the use of novel adjuvants to enhance and broaden...

Section Viral Vaccines

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The The Use Use of of Novel Adjuvants Novel Adjuvants to to Enhance Enhance and and Broaden Broaden the the Immune Response Immune Response

Elicited Elicited by by Human Human VVaccinesaccines

Ralf WagnerRalf Wagner

Section for Viral Section for Viral Vaccines Vaccines

PaulPaul--EhrlichEhrlich--InstitutInstitut

LangenLangen / Germany/ Germany


CCONTENTONTENT ANDAND SSTRUCTURETRUCTURE OFOF PPRESENTATIONRESENTATION

• WHY IS THERE A NEED FOR ADJUVANTS Open issues and challenging aspects where vaccine optimisation is needed

• BRIEF HISTORY OF ADJUVANTs and ADJUVANTED VACCINES

• MECHANISMS/MODES OF ACTION OF SELECTED NOVEL ADJUVANTS

Selection of those ADJUVANTS recently licensed with novel vaccines

• BRIEF OVERVIEW OF REGULATORY REQUIREMENTS FOR NOVEL ADJUVANTS

• ADJUVANT EFFECTS IN RECENTLY LICENSED NOVEL VACCINES Efficacy and Safety profiles of selected vaccines Special Issue: Narcolepsy associated with AS03-adjuvanted pandemic vaccine

• FUTURE PERSPECTIVES


WHY is there a NEED for (NOVEL) ADJUVANTS??WHY is there a NEED for (NOVEL) ADJUVANTS?? WHY is there a NEED for (NOVEL) ADJUVANTS??WHY is there a NEED for (NOVEL) ADJUVANTS??


(NOVEL) ADJUVANTS HOLD HUGE POTENTIAL FOR… (NOVEL) ADJUVANTS HOLD HUGE POTENTIAL FOR… (NOVEL) ADJUVANTS HOLD HUGE POTENTIAL FOR… (NOVEL) ADJUVANTS HOLD HUGE POTENTIAL FOR…

• Overall Increase in immune response against pathogen pathogen (number of doses needed)

• enhanced immune response to poorly immunogenic antigens subunit vaccines, expressed highly purified proteins (no good PAMP motif)

• promoting specific arms of the immune response (eg humoral, CMI, memory…)

• induction of a broader immune response resulting in better cross-protection to antigenically diverse/variable infectious agents (“antigenic drift”)

• specific immune response in specific populationsspecific populations

• efficient priming in naïve subjects

• enhancement of immune response in otherwise poorly responsive population groups (elderly, immune-compromised)

• antigen sparing to ensure vaccine supply vaccine supply in cases where production capacity is limited or huge amounts of doses are needed within a very short time frame (pandemic)


Hence, there a numerous good reasons Hence, there a numerous good reasons

for the development and integration of for the development and integration of

novel adjuvants into todaynovel adjuvants into today´́s and tomorrows and tomorrow´́s vaccines!!s vaccines!!


BRIEF HISTORY OF ADJUVANT DEVELOPMENTBRIEF HISTORY OF ADJUVANT DEVELOPMENT BRIEF HISTORY OF ADJUVANT DEVELOPMENTBRIEF HISTORY OF ADJUVANT DEVELOPMENT


From: De Souza Apostolico et al., 2016

AA CCENTURYENTURY OFOF AADJUVANTDJUVANT DDEVELOPMENTEVELOPMENT

Only during the last 30 years adjuvanted vaccines are more rapidly emerging

Licensed

Under (pre)clinical Development

• Positive opinion by EMA in Art. 58 procedure for „Mosquirix“

• Currently under EMA evalation in CP for “Shingrix” Zoster Vaccine


From: Di Pasquale et al., Vaccines 2015

TTHEHE NUMBERNUMBER OFOF ADJUVANTEDADJUVANTED VACCINESVACCINES ISIS CONSTANTLYCONSTANTLY INCREASINGINCREASING


OOVERVIEWVERVIEW TOTO AADJUVANTSDJUVANTS ININ LICENSEDLICENSED VVACCINESACCINES To be discussed in Presentation

