influenza update ds gr 2011

8/3/2019 Influenza Update DS GR 2011

1/84

Influenza Update

Dimitar Sajkov, MD, MMSc, DSc, PhD, FCCP, FRACP


2/84

BMJ Medical Milestones

Poll results: Top 5 Votes Proportion (%)

Sanitation 1795 15.8

(clean water and sewage disposal)

Antibiotics 1642 14.5

Anaesthesia 1574 13.9

Vaccines 1337 11.8 Discovery of DNA structure 1000 8.8


3/84

Influenza (Flu)

Highly contagious and potentially deadly disease

Spread through coughing, sneezing, hands

Caused by a virus and is not the same as acommon cold

It can cause serious and debilitating

complications such as pneumonia, especially inthe elderly and others in the 'at risk' group, suchas patients with COPD


4/84

Issues to be addressed

Epidemiology - H1N1 pandemics

Influenza vaccine correlates of protection

Role of adjuvants

Alternative manufacturing approaches

Clinical trial outcomes Lessons learned


5/84

Influenza Burden

Outbreaks yearly, usually in winter months 5-20% of population get the flu

Annually in Australia (non Pandemic): 1,500 deaths 80,000 GP visits and 15,000 hospitalisations

Annually in US: 200,000 hospitalizations 36,000 deaths


6/84

Influenza

Illness more severe for very young, elderly, orthose with pre-existing health conditions

People with a chronic disease, such as COPD,have a 40x increased risk of death from influenza

A combination of heart and lung diseaseincreases this risk 800x

1.4 million Australians aged under 65 are in the at

risk group


7/84

Influenza and TheRespiratory Epithelium

Normal Tracheal Mucosa

3 Days Post-Infection7 Days Post-Infection


8/84

Seasonal Flu vs Pandemic Flu

Seasonal

Occurs every year

Occurs during winter

(usually Dec-Mar)

Most recover in 1-2weeks without Rx

Very young, very old, ill

most at risk of seriousillness

Pandemic

Occurs infrequently(3 per century)

Occurs any time of year

Some may not recover,even with Rx

People of all ages may be

at risk


9/84

Pandemic Influenza

Past Pandemics:

2009 Swine Flu (H1N1)

1968 Hong Kong Flu (H3N2)

1957 Asian Flu (H2N2)

1918 Spanish Flu (H1N1)


10/84

1918-1919 Influenza pandemic

Worst of pastcentury

Estimated 20-40% of worldpopulation ill

40-50 millionpeople died

600,000deaths in US

High mortalityin youngadults


11/84

Infectious Disease Deaths 1900s


12/84

Loveland, 1917 & 1918Deaths by age, influenza/pneumonia (Sept - Dec)

0

2

4

6

8

10

12

14

16

18

0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 over

Age

Deaths

1917 (Sept-Dec) 1918 (Sept-Dec)


13/84

Why did young people die?

Over-reaction by the immune system calledcytokine storm

Those with the strongest immune systemsaffected

Older people and youngest often die of bacterialpneumonia complicating flu - treatable now withantibiotics

Even in 2011, no good treatment for cytokinestorm


14/84

How Ready Are We?


15/84


16/84

What happened

As with previous pandemics spread wasonly limited by the speed of travel

April 25 2009:WHO declared a public emergency of international concern

The Australian Health Management Plan for PandemicInfluenza was activated

2.35 millionpassengers flewto 1018 cities in

164 countriesfrom Mexicoduring

March/April


17/84

Initial Epidemiology

Novel Swine-Influenza A virus (genes from both NthAmerican and Eurasian swine virus lineages)

Widespread community transmission in Mexico,Canada, United States, Japan, Panama, (&Vic)

Household attack rate 25-30% High Hospitalization rates..especially young

Estimated mortality 0.4% in Mexico

Average age of deaths: 31 years

46% had no other illnesses

Pregnancy associated with severe disease


18/84

Global cases


19/84

Global totals


20/84

WHO Phases of Pandemic Alert


21/84

Australian influenza data 2007- 09


22/84

Laboratory confirmed cases of pandemic (H1N1) 2009

in Australia to 11 September 2009 by jurisdiction


23/84

A 15-fold increase in ICU load comparedto viral pneumonitis in previous winters


24/84

2009 H1N1 Pandemic Swine Flu

37,584 cases, 191 deaths in Australia

4,912 hospitalized cases

9 - 31% needed ICU

Younger age distribution Indigenous, pregnant women

Seroprevalence varies by age

20% in


25/84

ICU series:10% of ICU beds[peak utilisation]

722 admissions in Australia & NZ[H1N1\09 lab.confirmed] 15 times ICU admissions for usual Flu

