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Development of a Vaccine
François Meurice, MD, MPH
Ambassador Vaccines
Scientific Affairs & Public Health
GSK Vaccines Headquarters - Belgium
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Disclaimer
The content of this presentation is consistent with the approved
product informations of the addressed GSK products
History of vaccine development
Slide 2
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“With the exception of safe water, no other modality,
not even antibiotics, has had such a major effect on
mortality reduction…”1
Plotkin et al. Ch 1 in Plotkin et al. Vaccines. 6th Edition, Elsevier Saunders, 2012.
History of vaccine development
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The principle of vaccination was discovered before the
knowledge of pathogens and the immune system
• 1796: smallpox vaccine
introduced by Edward Jenner
• Jenner called this practice
‘vaccination’ from the Latin word
for cow, ‘vacca’
– Liquid from the pustules of
cowpox was used to inoculate
humans to prevent smallpox
• The ‘Jenner approach’ to
vaccination is considered as a
primitive example of a liveattenuated vaccine
Edward Jenner vaccinating his first patient.
Robert Thom, Collection of the University of Michigan Health System,
Gift of Pfizer Inc. UMHS.23
History of vaccine development
Slide 4
Bonanni et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 1–24
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The ‘germ theory’ opened the door to a pathogenbased approach
Louis Pasteur
Robert Koch
From ‘bad air’ and
‘body imbalance’…
to
…microorganisms
as causes of
infectious diseases
Microorganisms
Courtesy of CDC/Dr Ray Butler
Courtesy of CDC/Janice Haney
Carr/Jeff Hageman M.H.S.
History of vaccine development
Slide 5
Bonanni et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 1–24
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1970s–1980s
Major discoveries:
Split/subunit antigens
(1970s)
Recombinant DNA
protein antigens (1980s)
Whole
pathogen
Split
Subunit
History of vaccine development
Slide 6
Bonanni et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 1–24
CH/VAC/0002/17/20.01.2017/D
1980s–1990s
Major discoveries:
Conjugation of
polysaccharides (1980s)1
Reassortment of viral
genes (1990s)2
Bovine
rotavirus
Human
rotavirus
Polysaccharide
Protein
Human
Human/bovine
reassortment
1. Strugnell et al. Chapter 3 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier,
2011, pp. 61–88; 2. Bonanni et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1,
Amsterdam, Elsevier, 2011, pp. 1–24
History of vaccine development
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Many important vaccine technologies have been
developed since the late 18th century
Prostate cancer
Zoster
HPV
Meningitis C conjugate
Rotavirus**
Rotavirus
[Discontinued]
Influenza*
Pneumococcus conjugate
Meningococcus ACWY conjugate
Typhoid
Meningitis C conjugate
Varicella
Typhoid
Hepatitis A
Hib conjugate
Hepatitis B
[Hepatitis B]
Pertussis
Hib polysaccharide
Meningococcus (ACWY)
Influenza
Rubella
Mumps
Measles
Polio (OPV)
Dendritic cells
Polio (IPV)
Reassortant
Pneumococcus
Influenza
DNA recombinant
Yellow fever
Diphtheria
Polysaccharide conjugated
Tuberculosis
Tetanus
Plasma derived
Pertussis
Split, subunit
Variolation + vaccination (smallpox)
Live-attenuated
Inactivated
Toxoid
Polysaccharide
Split, subunit
Plasma derived
DNA recombinant
Polysaccharide conjugated
Reassortant, live-attenuated
Dendritic cells
Smallpox
Inactivated
Plague
Cholera
Typhoid
Rabies
Polysaccharide
Toxoid
Live-attenuated
Smallpox vaccination
Variolation
Smallpox eradicated
1750 1800 1850 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
*Reassortant; **Live-attenuated reassortant (human/animal species); Pandemic influenza vaccines were developed in 2009 using all
History of vaccine development
techniques previously developed for seasonal influenza
Slide 8
Bonanni et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 1–24
CH/VAC/0002/17/20.01.2017/D
Vaccine Development :
A complex system from inception to use
Vaccine
implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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A complex system from inception to use
Vaccine
implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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Economic
sustainability
The starting block
Medical need
•
•
•
•
•
•
Epidemiology
Target population
Disease burden
Health economics
Public perception
…
Medical
need
Scientific/technical
feasibility
•
•
•
•
•
•
Protection mechanism
Virulence factors
Target antigen
Tests methods
Animal model
…
Technical
feasibility
• Return on investment
can be predicted
• +/- Development
partnership or other
funding mechanisms
• Long term investment
is worth it
Research on
a vaccine
candidate
starts
Vaccine development
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Key steps in vaccine design
Identification and
selection of appropriate
antigen(s)
Is the elicited immune
response protective?