MF59MF59

MPLMPL

QS21QS21

AS01AS01

AS03AS03

AS04AS04


MODE/MECHANISMS OF ACTION OF SELECTED ADJUVANTSMODE/MECHANISMS OF ACTION OF SELECTED ADJUVANTS

What is knownWhat is known

What is proposedWhat is proposed

ImmuneImmune--potentiating effectspotentiating effects

Derived mainly from in-vitro and animal studies

MODE/MECHANISMS OF ACTION OF SELECTED ADJUVANTSMODE/MECHANISMS OF ACTION OF SELECTED ADJUVANTS

What is knownWhat is known

What is proposedWhat is proposed

ImmuneImmune--potentiating effectspotentiating effects

Derived mainly from in-vitro and animal studies

Potential immunological targets for adjuvants


1) Depot formation1) Depot formation

22) Secretion of cytokines) Secretion of cytokines

33) Immune cell recruitment) Immune cell recruitment

4) Antigen uptake4) Antigen uptake

6) Antigen processing6) Antigen processing

presentation on MHCpresentation on MHC

55) Maturation / Activation) Maturation / Activation

of immune cellsof immune cells

77) Activated APCs ) Activated APCs trafficktraffick

to draining lymph nodeto draining lymph node

8) 8) ImmunmodulationImmunmodulation

LymphLymph nodenode

APCAPC

OOVERVIEWVERVIEW TOTO IIMMUNOLOGICALMMUNOLOGICAL EEFFECTSFFECTS/F/FUNCTIONSUNCTIONS OFOF AADJUVANTSDJUVANTS

“Innate““Innate“

“Adaptive“

Adapted from: Awate et al., 2013


EXAMPLES EXAMPLES OOF ADJUVANTS AND THEIR MODE OF ACTIONF ADJUVANTS AND THEIR MODE OF ACTION EXAMPLES EXAMPLES OOF ADJUVANTS AND THEIR MODE OF ACTIONF ADJUVANTS AND THEIR MODE OF ACTION


MF59 AS03

Squalen 9,75 10,69

DL-α-Tocopherol --- 11,86

Tween 80 1,175 4,86

Sorbitan Trioleate (Span 85)

1,175 ---

Manufacturing Microfluidization

Particle size ≈ 150 nm 120-200 nm

OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS: C: COMPOSITIONOMPOSITION OFOF ASAS0303 ANDAND MF59MF59

Quantitative Quantitative CompositionComposition (mg/dose)(mg/dose)

StructuralStructural representationrepresentation ofof MFMF5959 – similar to AS03

https://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwjz8dyMyszUAhVQa1AKHZZPCfYQjRwIBw&url=https://www.researchgate.net/figure/236919252_fig1_Fig-1-Composition-of-MF59-emulsion-Sketch-of-MF59-emulsion-and-chemical-structures-of&psig=AFQjCNGTqhiO4hZLBlOd_dCjDU9fo5KUDw&ust=1498053435787333


MMODEODE OFOF AACTIONCTION OFOF OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS: AS: AS0303 ANDAND MF59MF59

Mostly affect innate immune responses to create a “pro“pro--inflammatory environment”inflammatory environment” as the basis for an efficient/enhanced adaptive immune response

Activation / Modulation of

“adjuvant core response genesadjuvant core response genes“:

• Cytokines, such as

- Chemokines, IFN, IL

• Innate immune receptors

• Adhesion molecules Recruitment/differentiation of Recruitment/differentiation of

immune cellsimmune cells to/at injection site:

• Monocytes

• Neutrophils, eosinophils

• Macrophages

• Dendritic cells, APC Trafficking to draining Trafficking to draining

lymph node:lymph node:

for induction of adaptive

immune response

Enhanced AB titersEnhanced AB titers

AB crossAB cross--reactivityreactivity

(higher B(higher B--cell diversity)cell diversity)

