nouveaux vaccins: tenez-vous bien et soyez prêts. le ... · of vaccine market (2016) $52 billion...
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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