• Understanding of disease pathogenesis
• Virulence factors
• Natural immune control mechanisms
•
•
•
•
Is a humoral (B-cell) response elicited?
Is a cell-mediated (T-cell) response elicited?
Is immune memory induced?
Is the elicited immune response providing adequate
protection with an acceptable safety profile?
History of vaccine development
Slide 12
Adapted from Leo et al. Chapter 2 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 25–59
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Challenges in vaccine development
• Better understanding of bacterial, viral and parasitic defence
mechanisms
• Defining (and targeting) appropriate correlates of protection
(animal model?)
• Targeting the CD8 compartment if necessary?
– Delivering antigen to the MHC class I pathway
• Formulation issues: need for conjugation? for an adjuvant?
• Compatibility of components, interference and stability
• Batch-to-batch consistency
• Suitable for manufacturing at large scale
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50
Vaccine development
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It takes many years to develop a vaccine
Pre-clinical
Clinical
5–15 years
5–15 years
Postlicensure
Indefinitely
• Safety surveillance continues indefinitely
• Additional clinical and epidemiological studies may be carried
out for new indications or to assess impact and safety
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50
Vaccine development
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Vaccine development: pre-clinical evaluation
Antigen
production
Antigen/adjuvant
compatibility*
Pre-clinical
evaluation
Adjuvant
selection based
on desired
response and
previous
experience*
Immune read-out
development
Non-clinical
toxicology
Antigen
selection
Host–pathogen
interaction
Protective
immune
mechanisms
*If adjuvant is needed
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50
Vaccine development
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Clinical studies
Early Phase
Phase I
N=20–80
Phase II
N=>100s
Phase III
N=1000s–10,000s
Phase IIIb/IV
Safety
Safety
Safety
Safety
Immunogenity
Immunogenicity
Immunogenicity
Proof of concept
Efficacy
Licensure
N=millions
Effectiveness
New indications
Dose ranging
Safety evaluation:
• Local
• Systemic
• AE
• SAE
Pharmacovigilance
AE, adverse event; SAE, severe adverse event
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam,
Elsevier, 2011, pp. 115–150; Douglas, Samant et al. Chapter 3 in: Plotkin et al. Vaccines, 6th edition, Philadelphia, Saunders, 2012,
pp. 33–43; Baylor, Marshall. Chapter 73 in: Plotkin et al. Vaccines, 6th edition, Philadelphia, Saunders, 2012, pp. 1427–46
Vaccine development
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Vaccine development steps: post-licensure evaluation
Phase IIIb, IV
studies
New indications
Vaccine
implementation
Effectiveness and
long-term safety
Vaccine licensure
Safety surveillance
systems
Health-economics
assessment
Impact of
vaccination
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50
Vaccine development
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Challenges in vaccine development
Measuring protective effects
• Immunological correlates of protection not always available
• Difficult to define clinical end-points for diseases with complex
host–pathogen interactions or pathogenesis
• Difficult to measure protective effect against chronic conditions and
cancers when they take a very long time to develop after infection
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50; Harper. Prophylactic human papillomavirus vaccines to prevent cervical cancer: Review of the Phase II and III trials . Therapy
2008;5(3):313–324.