Expanded Expanded TTHH cells activity cells activity

EEFFECTSFFECTS ONON ADAPTIVEADAPTIVE IMMUNEIMMUNE RESPONSERESPONSE

EEFFECTSFFECTS ONON ADAPTIVEADAPTIVE IMMUNEIMMUNE RESPONSERESPONSE


AADJUVANTDJUVANT EEFFECTFFECT ONON IIMMUNOGENICITYMMUNOGENICITY –– SSTUDYTUDY DDESIGNESIGN

Study in Study in seronegativeseronegative ferretsferrets

Vaccine Formulations applied:

A - Plain (non-adjuvanted) pandH1N1 antigen (split), 10µg/dose

B - pandH1N1 antigen with MF59 (oil-in-water) adjuvant (Focetria® )

C - pandH1N1 antigen with AS03 (oil-in-water) adjuvant (Pandemrix® )

D - pandH1N1 antigen with Diluvac® (well established veterinary adjuvant)

days 0 21

ChallengeChallenge

Immunization schedule

1st dose 2nd dose

8 42

4 months

Blood draws

for serologicalserological examinationexamination


immunisation

immunisation

ADJUVANTS EFFECTS ON IMMUNOGENICITY – RESULTS

HI-titers against A/HH/05/2009

VN-titers against A/HH/05/2009

Schmidt et al., 2016


AS04 AS04 ADJUVANTADJUVANT COMPLEXCOMPLEX: MPL : MPL ADSORBEDADSORBED TOTO AIOHAIOH33

Composition:Composition: MPL (50µg) adsorbed to AlOH3 (500µg) MPL (50µg) adsorbed to AlOH3 (500µg) – per dose of “Cervarix” vaccine (3-O-desacyl-monophosphoryl lipid A) • Lipid A is a component of the LPS complex of bacterial cell walls with pronounced

immune-stimulatory effect • Lipid A shows high toxicity, pyrogenicity

MPL is detoxified version of Lipid A that retains the immuneMPL is detoxified version of Lipid A that retains the immune--stimulatory activitystimulatory activity Detoxification of Lipid A by removal of phosphate group and fatty acid

Due to the production/detoxification procedure MPL is a mixture of congeners with different numbers of fatty acid side chains (4-7)

Lipid ALipid A MPLMPL

Detoxification

http://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwjFk4WK8szUAhVLPFAKHTrlDEcQjRwIBw&url=http://www.mdpi.com/1660-3397/11/2/363/htm&psig=AFQjCNEPkiCAQajf06Kg7OPHqpyb3Zj-fA&ust=1498064145393465

http://www.google.de/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=0ahUKEwjFk4WK8szUAhVLPFAKHTrlDEcQjRwIBw&url=http://www.mdpi.com/1660-3397/11/2/363/htm&psig=AFQjCNEPkiCAQajf06Kg7OPHqpyb3Zj-fA&ust=1498064145393465


Adapted from: De Souza Apostolico et al., 2016

AS04 AS04 ADJUVANTADJUVANT COMPLEXCOMPLEX: A : A POTENTPOTENT TRLTRL--4 4 AGONISTAGONIST

LPSLPS Lipid ALipid A

MPLMPL

TLRTLR--44

Like LPS, MPL exhibits its adjuvanting function via the TLR-4 signalling pathway

Upon Binding of MPL to TLR-4 and MD2

activationactivation ofof intracellularintracellular pathwayspathways MyD88MyD88 IL,TNFIL,TNFαα

TRIFTRIF InterferonInterferon

ProPro--inflammatoryinflammatory statestate IncreaseIncrease inin AdaptiveAdaptive ABAB responseresponse (TH(TH11))

