Transcript Update on Pandemic Vaccine Development 3rd WHO WPRO/SEARO NIC Meeting 18-20 August, 2009, Beijing Masato Tashiro, MD., PhD. Director, WHO Collaborating Centre for Reference and Research.

Update on Pandemic Vaccine
Development
3rd WHO WPRO/SEARO NIC Meeting
18-20 August, 2009, Beijing
Masato Tashiro, MD., PhD.
Director, WHO Collaborating Centre
for Reference and Research on Influenza
NIID, Tokyo
State-of-the-Art
H5N1 Vaccine Developments
and Clinical Trials
1.H5N1 vaccines-specific issues
# Wild-type virus: highly pathogenic
Vaccine seeds to be modified to low
pathogenic
# Low immunogenic in humans
A high dose of antigens required
# Antigenic divergence among clades
Less cross-immunity
# Adjuvant is needed and beneficial
Better immunogenicity
Antigen sparing
Cross protection
2.Vaccine formulations (20~ clinical trials)
a. Inactivated split vaccines
# Plain split vaccines (egg-grown)
[Sanofi]
Less immunogenic
90 mg HA x 2 shots
insufficient in young adults
45 mg HA x 2 shots
similar with elderly and children
a. Inactivated split vaccines (cont.)
# Adjuvanted split vaccines (egg-grown)
Alum less beneficial
[Japan, Sanofi, Novartis]
MF-59 (oil-in-water emulsion)
[Novartis]
3.8; 7.5~ mg x 2 shots
efficient in adults, elderly, children
AS03 (oil-in-water emulstion)
[GSK]
3.8~ mg x 2 shots
efficient in adults, elderly,
b. Inactivated whole virus vaccines
# Plain whole virus vaccine
Vero cell-grown, wild-type virus [Baxter]
3.8; 7.5~ mg x 2 shots
efficient in adults and children
(Alum rather reduced immunogonicity)
# Adjuvanted whole virus vaccines (eggs)
Alum phosphate [Omni]
6 mg x 2 shots in adults
Alum hydroxide [Japan, Sinovac, CSL,
Microgen]
5~15 mg x 2 shots in adults
c. Live attenuated vaccines
# ca A/Ann Arbor/6/60 [MedImmune]
Less immunogenic due to restricted
replication of reassortant H5N1 in URT
d. Component vaccines [Protein Science]
# rHA protein produced in silk worm by
a baculovirus vector
Priming effect to a different clade virus
more than 10 years
3. Routes of immunization
# i.m.
local reactions less obvious
# s.c.
local reactions more visible
# intradermal
Antigen retention for a long period
No ~ remarkable benefit
# Skin patch; jet injectors
New devices in trials
# intranasal
ca-LAIV
Inactivated vaccines
Mucosal adjuvants (TLR3 agonist)
Applicating devices
Remaining issues of H5N1 vaccines
1) Standardization of neutralizing test and
harmonization of expression of antibody titers
2) Correlation between serum Ab titers and protective
effect?
3) Establishment of evaluation criteria for efficacy
of pandemic vaccines in clinical trials
4) Duration of serum antibodies?
5) Cross-protection against different Clades and
subclades as well as antigen-drifted viruses?
6) Children, pregnancy, elderly, high risk groups?
7) Prime-boost effects by different formulation vaccines?
4. Cross reactive immunity
Serum antibodies cross-reactive with different
clades and subclades of H5N1 viruses were
induced by;
• Alum-adjuvanted whole virus vaccines
• New adjuvant-mixed split vaccines
• Vero cell-grown, wild-type whole virus
vaccine
Stockpiling of pre-pandemic vaccines and
prime-boost strategies became realistic.
A(H1N1)2009 pandemic
 A(H1N1)pdm virus
• Low pathogenic (different from H5N1)
• No genetic markers for severe disease
(different from H5N1 and Spanish flu)
• Higher virulence in animal models than seasonal flu
• Not yet well-adapted to humans (less transmissible)
• Genetically and antigenically homogeneous among
isolates worldwide, similar to a reference virus;
A/California/07/2009(H1N1)pdm
• No genetic and phenotypic difference for fatal cases.