Vaccine development
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A complex system from inception to use
Vaccine
implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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Vaccine safety assessment
Vaccine development
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Pre-clinical development
Safety assessment, monitoring and risk minimisation
Preclinical assessment
•
•
•
•
Toxicology studies:
− In vitro and in vivo (animal) studies
− Single dose toxicity
− Repeated dose toxicity
− Local tolerance, genetic toxicology
− Reproductive toxicology (if
applicable)
− Teratogenicity
− General safety profile
Mode of action
Dose ranging
Quality control testing
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp. 115–
Vaccine development
50; Garçon et al. The safety evaluation of adjuvants during vaccine development: The AS04 experience. Vaccine 2011;29(27):4453–4459
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Clinical development
Safety assessment, monitoring and risk minimisation
Clinical Phase I–III assessment*
• Clinical trials (respecting all GCP standards)
• Local and systemic solicited symptoms
• Unsolicited symptoms (common and uncommon AEs)
• SAEs and AESI** evaluation
• Overall safety analysis
• Dose and schedule selection
• GLP/GMP quality controls testing
*Note: Other preclinical testing, e.g. toxicology and mode of action studies, continue in parallel with the clinical assessment; **if requested; GCP, good
clinical practice; AESI, adverse events of special interest; GMP, good manufacturing practice; GLP, good laboratory practice
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp.
115–50; Garçon et al. The safety evaluation of adjuvants during vaccine development: The AS04 experience. Vaccine 2011;29(27):4453–4459
Vaccine development
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Clinical safety evaluation: reporting of adverse events
in phase I–III studies
Example: AS04/HPV-16/18
Dose 1*
Month 0
Solicited
symptoms
Unsolicited
symptoms
Dose 2*
Month 1
7 days
30 days
7 days
30 days
Dose 3*
Month 6
Long-term
*3 dose schedule Cervarix®
(see www.swissmedicinfo.ch for follow-up
dosage, application)
7 days
30 days
Throughout study
SAEs
Pregnancies*
MAEs
& NOCDs**
• MAEs, i.e. any AE resulting in an unscheduled interaction with a healthcare provider, and NOCDs (e.g. immune-mediated disorders)
• Investigators invited to report SAEs they assess as related to candidate vaccine indefinitely
*Pregnancies, if relevant, followed up until outcome; **Specific to HPV programme; MAE, medically attended adverse event;
NOCD, new onset chronic disease; HPV, human papillomavirus
Verstraeten et al. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines.
Vaccine 2008;26(51):6630–6638; Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1,
Amsterdam, Elsevier, 2011, pp. 115–150; Descamps et al. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer
prevention: a pooled analysis of 11 clinical trials.Hum Vaccin 2009;5(5):332–340; Product information Cervarix®, www.swissmedicinfo.ch, accessed
January 17, 2016
Vaccine development
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At registration and post-licensure
Safety assessment, monitoring and risk minimisation
At registration stage
•
•
•
Pregnancy registries (if applicable)
Post-approval safety
surveillance/studies
Additional requests for analysis
Post-licensure
•
•
•
•
•
•
Phase IIIb/IV studies
Sustained pharmacovigilance
surveillance, rare events
Cases/cluster detection
Quantitative and
qualitative analysis
Overall on-going safety evaluation
Periodic safety reports
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp.
115–50; Garçon et al. The safety evaluation of adjuvants during vaccine development: The AS04 experience. Vaccine 2011;29(27):4453–4459
Vaccine development
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Challenges in vaccine development
Safety assessment
Concerns about vaccines and
immune mediated disorders
• Benefit/risk ratio acceptance
different for public health needs
and individuals
• A potential safety concern that
needs to be addressed for new
and old vaccines
• Continued safety monitoring
is crucial
• Increasing knowledge on how
vaccines immune response works
can provide reassurance
• Evaluation of temporal associations
of adverse events after vaccination
• Need to compare frequency of rare
adverse event after vaccination
with incidence in the unvaccinated
population (expected cases)
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50; Spier. Perception of risk of vaccine adverse events: a historical perspective.Vaccine 2001; 20(S1):S78–S84
Vaccine development
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Safety and effectiveness/Impact vaccine studies
• Vaccine safety studies measure predictable (e.g. fever,
anaphylaxis) and uncommon (e.g. GBS, intussusception) or
unpredicatble (e.g. narcolepsy) adverse reactions (including
vaccine failure = lack of effectiveness)
• Effectiveness / Impact studies assess reduction in disease
incidence in routine medical practice
– Changing epidemiology
– Healthcare use, societal impact
– Coverage, Compliance, Herd protection
– Cold chain, storage…
Vaccine development
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A complex system from inception to use
Vaccine
implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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Vaccine bulk manufacturing
and formulation
Vaccine development
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Specifics of the vaccine manufacturing process
• Long production time
• Flu vaccine, 4-6 months; Pneumococcal >1 year
• Hexavalent DTPa-based: up to 2 years
• Inherent variability of the
biological systems
• Long release time
• Biological testing (in-vivo / in-vitro): numerous tests and lengthy
documentation for release of a lot: cost, resource, capacity – this
can take up to 70% of the total manufacturing time!