Other agonists: - dsRNA: TLR-3 - ssRNA: TLR-7 - CpG: TLR-9

APC


AS01 AS01 ADJUVANTADJUVANT COMPLEXCOMPLEX: MPL : MPL PLUSPLUS QSQS--2121

AS01: liposome-based complex containing two immune stimulants and cholesterol - MPL - QS-21: Saponin molecule extracted from the bark of Quillaja saponaria (fraction 21)

water-soluble triterpene glycoside with amphiphillic character hemolytic activity – eliminated in cholesterol-containing liposomes (as in AS01) exact mechanism of adjuvanting function currently not fully understood

Adapted from: Didierlaurent et al., 2017

Chemokine release attracts granulocytes and monocytes

Activated APC Trafficking to draining lymph node

Induction of IFN-pathway Proinflammatory cytokines

Cellular and cytokine reponses peak at day 1 resolved by day 7

AAIMIM: E: ENHANCEDNHANCED CELLULARCELLULAR ANDAND HUMORALHUMORAL IMMUNEIMMUNE RESPONSESRESPONSES

Antigen-specific - CD4+ T-cells - CD8+ T-cells


REGULATORY ISSUESREGULATORY ISSUES

Brief overview to Existing Guidance

and pivotal Licensing Requirements

REGULATORY ISSUESREGULATORY ISSUES

Brief overview to Existing Guidance

and pivotal Licensing Requirements


Regulation/licensure of adjuvanted vaccines is quite challenging:

- extremely diverse nature of substances (origin, composition, manufacture, antigens…)

- extremely diverse functions/modes of action (multiple factors and mechanisms)

- extremely diverse safety profile

⇒ Difficult/Impossible to conclusively predict all potential safety risks

Selected Available regulatory guidance/recommendations:

- Guideline On aadjuvants djuvants In Vaccines For Human Use (EMEA/CHMP/VEG/134716/2004)

- Guidelines on the nonnon--clinical evaluation clinical evaluation of vaccine adjuvants and adjuvanted vaccines (WHO, 2013)

- Guideline on clinical evaluation clinical evaluation of new vaccines (EMEA/CHMP/VWP/164653/2005)

- Guidelines on clinical evaluation clinical evaluation of vaccines: regulatory expectations (WHO, 2017)

LLICENSINGICENSING RREQUIREMENTSEQUIREMENTS FORFOR NOVELNOVEL ADJUVANTEDADJUVANTED VVACCINESACCINES

Basic framework of concepts rather than specified instructions for individual substances


LLICENSINGICENSING RREQUIREMENTSEQUIREMENTS FORFOR NOVELNOVEL ADJUVANTEDADJUVANTED VVACCINESACCINES

Quality: Comprehensive data package required description, source materials, manufacturing process, in-process controls, testing programme and

specifications, physico-chemical identification, impurities, association with antigen, stability,

Guiding principle: Evaluate Adjuvant alone AND adjuvant in combination with specific antigen!! Inclusion of adjuvants to be justified ⇨ Clear emphasis on safety over efficacy for healthy recipients

Preclinical: Comprehensive data package required Mode of action: immunological effects, Suitability of animal models (species specificty of immunity),

protection vs immunogenicity, dose-response, repeated doeses

Safety: local tolerance, systemic toxicity, reprotoxicity (women pregnant or child-bearing age),

hypersensitivity, pyrogenicity, distribution (case by case)

Clinical: Comprehensive data package required Efficacy: immune response (AB, humoral, CMI,…), specific population/age groups (start with healthy

adults), adhere to requirements for “first in man” trials, dose-finding studies Safety: adverse events, local and systemic effects, monitoring of clinical parameters, adhere to

requirements for “first in man” trials

Brief outline of requirements Brief outline of requirements (not exhaustive):


ADJUVANT EFFECTS IN SELECTED VACCINESADJUVANT EFFECTS IN SELECTED VACCINES

Efficacy and Safety ProfilesEfficacy and Safety Profiles

ADJUVANT EFFECTS IN SELECTED VACCINESADJUVANT EFFECTS IN SELECTED VACCINES

Efficacy and Safety ProfilesEfficacy and Safety Profiles

…no turning to real life data….