93% 35; Asthma/COPD common

65% mechanical ventilation

Mortality 14%

ECMO

18 times usual usage of ECMO

n=68 [10 pregnancy /3 children]Median age 34 years

obesity, asthma and diabetes mellitus common

21% mortality


26/84

Outcomes

Mild seasonal influenza

0.1% case fatality (very old + very young)

Pandemic influenza

> 2% case fatality (mostly young adults)

2009 H1N1 pandemic

0.5% case fatality


27/84

Influenza Prevention

Yearly influenza shot

Avoid those who are ill

Wash your hands

Antivirals (in special circumstances)

If you are ill - dont come to work, cover coughsand sneezes


28/84

Influenza Prevention

Annual vaccination is the single most effective measureto prevent influenza, but

Only 42% of the at risk group


29/84

Best way of prophylaxis

Reported 50 100% effective to reduce mortality and morbidity inseasonal epidemics

Age dependant

Similarity of vaccine antigen to circulating strain

Commercial influenza Trivalent Inactivated Vaccine (TIV)

No adjuvants

Low immunogenicity hence require multiple dose

Good antibody and weak cellular response

Less effective in young infants and elderly > 65 years Limited supply (production and transportation)

urgent need for improved vaccination strategy!!


30/84

Influenza Virus types

Type A: Infects humans and other animals More severe illness

Causes regular epidemics; can cause pandemics

Type B: Infectious only to humans Causes epidemics, but less severe illness


31/84

Influenza A

Subtyped by surface proteins:

Hemagglutinin (H)

16 different types

Helps virus entercells

Neuraminidase (N)

9 different types

Helps virus leave cellto infect others


32/84

Influenza A

All known subtypes ofInfluenza A found in birds

H5 and H7 cause severeoutbreaks in birds

Human disease usually due to

H1, H2, H3 and N1 and N2.


33/84

Influenza

The flu virus constantly changes

When it does, vaccines will be less efficient

Immune system may be unable to recognizenew virus

No immunity in population for new virus potential for pandemic


34/84

Vaccine Development Inactivated trivalent vaccine (killed vaccine)

2 A, 1 B Effectiveness of vaccine depends on match between

circulating strains and those in vaccine

A/Perth/16/2009

(H3N2)-like

2010 - 2011 Influenza Season

A/California/7/2009(H1N1)-like

B/Brisbane/60/2008

(Victoria lineage)


35/84

Influenza Vaccine Production

Flu vaccines first produced in 1940s

Only few manufacturers

6-9 months to produce vaccine


36/84

Prior Year

January

February

March

April

Surveillance oncirculating strains

Selection ofspecific strains

Preparationand distributionof virus stock tomanufacturers

Seed poolsinoculated into

eggs

N Engl J Med 351;20 November 11, 2004


37/84

N Engl J Med. 351;20 November 11, 2004

May

June

July

August

September

October

Harvest andconcentration

of fluids

Vaccine inactivated

and purified

Vaccine blended,content verified

Packaging, labeling,delivery


38/84

Major Challenges to Influenza VaccineDevelopment

Accelerate development of cell culture-based(recombinant) vaccine technology

Develop novel vaccine approaches Evaluate dose-sparing strategies, especially

adjuvants

Broaden the use of live, attenuated vaccineapproaches


39/84

Faster vaccine production

Not vulnerable to loss of egg supply

Highly scalable

GMP compliant Better characterised and more consistent product

Preserves wild type HA sequence and avoids egg-adaptation

Avoids contaminants (egg proteins, viral RNA, antibiotics,

formalin, preservatives, bird adventitious agents)

Avoids risk of egg allergy

Reduced likelihood of adverse reactions

Recombinant vaccines: potential benefits


40/84

Vaccine Adjuvants

Reduce amount ofantigen needed

Promote earlier,

stronger, moredurable immuneresponses

May increasecross-protectiveimmune response

A

ntibodyRespons

e

Days

Vaccine withadjuvant

Vaccine withoutadjuvant


41/84

Adjuvant Majorcomponent

Developer Antibodyinduction

CD8response

Tolerability Potential SafetyIssues

Alum Aluminiumsalt

- ++ - +++ Injection pain, granulomas,eosinopjilia, macrophagic

myofasciitis

MF59 Squalene Novartis ++ + ++ Injection pain, adjuvant

arthritis

Montanide Oil-wateremulsion

Seppic +++ + + Injection pain, adjuvantarthritis

QS21 Saponins Antigenics +++ +++ - Injection pain, haemolysis

Iscomatrix Saponins

liposomes

CSL +++ + ++ Injection pain, haemolysis,

autoantibodies, hepatitis

MPL/alum LPSderivative

alum

GSK(Corixa)