• Distinguishable from seasonal viruses and seasonal
vaccines will not be effective.
A(H1N1)2009 pandemic
Disease burden and social impact
• In most cases, mild illness similar to seasonal flu
• Moderate disease burdens (particularly in high risk
groups), but far less than H5N1
• Impact on health care systems in several countries
• Not yet real pandemic (herald wave ~1st wave)
• But, bigger outbreaks likely in the near future.
• Resistant to admantanes.
• Sensitive to NA inhibitors. But drug-resistant virus
has appeared sporadically.
Pandemic vaccine viruses (WHO)
• Reassortant viruses: 10
– Classical
• NYMC-X179A and IVR-153 (from A/California/7/2009)
– Reverse Genetics
• NIBRG-121 (from A/California/7/2009)
• CBER-RG2 (from A/California/4/2009)
• IDCDC-RG15 and IDCDC-RG20 (from A/Texas7/2009)
• NIBRG-122 (from A/England/195/2009)
• IDCDC-RG18 (from A/Texas/5/2009 and A/New
York/18/2009)
• IDCDC-RG22 (from A/New York/18/2009)
• Wild type viruses
– A/California/7/2009
– A/California/4/2009
– A/Texas/5 /2009
– A/England/195/2009
– A/New York/18/2009
Recent development of high yield vaccine viruses
Less efficient recovery of viral proteins of current vaccines
• NIBRG-121xp
– 13 passaged of NIBRG-121 in eggs
– A 2.5-fold increase in yield in preliminary evaluation
• Similar to normal seasonal H1N1 component
– Further evaluation ongoing by manufacturers, ERLs and
CCs
• X-181 series; new reassortants of X-179A,
– 30- 50% compared to normal seasonal H1N1 component
Similar to poor growing B component
– 2-fold increase in yield in eggs
• Wild type vaccine viruses
– A/California/7/2009 – similar to normal seasonal H1N1
component in Vero-cell
To change or to remain the vaccine seed virus?
Vaccine potency reagents (1)
• General preparation process
– Prepared independently by 4 ERLs (CBER/FDA, NIBSC,
NIID and TGA)
– Reference antigen – large amount of bulk antigen from
manufacturers
• Egg-based for testing of egg-based vaccines
• Cell-based for testing of cell-based vaccines
– Reference antiserum – from sheep by ERLs or for ERLs
by local manufacturers
• Small amount of purified HA
– Distribution
• Exchange among ERLs immediately for calibration
• Once available, antigen and antisera distributed to
requesting manufactures in parallel to the calibration
among ERLs
• Requests directly to originating ERLs
Vaccine potency reagents (2)
• Available pandemic vaccine reagents:
– First available reference antigen
• Egg-based (NYMC X-179A)
• Prepared by CSL and labelled by TGA (9000 vials)
– First available reference antiserum
• A/California/7/2009 (egg)
• First lot prepared by NIBSC (2000 vials)
• Limited ongoing distribution:
• Larger distribution on going
• Subsequent development
– Reference antigen
• Egg-based by NIBSC, CBER and NIID
• Vero cell-based by NIBSC
– Antisera
• CBER and TGA recommend to source from NIBSC
• A/California/7/2009 (egg) by NIID
Clinical studies of
A(H1N1)2009 pandemic vaccines (1)
1. Conventional seasonal vaccine formulation
(Egg-grown split vaccine without adjuvant)
To answer three primary questions (USA, CSL, others):
• Safety in healthy people of various ages?
• To determine a vaccine dose and vaccination times
needed to induce a protective immune response?
• Safety and efficacy of simultaneous administration
with seasonal influenza vaccine?
Clinical studies of
A(H1N1)2009 pandemic vaccines (2)
2. Adjuvanted vaccines with reduced antigens
• AS03 [GSK]
• MF59 [Novartis]
Mock-up dossier of H5N1 pre-pandemic vaccines
[EMEA]
3. Tissue culture cell-derived vaccines
• Vero cell-derived [Baxter]
4. Cold-adapted live vaccine
• [MedImmune]
Increase influenza vaccine production and supply
 IFMPA to increase production capacity of trivalent vaccine from
800 million to1 billion doses by 2012 (2007).