CCERVARIXERVARIX: AS04 : AS04 ADJUVANTEDADJUVANTED HHUMANUMAN PPAPILLOMAVIRUSAPILLOMAVIRUS VVACCINEACCINE

Types contained in the vaccine: HPV-16/18, VLP expressed in insect cells Facts on Immunogenicity: - High GMTs after vaccination (≈ 12-fold higher than after natural infection)

- Almost all vaccinees negative at baseline seroconverted post vaccination (p.v.)

- GMTs peak at months 7 p. v., reach plateau after 18-24 months p. v. and then slightly

decline – but still ≈ 10-fold higher than after natural infection after 9 years

- Functional neutralising AB

- Robust immune response in all tested age groups (10-14 yoa, 15-25 yoa, > 25 yoa)

- Serum AB correlated with AB detected in cervico-vaginal secretions (mucosal AB)

• Head-to-head comparison with Al-Phosphate adjuvanted vaccine:

- Higher GMTs for Cervarix in all age strata

- 2,7-fold higher antigen-specific B-cells for Cervarix

Cave: Clinical relevance of these findings currently unknown (different antigens!)

Could contribute to long-term persistency of AB



Overview to selected vaccine efficacy (VE) data from clinical trials against HPV16/18:

VE against virologicalvirological endpointsendpoints in ATP cohort (acc.to protocol, negative at baseline, 15-25 yoa)

VE against highhigh--grade cervical lesions associated with HPVgrade cervical lesions associated with HPV--16/1816/18 in ATP cohort (as above)

Very high vaccine efficacy in subjects negative at baseline Efficacy is lower in subjects with baseline immunity (data not shown)

Data extracted from SmPC



Overview to selected vaccine efficacy (VE) data from clinical trials: CROSSCROSS--PROTECTIONPROTECTION

VE against highhigh--grade cervical lesions irrespective of HPV DNA type in lesionsgrade cervical lesions irrespective of HPV DNA type in lesions

In naive subjects very high efficacy against CIN3+ irrespective of HPV type!!

Protection also against non-vaccines HPV types

Cross-protection data for non-vaccines types available: - Against HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 - 6-months persistent infection: 0 – 77% efficacy - CIN2+ : 26.8 – 87.5% efficacy There is good cross-protection to certain non-vaccine HPV-types


CCERVARIXERVARIX--AS04: CAS04: CLINICALLINICAL SSAFETYAFETY EEVALUATIONVALUATION

Safety profile of “Cervarix” Pooled analysis of clinical trial data available from more than 30.000 girls and women (≈ 46.000 doses) Higher rates in vaccinees for solicited local events (injection site) – but mild and short duration Summary of main findings: Serious adverse events 2.8% Cervarix vs 3.1% control pregnancies outcomes no differences medically significant conditions 19.4% vs 21.4% new onset of chronic diseases 1.7% vs 1.7% new onset of autoimmune diseases 0.4% vs 0.3 %

Overall acceptable and favourable safety profile

From: Angelo et al., 2014

• Unsolicited adverse events

• Medically significant conditions

• Serious adverse events

• Potentially immune-mediated diseases

No increase in safety signals after “Cervarix” vaccination


From: Garcon et al., 2012

OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS FORFOR IINFLUENZANFLUENZA VVACCINESACCINES: AS03: AS03

0

50

100

150

200

250

300

350

0

50

100

150

200

250

300

350

400

450

after dose 1 after dose 2

Non-adjuvanted

AS03 adjuvanted

HI-Titer

Neutralization-Titer

3.8 7.5 15 30 3.8 7.5 15 30 µg antigen

AS03 strongly increases AS03 strongly increases adapativeadapative immune response in H5N1 pandemic influenza vaccineimmune response in H5N1 pandemic influenza vaccine (same as for MF59-adjuvanted vaccine)