+++ + ++ Injection pain, adjuvantarthritis, fever

CpG BacterialDNA

Coley + ++++ ++ Injection pain, fever, lupus

Advax Inulin Vaxine +++ +++ ++++ None

Candidate Human Adjuvants


42/84

Adjuvants

Alum (aluminium phosphate) currently themain vaccine adjuvant

Good at stimulating antibodies

Very poor at stimulating cell-mediated immunity

Poorly effective at inducing enhanced immuneresponses against influenza haemaggultinin


43/84

Gamma-Inulin

Potent humoral and cellular immune adjuvant

Works via activation of the alternate complement pathwayresulting in levels of activated C3 activates the innate

immune system and results in an improved vaccineresponse

Micro-particulate inulin (Advax) is particularly effective atboosting cellular immune responses without the normal

toxicity exhibited by other cellular adjuvants such asFreunds complete adjuvant


44/84

Gamma-Inulin

Can be combined with a variety of other human approvedadjuvant components, e.g. aluminium phosphate, toproduce specialised adjuvants with strong cell-mediated(Th1) and humoral (Th2) activity

Successfully tested in multiple animal models incombination with many standard vaccine antigensincluding influenza haemagglutinin, and have also beensuccessfully validated in human trials including in avaccine based on the E7 protein of human papillomavirus, and in a hepatitis B prophylactic vaccine

Safe and effective for use in humans


45/84

Inulin adjuvants when added to current unadjuvnated influenzavaccines, e.g. Fluvax, can:

enhance the kinetics and magnitude of anti-influenza humoraland cellular protective immune responses

induce a more robust Th1-type response for more effectiveinfluenza virus clearance thereby reducing viral transmission time

increase the longevity and durability of influenza vaccineinduced protection


46/84

Advax

Extensively tested in animals in combination with commercialinfluenza vaccines with no major toxicity in any of the species tested

Produced strong combined antibody and T-cell immunity toinfluenza, with responses up to 100x superior to the immune

responses generated by the commercial influenza vaccine alone

Dramatic antigen sparing effect - Allowed the normal immuneresponse to be obtained to influenza vaccine at 1/10 the normaldose, that if confirmed in human trials could mean that in event of apandemic that limited influenza vaccine supplies could be stretched

10 fold, and thereby potentially save many additional lives within thepopulation

0 t i i i


47/84

Day

0

14

R1

R2

S1

S2

S3

S4

R7

R6

S5

1st immunisation

WeekPost-Immunisation

2

2nd immunisation

S12

S13

4

6

8

10

24

23

5

9

26

29

Serological analysis

Recall assay

Vaccine antigenTrivalent Inactivated Vaccine

(TIV) (Kitasato Institute, Japan)(15 ng HA antigen/strain per dose i.m.)

A/New Caledonia/20/99 IVR116 (H1N1)

A/Hiroshima/52/2005IVR IVR116 (H3N2)

B/Malaysia/2506/2004 (Influenza B)

Immunisation groups (1 mg/dose)

Non adjuvanted (control)

ADVAX-1

ADVAX-2

ADVAX-3


48/84

Serology assayIn vitro cellular assay

Antibody subclass

I. IgMII. IgG (total)III. IgG1IV. IgG2a

ELISA

Antigen-specificlymphoproliferation

CFSE recall assay

CD4+, CD8+ T cells

Spleen cellsserum

HA neutralizingantibody

Hemagglutination

Inhibition (HI) assay

Protection: 40 titre

Th1/Th2 Cytokine profile

ELISA

supernatant

IFN-, IL-10


49/84

Hemagglutination Inhibition (HAI) assay

Protective HA neutralising antibody

Antibody ELISA

Evolution of antibody subclass over time

The effect of MPI adjuvants on anti-influenzahumoral responses


50/84

To measure protective HA neutralising antibody levels after immunisation

erythrocytes hemagglutinationInfluenza virus

Anti HA antibodies

Antibody/antigencomplexes

No hemagglutination


51/84


52/84


53/84


54/84

Non Adjuvanted MPI (Advax) adjuvanted

Slower response Quick response (immediateprotection?)

