dis. 2015 Mar;15(3):340-7.

Shortages are InevitableBoth Stockpiling & Not Stockpiling have Costs

• USA stockpiling pediatric vaccines since 1983

• Used to be cheap (few vaccines, low cost)

• Looked at 2 scenarios (high vs low stockpile)- high: 6 months supply for all kids

- low: 50% of high or current stockpile (lower value)

CONSEQUENCESCost Vaccine-Preventable Deaths

Cases

Low $600M 376,000 1774

High $2B (+$1.6B) 7100 508

Shreshtha SS et al. Modeling the national pediatric vaccine stockpile: supply shortages, health impacts and cost

consequences. Vaccine. 2010 Aug 31;28(38):6318-32.

sites.google.com

Le monde du vaccin

se diversifie

Donald P. Francis et al. Global vaccine supply. The increasing role of manufacturers from middle income countries.

Vaccine, Volume 32, Issue 41, 2014, 5259 - 5265

Expansion of Capacity in Low-

and Middle-Income Countries

Developing Country Vaccine

Manufacturers Network

www.dcvmn.org Pagliusi S et al Developing Countries Vaccine Manufacturers Network: doing good by making high-quality

vaccines affordable for all. . Vaccine. 2013 Apr 18;31 Suppl 2:B176-83.

Rapid Expansion of Targets

China

Attenuated Japanese B Encephalitis Vaccine

Enterovirus 71 Vaccine

http://www.newscientist.com/data/images/ns/cms/dn9642/dn9642-1_800.jpg

World Happiness

http://www.ifpma.org/influenza/content/images/map_IVS_production_sites.gif

The Politics of Pandemic

Influenza

thecoolestducks.tumblr.com io9.com

The last Time This Happened?

shrinknextdoor.com

Je vais tuer quelqu’un …

Vaccines are ‘Good’

Vaccines are ‘Bad’1990 1992 1994 1996 1998 2000 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

10

8

6

4

2

0

Bad Math

Probability

Philosophy

www.sodahead.com

Simple Math

98 vaccinated subjects

• seroconversion 95%

• 93 protected & 5 susceptible

2 unvaccinated subjects

• 2 susceptible

Outbreak 4 cases 2 cases

Attack Rate 4% 100%

Two Unlikely Events Occurring

Close Together MUST be Related

anysportanytime.ca earthtodave.com

The Trolley Argument

picturebugs.blogspot.com

You

Pokenindia.com

123rf.com

123rf.com

www.mirror.co.uk

We’re Often Afraid of

the Wrong Stuff?

knowyourmeme.com

In an article reported by News24.com, a South African online news Web site, Sule Ya'u Sule, speaking for the governor of Kano, is quoted as saying: “Since September 11, the Muslim world is beginning to be suspicious of any move from the Western world…Our people have become really concerned about polio vaccine” [14]. In the same article, Datti Ahmed, a Kano-based physician who heads a prominent Muslim group, the Supreme Council for Sharia in Nigeria (SCSN), is quoted as saying that polio vaccines were “corrupted and tainted by evildoers from America and their Western allies.” Ahmed went on to say: “We believe that modern-day Hitlers have deliberately adulterated the oral polio vaccines with anti-fertility drugs and…viruses which are known to cause HIV and AIDS” [14].

Bad Press in a Polarized World

Affects Us All

Polio - global status 2005-06http://www3.who.int/whosis/menu.cfm?path=evidence,burden

Polio Eradication in 2012?

Syria

Polio is a Classic ‘Tip of the Iceberg’ Disease

If you Find Two Cases - There are 2000 More in the Community

... and in 2014/15 … Back

to 2004

www.cdc.gov

Polio (Montreal Gazette)

February 2016

2014 - The Magic (Measley) Kingdom

• 178 cases in Disneyland outbreak

• 17 states + Mexico + Canada

• vaccination status for 34 and 82% unvaccinated

www.motherjones.com

McCarthy M. Measles outbreak linked to Disney theme parks reaches five

states and Mexico. BMJ. 2015 Jan 23;350:h436.

Accumulating Susceptibles

US birth cohort ~4 million/yr

20

15

10

5

05 10 15 20 25 30

85% 2-doses (95% VE)

(170K/yr).

8% 1-dose (90% VE)

(32,000)

2% Unvaccinated

(80,000)`

5% Vaccine refusal

(200,000)

Waning immunity 0.5%/yr

(5%/decade ~200,000)

Millions

We are

probably

around

here

The Donald: the Latest Moron

‘People that work for me, just the

other day, 2years old, beautiful child

went to have the vaccine

and came back and a week later, got a

tremendous fever, got

very, very sick, now is autistic.’

‘You take this little beautiful baby,

and you pump — it looks just like it’s

meant for a horse.’

www.urbandojo.com

Malgré tous ses

issues … je reste

optimiste

Vaccines completely

changed one aspect of

medicine …

We are poised

for ‘Phase 2’ …

www.bt.cdc.gov

abcnews.go.com

‘Don’t count your children until

measles has passed’

Thank you for your attention

Arabic proverb cited by Morley 1973

freethoughtblogs.com