From: Leroux-Roels, Lancet 2007

OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS FORFOR IINFLUENZANFLUENZA VVACCINESACCINES: AS03: AS03

AS03 effect on AS03 effect on SeroconversationSeroconversation rates rates after H5N1 pandemic Influenza vaccinationafter H5N1 pandemic Influenza vaccination

Against vaccine-homologous Influenza strain (A/Vietnam/1194)

Against vaccine-heterologous Influenza A strains as indicated

3.8µg 3.8µg AS03

3.8µg 3.8µg AS03

3.8µg 3.8µg AS03

Indonesia/5/05Indonesia/5/05 Clade 2.1.3Clade 2.1.3

Turkey/Turkey/1/05Turkey/Turkey/1/05 Clade 2.2Clade 2.2

AAnhui/1/05nhui/1/05 Clade 2.3.4Clade 2.3.4


From: Khurana et al, 2011

OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS FORFOR IINFLUENZANFLUENZA VVACCINESACCINES: MF59: MF59

Binding capacity of serum IgG to HA1 protein (by surface plasmon resonance) • MF59 strongly increases binding to HA1 • Most prominent effect in toddlers (naïve)

IgG avidity to HA protein MF59 strongly increases avidity Again, most prominent effect in toddlers (naïve)


OOILIL--ININ--WWATERATER AADJUVANTSDJUVANTS: O: OVERALLVERALL SSAFETYAFETY PPROFILEROFILE

Safety profile of vaccines adjuvanted with AS03 or MF59 Large data base available from clinical trials – children and adults/elderly Almost 200 Mio doses of MF59-vaccine administered (“Fluad” for elderly!! Licensed for 20 years) “Focetria” (MF59) and “Pandemrix” (AS03) used in “Swineflu pandemic” mass vaccination campaign

Summary of main findings:

In children: - slightly higher rates of mild-to-moderate local reactions at injection site

(such as pain, redness, swelling, tenderness) - Slightly higher rates of solicited systemic reactions

(myalgia, headache, fatigue, malaise) - For AS03: increased frequency of fever after second dose (in < 5 yoa)

In adults: No significant differences as compared to non-adjuvanted influenza vaccines No specific safety signals in Pharmacovigilance databases (1997 – 2006)

Overall, “Focetria” with slightly better tolerability than “Pandemrix” (→ higher oil and tocopherol content)

Both vaccines with acceptable and favourable overall safety profile However: Pandemrix Association with NarcolepsyNarcolepsy


What happened in the aftermath of the “Swineflu vaccination campaign”…. In 2009: Mass vaccination campaign in EU against “Swineflu“ A/H1N1 influenza pandemic: - AS03 adjuvanted vaccine “Pandemrix”: more than 30 Mio doses administered in EU - MF59 adjuvanted vaccine “Focetria”: several Mio doses (much less that “Pandemrix”) In 2010: first reports from scandinavian countries Finland and Sweden - Increase in narcolepsy incidence – more than 10-fold as compared to background incidence - Potential Association with AS03-adjuvanted vaccines (Pandemrix and Arepanrix)

Later also detected in other EU countries – but mosly to much less extent

In total, so far more than 1300 cases of vaccine-associated (excess) cases of Narcolepsy

registered by the European Medicines Agency (EMA)

AASSOCIATIONSSOCIATION OFOF AS03 AS03 ADJUVANTEDADJUVANTED PANDEMICPANDEMIC VACCINEVACCINE WITHWITH NNARCOLEPSYARCOLEPSY

Narcolepsy • rare chronic sleep disorder with excessive daytime sleepiness that can be associated with cataplexy. • Incident rate is about 0.74 – 1.37 per 100.000 person-years. • Strong association with HLA DQB1*06:02 genotype • Caused by selective loss of hypocretin-producing cells in the hypothalamus and resulting low

hypocretin levels in CSF, probably as consequence of an autoimmune disorder



Data from Finland: Number of cases per age and reporting year

Annual incidence by age group and year of diagnosis

Clear increase in Narcolepsy cases in children and adolescents (less than 20 yoa) following “Pandemrix” vaccination A clear signal of association! Regulatory Measures imposed by EMA Investigations into potential mechanisms