 Global pandemic vaccine production capacity to increase to
~4.5 billion in 2010 (2008)
 WHO provided grants to 6 countries for establishing pilot
production of H5N1 vaccine (Brazil, India, Indonesia, Mexico,
Thailand, and Vietnam), and technical assistance to others (2007).
 WHO has prepared international stockpile of H5N1 vaccines (2008)
– Target of 150 million doses
• 50 million : rapid containment operations
• 100 million : maintain essential services in low/middle
income countries
Vaccination strategy for Pandemic vaccines
(SAGE Reccomendations, July 2009)
Three objectives :
• Protect the integrity of the health-care system and the
country's critical infrastructure;
• Reduce morbidity and mortality; and
• Reduce transmission of the pandemic virus within
communities.
• The following groups for consideration (countries need to
determine their order of priority)
– Pregnant women
– Above 6 months with one of several chronic medical
conditions
– Healthy young adults of 15 to 49 years of age
– Healthy children
– Healthy adults of 50 to 64 years of age and
– Healthy adults of 65 years or above.
• post-marketing surveillance/ information(quality/efficacy, safety)
A(H1N1)2009 pandemic vaccines
 Demand for pandemic vaccines:
• A(H1N1)2009 pandemic likely moderate,
similar to Asian flu (1957) or Hong Kong flu (1968)
• Larger outbreaks with more disease burdens
and social impact likely occur in the near future.
• Seasonal influenza may not disappear, still
causing substantial burden and impact.
• Balance with seasonal flu
 By risk assessment and priority groups identification,
how many doses are actually needed urgently?
A(H1N1)2009 pandemic vaccines
 Vaccine antigens likely highly immunogenic
(similar to seasonal flu; different from H5N1)
• Seasonal vaccine formulations likely work.
• From technical point of view, approaches taken
for H5N1 vaccines are not necessarily required.
high dose; new adjuvants
 Adjuvants are benefitial for antigen-sparing and
supply of more vaccines in a short time.
• However, there are safety concerns, high price and
logistics issues about new adjuvanted vaccines.
 New adjuvants are actually needed when
considering the vaccine demand and the benefit,
risk, and cost of adjuvanted vaccines?
Pandemic Influenza Vaccines (1)
• Based on;
Seasonal influenza vaccination policy
surveillance (disease/social/economic burdens)
policy making and decision
establishment
implementation and achievement
technology/production/QAQC capacity
access to vaccines
vaccination logistics
surveillance and monitoring
(epi. and virus, efficacy, adverse events)
Pandemic Influenza Vaccines (2)
Specific issues;
• Secured access to vaccines
Vaccine demand: by all countries
Production capacity: limited in a short time
Supply: gradually and short in time
Competition for early/sufficient/prioritized
Advanced contract of purchase
Cost/contract
Equitable supply of affordable vaccines
Rich countries vs. low income countries
Principles to Guide Global Allocation of Pandemic Vaccine
(Yamada, Bill and Melinda Gates Foundation, NEJM, 2009)
1. The global community should take steps to protect all populations,
including those without resources to protect themselves.
2. Vaccination should be considered in the context of comprehensive
pandemic preparedness and response efforts in all nations.
3. Developed countries and vaccine manufacturers should urgently
agree upon a mechanism to ensure access to vaccine by
developing countries.
4. Influenza vaccine manufacturers should identify strategies such as
tiered pricing and donations to make pandemic vaccine more
accessible to developing nations.
5. Pandemic vaccines allocated to developing nations should become
available in the same time frame as vaccines for developed nations.
6. The global community should obtain data to help establish a
consensus on the safety and efficacy of adjuvants, and efforts
should be made to ensure the fullest use of this and other dosesparing strategies.
7. All countries obtaining pandemic vaccine should ensure that
mechanisms are in place to provide the vaccine to their
populations, to ensure that this scarce resource is not wasted,
and donors should be prepared to provide resources and technical
assistance to help countries bolster these mechanisms.
8. The World Health Organization is uniquely positioned to lead
the global response to a pandemic virus and should support
governments and industry in their efforts to implement these
principles.