Lower magnitude (for influenza Bconsistently below protective level)

Enhanced antibody production withincreased immunogenicity of TIV

Shorter lived Consistently above protective level upto 26 weeks p.i

Weakest IgG2a induction Strong IgG2a : enhanced cellularresponse


55/84

5 weeks p.i

%C

D8+P

roliferation

%C

D4+P

roliferation

45 ng TIV 45 ng TIV + 1 mgADVAX-1

45 ng TIV + 1 mgADVAX-2


29 weeks p.i

45 ng TIV 45 ng TIV + 1 mgADVAX-1




56/84

Responses Non Adjuvanted

MPI (Advax)adjuvanted

Humoral Slow and lower magnitude Short lived and waned below

protective level

Quick and higher magnitude Enhanced longevity of protective level Strong IgG2a ( cellular response)

Cellular Consistently weak CD4+ andCD8+ recall response over time

Robust induction of CD4+ and CD8+recall responses

Waned over time but remainedsuperior to non-adjuvanted group

Cytokine Typical IFN- antiviralresponses

Enhanced IL-10 and IFN- production Bias towards Th1 responses

MPI adjuvants enhance the durability of influenzavaccine responses in murine model


57/84

Phase 1/2 adjuvanted influenza

150 subjects randomised into 3 groups of 50

Group 1 standard unadjuvanted 45ug HA vaccine

Group 2 15ug HA plus Advax D 20mg

Group 3 15ug HA plus Advax PD 20mg Blood taken at days 0, 7, 21, (120)

Primary endpoint 1 Safety analysis

Primary endpoint 2 - TGA vaccine release criteria at day 21

Secondary endpoint T-cell responses


58/84

TGA influenza vaccine release criteria Modeled on WHO criteria

Two categories 18-60 and >60 50 subjects per group

To pass must meet at least one criteria for each of 3 serotypes

18-60 years >60 years

Seroconversion

HI*4 or HI40% >30%

Mean GMTincrease

>2.5 >2

Seroprotection

HI>1:40

>70% >60%


59/84

Performance Advax influenza antigen-sparing vaccine against H1N1 serotype

50 subjects per group

To pass must meet at least one criteria

Influenza H1N1 Passcriteria

Fluvax 45ugunadjuvanted

Fluvax 15ug+Advax

Result

Mean GMT increase >2.5 2.78 3.27 Pass

Seroconversion

HI*4 or HI40% 48% 54% Pass

Seroprotection

HI>1:40

>70% 98% 100% Pass


60/84

Advax is not associated with anyextra injection site pain

0

2

4

6

8

10

Fluvax Fluvax1/3

+Advax

pain score

O


61/84

Other potential benefits of incorporatingAdvax in influenza vaccines as seen in

animal studies

Enhances flu vaccine responses in neonates

Improves flu vaccine responses in the elderly

Improves vaccine responses in diabetes, obesityor chronic disease

Enhances influenza viral protection even further

over current vaccine by inducing anti-influenza Tcells as well as neutralising antibodies


62/84

Influenza vaccine trials at FMC

H1N1 Adjuvanted RecombinantVaccine Trial

Efficacy in high risk groups - ENINVAT

COPD Diabetes mellitus

CVD

Renal impairment

over 60s

Paediatric populations


63/84

ENINVAT

- Enhanced Influenza Vaccine Trial

Randomized, Controlled Trial of an

Enhanced Potency Seasonal InfluenzaVaccine in Subjects with Chronic Diseasesand Elderly


64/84

Objectives

Primary Endpoints:

Efficacy:Seroconversion and seroprotectionrates for each included serotype foradjuvanted versus unadjuvanted influenzavaccine

Safety:Adverse event rates and tolerability ofadjuvanted versus unadjuvanted influenzavaccine


65/84

Objectives

Secondary Endpoints:Kinetics and persistence of seroconversion,

seroprotection and T-cell immunity foradjuvanted versus unadjuvanted influenza

vaccineDegree of cross-protection against drifted

influenza strains for adjuvanted versusunadjuvanted influenza vaccine

Rates of influenza-mediated respiratory tractinfections and hospital admissions foradjuvanted versus unadjuvanted influenzavaccine


66/84

Study

Site FMC

Design - a single-centre Phase 2/3 RCT

Subjects - >1000 patients and elderlysubjects (200 per 4 at risk groups plus 200healthy volunteers over 65 y.o.) recruitedand randomised 1:2 to receive either thestandard commercial influenza vaccinealone, or combined with 20 mg Advax


67/84

Progress

Recruited and randomised 1,400 subjectsover 2008 - 2011 seasons

Monitored by a safety committee No significant safety issues with Advax

Preliminary efficacy results encouraging

Results expected late 2011


68/84

Expected Findings

Inulin-adjuvanted influenza vaccine Is safe for vaccination of elderly patients

Has superior immunogenicityHas significant antigen-sparing properties

May show a trend towards reduced infectiveexacerbations of COPD

Pilot data will be collected to design a largemulticentre RCT of Advax on morbidity andmortality