Incidence peak follows vaccination peak



Potential proposed mechanisms for Pandemrix / AS03 to cause Narcolepsy: Issue still very much under debateSome putative modes of action / mechanisms have been described:

None of these has been finally proven and/or confirmed. Currently no confirmed causative role for “YET: temporal association of narcolepsy with “

Potential proposed mechanisms for Pandemrix / AS03 to cause Narcolepsy: Issue still very much under debate Some putative modes of action / mechanisms have been described: AB induced against the NP component of “Pandemrix” cross-react with hypocretin receptor type 2

and lead to disruption of hypocretin signalling in the brain

Molecular similarity between influenza HA-Epitop and hypocretin causes HA-directed AB to react with and inactivate hypocretin

Alpha-tocopherol in AS03 (not present in MF59) triggers a pathway that finally leads to a degradation

of hypocretin producing neurons

None of these has been finally proven and/or confirmed. Currently no confirmed causative role for “Pandemrix”/AS03 in the emergence of Narcolepsy YET: temporal association of narcolepsy with “Pandemrix” vaccination is evident!!


AADJUVANTDJUVANT AS01 AS01 ININ MMALARIAALARIA/H/HEPATITISEPATITIS B VB VACCINEACCINE ““MMOSQUIRIXOSQUIRIX””

Vaccine Composition (per dose):Vaccine Composition (per dose): 25 µg of RTS,S: Portion of P. falciparum circumsporozoite protein fused with hepatitis B surface antigen (RTS), and combined with hepatitis B surface antigen (S) AS01 adjuvant: Quillaja saponaria Molina, fraction 21 (QS-21) (25 µg) and MPL (25 µg)

Clinical evaluation:Clinical evaluation: Large Phase III trial in seven sub-Saharan African countries Almost 9.000 young children (5-17 months) and 6500 infants (6 – 12 weeks) included 3 doses to be given at monthly intervals, booster dose at 18 months after first dose recommended Vaccine showed moderate efficacy (VE) against malaria clinical manifestations:

Clinical Malaria Severe Malaria Hospitalisation VE VE againstagainst: :

young children

infants

VE quite rapidly decreasing – can be slightly improved by the fourth recommended dose


AADJUVANTDJUVANT AS01 AS01 ININ HHERPESERPES ZZOSTEROSTER (S(SHINGLESHINGLES) V) VACCINEACCINE ““SSHINGRIXHINGRIX”” Currently under evaluation for licensure in the EU

Vaccine Composition (per dose):Vaccine Composition (per dose):

Indication: For ) in 2 doses to be administered

Clinical evaluation:Clinical evaluation:Two large Phase III trials

Evaluation for efficacy (HZ and PHN) and safety

Vaccine Composition (per dose):Vaccine Composition (per dose): 50 µg of gE antigen: Varicella Zoster Virus (VZV) glycoprotein E (gE) produced by recombinant DNA technology in Chinese Hamster Ovarian (CHO) cells AS01 adjuvant: Quillaja saponaria Molina, fraction 21 (QS-21) (50 µg) and MPL (50 µg)

Indication: For prevention of herpes zoster (HZ) and HZ-related complications, such as post-herpetic neuralgia (PHN) in adults 50 years of age or older 2 doses to be administered

Clinical evaluation:Clinical evaluation: Two large Phase III trials

≥ 50 yoa: > 15.000 subjects ≥ 70 yoa: ≈ 14.000 subjects

Evaluation for efficacy (HZ and PHN) and safety


AADJUVANTDJUVANT AS01 AS01 ININ HHERPESERPES ZZOSTEROSTER (S(SHINGLESHINGLES) V) VACCINEACCINE ““SSHINGRIXHINGRIX””

Vaccine efficacy against Shingles and PHNVaccine efficacy against Shingles and PHN