• Release needed for each single batch supplied (20–50% of this
release time is with the release authority)
International Federation of Pharmaceutical Manufacturers and Associations. The complex journey of a vaccine. 2014. Available at: http://www.ifpma.org/resourcecentre/the-complex-journey-of-a-vaccine-2/. Accessed January 2017
Vaccine development
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Vaccine manufacture is a multi-step process
Formulation &
Filling
Packaging &
Distribution
Growing the
organism
Formulating
the vaccine
Packaging
the
vaccine
Purifying
the antigen
Filling the
vaccine
Freezedrying
Storing the
vaccine
Release
Distribution
(Internal & by the authorities)
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011, pp.
115–50; International Federation of Pharmaceutical Manufacturers and Associations. The complex journey of a vaccine. 2014. Available at:
http://www.ifpma.org/resource-centre/the-complex-journey-of-a-vaccine-2/. Accessed January 2017
Quality Assurance & Quality Control
Antigen
manufacture
Vaccine development
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A complex system from inception to use
Vaccine
Implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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Vaccine approval process by
regulatory authorities
Vaccine development
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Main regulators deliver guidelines, directives, technical
reports, monographs, pharmacopeia
BGTD
HPFB Inspectorate
MHRA
FDA
EMA
WHO
PMDA Japan
Drug Controller of
India, MOH &
Welfare
Singapore MOH
NRAs
WHO
TGA - Therapeutic Goods
Administration
International Conference of
Harmonisation
BGTD, Biologics and Genetic Therapies Directorate; HPFB, Health, Product and Food Branch; MHRA, Medicines and Healthcare products
Regulatory Agency; EMEA, European Medicines Agency; PMDA, Pharmaceuticals and Medical Devices Agency; MOH, Ministry of Health
Vaccine development
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Vaccine approvals outside EU and USA
• Approval in countries outside the EU and
USA is country-specific, based on national regulatory
authorities (NRAs)
• Approval in countries without functional NRAs:
– WHO has a system for prequalification of vaccines
destined for countries without functional NRAs
– WHO has a service to determine the acceptability of
vaccines from different sources for supply to UNICEF,
GAVI and other agencies that purchase vaccines
UNICEF, United Nations Children’s Fund; GAVI, Global Alliance for Vaccines and Immunisation
Leroux-Roels et al. Chapter 5 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011,
pp. 115–50
Vaccine development
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What is the role of the NRA* after registration?
Inspections
at regular
intervals
Lot-to-lot
release
Review of
commitments
Postlicensure
activities
Postlicensure
surveillance
NRA: National Regulatory Authority
Regulatory
actions
Vaccine development
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A complex system from inception to use
Vaccine
Implementation
Research
Approval
process/
licensure
Safety and
quality control
Manufacturing
Vaccine development
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Vaccine introduction and implementation
Vaccination
calendar
National/
Supranational
recommendations
Risk
groups
Universal mass
vaccination
Catch-up
vaccination
Vaccine development
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Political and Public Health Priorities
A disease is a public health priority when:
• There is a high burden of disease and serious consequences
for the health of the population,
• The scientific community, political authorities and general
population consider it a serious public health problem and
• There is a consensus among opinion-makers, politicians,
technical personnel and the public that this problem should be
solved
PAHO Field Guide: Introduction and Implementation of new vaccines 2010. Scientific and Technical Publication N°632. Accessed on 22/12/2016 at:
http://new.paho.org/hq/dmdocuments/2010/FieldGuide_NewVaccines_1stEd_e.pdf?ua=1
Vaccine development
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Factors to consider for vaccine introduction
Political and Technical
Political and public
health priorities
Burden of disease
Comparison with other
interventions (including
other vaccines)
Vaccine safety, efficacy
and quality
Economic and