T diti l fl i h


69/84

Traditional flu vaccine approach

Battery egg production

Embryo detection Virus inoculation

Egg incubation

Virus harvesting

Virus inactivation(formaldehydeB-propiolactone)

preservatives - ethyl mercuryadjuvants - aluminiumhydroxide/squalene oil

Inactivatedvaccine

Recombinant flu vaccine approach


70/84

Recombinant flu vaccine approachNew flu virus sequenced Haemagglutinin gene cloned Insect cell

expression

GMP cell culture/protein purificationAdjuvant

additionAdjuvantedRecombinant H1N1/2009vaccine


71/84

Baculovirus expression system

Source: Protein Sciences


72/84

Source: Protein Sciences


73/84

Ad dj t


74/84

Advax adjuvant

Nano-particle made from delta inulin isoform

Advax provides

Enhanced antibody and T-cell responses

Antigen-sparing

Prolonged immune memory

Restoration immune defects (neonates, elderly etc) TLR independent

Avoids reactogenicity/toxicity of other adjuvants

Avoids formulation complexity

TEM of Advax particles Advax chemical structure Plant source


75/84

Advax enhances influenza vaccineimmunogenicity

No Adjuvant Advax0.0

0.5

1.0

1.5

2.0

2.5

IgG Titer

***

IgGT

iter(OD)


0.2

0.4

0.6

0.8IgG1 Titer

***

IgG1Titer(OD)


0.5

1.0

1.5

2.0IgG2a Titer

*

IgG2aTiter(OD)

No Adjuvant Advax0

50

100

150 HI Titer

**

HIGMT


76/84

Advax enhances vaccine immunogenicityin the elderly

No Adjuvant CpG Advax

0

20

40

60

***

n.s

HIGMT

No Adjuvant CpG Advax

0.0

0.2

0.4

0.6

0.8

***

n.sTotalIgG

(OD)

Old Balb/c mice were immunized with influenza vaccine alone, CpG or Advaxon day 0 and day 14 then serum was collected for HAI and ELISA assay


77/84

Late April 2009 A/H1N1/California/2009 sequence available

Early May - teleconference Vaxine and Protein Sciences

11 June 2009, WHO declared a pandemic

June 2009, Protein Sciences produced a GMP rHA for H1N1/2009,

that was then formulated with Advax adjuvant to increaseimmunogenicity

July 2009 immunization 272 subjects with 2 doses of vaccine +/-

adjuvant

August 2009 preliminary trial results

Represents one of the fastest vaccine developments in history

H1N1/2009 vaccine timelines

Recombinant H1N1/09 approach


78/84

Recombinant H1N1/09 approach

Two doses 3 weeks apart of recombinant H1/2009 antigenat 3 doses (3, 11, 45ug) without or with Advax adjuvant

Target: 6 groups of 50 subjects (300 total). Ages 18-70

Recruitment time frame 3 weeks. Budget $0

Trial endpoints:

Sero-protection against H1N1/2009 (haemagglutinininhibition assay 3 weeks after 1st and 2nd doses ofvaccine)

Vaccine safety by solicited and unsolicited adverse eventsand routine safety bloods

Vaccine tolerability by visual analogue pain scores

Source: Prof. N. Petrovsky


79/84

H1N1/2009 trial result summary

80% of subjects


80/84

Innovation in flu vaccine design Genetically-engineered pure recombinant protein

Plant-sugar derived immune-enhancer (Advax) Doesnt involve production of flu virus

Egg independent

No problems of egg allergy

Bird flu wont disrupt vaccine supply

Highly pure protein vaccine (no antibiotics, formaldehyde,

viral RNA, ethyl mercury preservative)

Result: Faster, purer, safer, more scalable, pandemic

vaccine

Wh i lt ti d d


81/84

Why new vaccine alternatives are needed


82/84

Lessons learned

The past future Pandemic planning = structure and flexibility Pandemic = widespread transmission virulence In Epidemiology, the denominator is important Poor diagnostics = huge handicap

Small numbers can overwhelm critical care services Health care system buy in and assessing/responding to new

information critical Important to maintain a balanced message Political and media imperatives significant Vaccination not straightforward

H1N1/2009 was only a practice run

Pandemic vaccine plans need more investment Danger of complacency Egg-based manufacture too slow, cumbersome and inadequately scaleable Multiple product recalls due to inadequate potency, poor stability New technologies are needed to better counter future pandemics

Pandemic Crisis Management Plan


83/84

Pandemic Crisis Management Plan


84/84

influenza update ds gr 2011

Documents