Shingrix Non-adjuvanted Zoster vaccine control

against against HZHZ

against against PHNPHN

• VE of Shingrix much higher than that of the non-adjuvanted control

• Strong adjuvanting effect for AS01 in combination with the VZV antigen


AADJUVANTDJUVANT AS01 AS01 ININ HHERPESERPES ZZOSTEROSTER (S(SHINGLESHINGLES) V) VACCINEACCINE ““SSHINGRIXHINGRIX””

In humans In humans AS01 strongly enhances the AS01 strongly enhances the frequency of VZV frequency of VZV gEgE--specific CD4+ Tspecific CD4+ T--cellscells


SSAFETYAFETY PPROFILEROFILE OFOF AADJUVANTDJUVANT AS01AS01

In children: data from “Mosquirix” vaccine trials Overall, acceptable safety profileSimilar numbers of severe adverse events as compared to control vaccine groupsCertain systemic symptoms (fever, drowsiness, irritability) slightly higher in “ Increased number of Meningitis in But relatedness to vaccination is questionable and currently unclear: Most likely a “chance finding”

In adults and elderly: Data from “Overall, acceptable safety Rate of serious adverse events not increased by “No difference in long

In children: data from “Mosquirix” vaccine trials (more than 10.000 children included for safety)

Overall, acceptable safety profile Similar numbers of severe adverse events as compared to control vaccine groups Certain systemic symptoms (fever, drowsiness, irritability) slightly higher in “Mosquirix” recipients Increased number of Meningitis in Mosquirix group. But relatedness to vaccination is questionable and currently unclear: Most likely a “chance finding”

In adults and elderly: Data from “Shingrix” trials (Lal et al., NEJM 2015)

Overall, acceptable safety profile Rate of serious adverse events not increased by “Shingrix” vaccination (within 30 day p. v.) No difference in long-term follow up (3,5 years) between Vaccine and placebo recipients

Higher rate of solicited and unsolicited adverse symptoms mostly mild-to-moderate, transient (1-3 days)

• injection-site reactions (81,5% for Shingrix vs 11,9% for placebo) (such as pain)

• systemic reactions 66,1% vs 29,5%) (such as myalgia)


FUTURE PERSPECTIVES FUTURE PERSPECTIVES FUTURE PERSPECTIVES FUTURE PERSPECTIVES

Huge Battery of novel adjuvants currently under preclinical and/or clinical investigationHuge Battery of novel adjuvants currently under preclinical and/or clinical investigation

There are currently several There are currently several

Major Questions and Issues to be addressed/answered in the futureMajor Questions and Issues to be addressed/answered in the future

Huge Battery of novel adjuvants currently under preclinical and/or clinical investigationHuge Battery of novel adjuvants currently under preclinical and/or clinical investigation

- dsRNA analogues, SSDNA: poly I:C, CpG motifs

- Lipid A analogues: GLA, RC529,…

- Flagellin

- Saponins

- ISCOMS

- Cationic liposomes; CAF

- Polysaccharides: Inulin

There are currently several There are currently several important Unknowns (Mechanisms, important Unknowns (Mechanisms, SafeteySafetey))

Major Questions and Issues to be addressed/answered in the futureMajor Questions and Issues to be addressed/answered in the future

• Are these adjuvants applicable to be used for human vaccines?

• Detailed knowledge on the mode of action

• Do they allow for deliberate shaping of the vaccine immune response induced?

(eg for efficient priming, immune senescence,…)

• Can we better understand antigen-specific effects of individual antigens?

• (How) can we prevent/minimise very rare serious adverse events?


THANK YOU VERY MUCH FORTHANK YOU VERY MUCH FOR

YOUR ATTENTION!!!YOUR ATTENTION!!!

Any Questions?? Any Questions??

THANK YOU VERY MUCH FORTHANK YOU VERY MUCH FOR

YOUR ATTENTION!!!YOUR ATTENTION!!!

Any Questions?? Any Questions??

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