financial criteria
New vaccine
Feasibility and Scheduling
Characteristics of vaccine
presentation
Vaccination program
performance
Availability of vaccine supply
Introduction Decision at Country Level
PAHO Field Guide: Introduction and Implementation of new vaccines 2010. Scientific and Technical Publication N°632. Accessed on 22/12/2016 at:
http://new.paho.org/hq/dmdocuments/2010/FieldGuide_NewVaccines_1stEd_e.pdf?ua=1
Vaccine development
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Summary
• Development and assessment of vaccines is
constantly improving and evolving
• The aim is production of robust evidence to assess
benefit–risk profiles
• From concept to licensure, it takes many years to develop
a vaccine
• Every step of development and formulation follows standard
procedures and is carefully monitored
• Vaccine licensure is performed under the control of
regulatory agencies
Vaccine development
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Every year…
Equivalent to the
population of Paris2
2.5 million deaths
are averted through
immunisation1
750,000 children
are saved from
disability2
Today, 30 diseases can be
prevented or their incidence
lowered through vaccination1,3,4
1. WHO, UNICEF, World Bank. State of the world’s vaccines and immunization, 3rd edition. Geneva, 2009; 2. Ehreth. The value of
vaccination: a global perspective. Vaccine 2003; 21(27-30):4105-4117; 3. Gray GC. Chapter 9 in: Plotkin et al. Vaccines, 6th edition,
Philadelphia, Saunders, 2012, pp. 113–27; 4. CDC. Vaccine information statements. Available at:
http://www.cdc.gov/vaccines/hcp/vis/index.html?s_cid=cs_000 (accessed October 2014)
History of vaccine development
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Adverse event reporting
For reporting of adverse events after use of a GSK product
please report to: [email protected]
Vaccine development
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Short product information (GSK product)
Cervarix®, vaccin HPV-16/HPV-18
PA: Protéines L1 de papillomavirus humain des types 16 et 18. I: Prévention des lésions précancéreuses et des
cancers du col de l’utérus dus aux HPV-16 et HPV-18 chez les jeunes filles et les femmes à partir de l’âge de 10 ans.
P/M: Doses de 0,5 ml chacune par voie intramusculaire. Âge de 10-14 ans: 2 doses (mois 0, 6) ou 3 doses (mois 0, 1,
6). A partir de 15 ans: 3 doses (mois 0, 1, 6). Non recommandé chez les filles de moins de 10 ans. CI: Hypersensibilité
à l’un des composants du vaccin, maladie fébrile aiguë sévère. MG/P: Ne pas injecter par voie intravasculaire ou
intradermique; réactions anaphylactiques; réaction psychogène à l’injection (p.ex. syncope); précaution en cas de
thrombocytopénie ou trouble de la coagulation; pas d’effet thérapeutique (pas indiqué pour le traitement du cancer du
col de l’utérus ou des néoplasies intra-épithéliales); protection limitée contre d’autres types d'HPV (maintenir les
mesures de précaution appropriées contre les maladies sexuellement transmissibles); ne remplace pas le dépistage
régulier du cancer du col de l’utérus; réponse immunitaire à la vaccination peut être insuffisante en cas
d’immunodéficience (par ex. due à un traitement immunosuppresseur). IA: Administration simultanée possible avec
dTpa, dTpa-IPV, hépatite A/B en des sites d’injection différents. G: Femmes enceintes et femmes prévoyant une
grossesse: ne vacciner qu’après la fin de la grossesse. EI: très fréquents: douleurs, rougeur, gonflement au site
d’injection; céphalées; myalgie; fatigue; fréquents: symptômes gastro-intestinaux, dont nausées, vomissements,
diarrhée, douleurs abdominales; démangeaisons/prurit, éruption cutanée, urticaire; arthralgie; fièvre (≥ 38°C);
occasionnels: entre autres, lymphadénopathie (généralisée, sévère dans des cas isolés), induration, paresthésie au site
d’injection; surveillance post-commercialisation: réactions allergiques incluant œdème de Quincke et réactions
anaphylactiques. Cons.: Conserver entre +2°C et +8°C. Ne pas congeler. Emb.: seringue préremplie (aiguilles
séparées), x1 et x10. Cat. de remise: B. Mise à jour de l’information: octobre 2015. GlaxoSmithKline AG. Une
information détaillée est disponible sur www.swissmedicinfo.ch. Veuillez annoncer tout effet indésirable à
[email protected].
Vaccine development
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Thank you for your attention !
Vaccine development
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