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Building Immune Defence Priority Research Programme

MICROBIOTA NUTRITION IMMUNE SYSTEM

When it is obvious that the

goals cannot be reached

don’t adjust the goals; adjust the action steps

Confucius

Food-health relationships for respiratory immune defence against infection and pollution driven inflammation

• 77% of Chinese consumers ranked ‘immune enhancement’

as important

• The outbreak of severe acute respiratory syndrome (SARS),

bird and swine flu coupled with Asia’s ageing population is driving the growth of the immune health F&B market

• Air pollution crisis across Asia presents a threat to human

health These perspectives suggest a potential high adoption rate for F&B solutions targeting respiratory immune defence

Building Immune Defence Team

Immune defence against infection lead

• rganisation. Elizabeth Forbes-Blom, Hazel

Poyntz, Aurélie Gestin, Anna Mooney Irene Braithwaite, Nick Shortt, Jenny Sparks, Darmiga Thayabaran, Tess Ostapowicz Wayne Young Sally Poppitt, Amy Liu, Audrey Tay Pollution inflammation lead organisation. Roger Hurst, Odette Shaw, Greg Sawyer Amber Parry-Strong Sarah Elliott In consultation with the Immune Industry Reference Group; Consumers Insights and Science of Food research themes.

Building Immune Defence

Overall goal: Fast-track opportunities for NZ companies to develop foods and beverages with scientifically validated immune defence benefits

• Provide a causal relationship for the beneficial modulation
• f immune defence
• Identify associated nutrition responsive biomarkers

(established and new) of the physiological and immunological processes

• Examine the efficacy of these biomarkers to respond to food

interventions in mouse models

2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2018-19 Oct - Mar

F&B candidates identified across the programme and incorporated into research design IRG meetings Collaboration with the Consumer Insights and Science of Food programmes will support the design, development and testing of potential product solutions Objective 3

Building immune defence – Tranche 1 timeline

Objective 1.1 Complete exploratory study Association of gut microbiota community types to antibody responses following seasonal flu vaccine.

2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2018-19 Oct - Mar

F&B candidates identified across the programme and incorporated into research design IRG meetings Collaboration with the Consumer Insights and Science of Food programmes will support the design, development and testing of potential product solutions Objective 3

Building immune defence – Tranche 1 timeline

Objective 1.2 Systems immunology approach to predict magnitude of the human immune response integrated with data from Objective 1.1 (including biomarker identification) F&B candidates identified across the programme and incorporated into research design IRG meetings Collaboration with the Consumer Insights and Science of Food programmes will support the design, development and testing of potential product solutions Objective 3

2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2018-19 Oct - Mar

Building immune defence – Tranche 1 timeline

Objective 1.3 Pre-clinical mouse model of altered gut microbiota to examine the impact on immune defence following seasonal flu vaccination Lead food candidates examined in pre-clinical mouse model for efficacy to beneficially modulate immune defence following seasonal flu vaccine

2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2018-19 Oct - Mar

F&B candidates identified across the programme and incorporated into research design IRG meetings Collaboration with the Consumer Insights and Science of Food programmes will support the design, development and testing of potential product solutions Objective 3

Building immune defence – Tranche 1 timeline

Objective 2 Two pre-clinical models of pollution exacerbated respiratory inflammation developed to enable the measurement of food-health relationships Lead food candidates examined in pre- clinical models for efficacy to beneficially modulate immune defence following pollution exposure

2015-16 Oct - Sept 2016-17 Oct - Sept 2017-18 Oct - Sept 2018-19 Oct - Mar

F&B candidates identified across the programme and incorporated into research design IRG meetings Collaboration with the Consumer Insights and Science of Food programmes will support the design, development and testing of potential product solutions Objective 3

Building immune defence – Tranche 1 timeline

• Influenza epidemics occur

virtually every year

Building immune defence against respiratory tract infection

• Influenza epidemics occur

virtually every year

• Link between reduced

productivity and cognitive impairment well recognised

Systemic

• Fever

Nasopharynx

• Runny nose
• Sore Throat

Intestinal

• Diarrhoea

Psychological

• Lethargy
• Reduced cognitive

function Respiratory

• Coughing

Gastric

• Nausea
• Vomiting

Building immune defence against respiratory tract infection

• Influenza epidemics occur

virtually every year

• Link between reduced

productivity and cognitive impairment well recognised

• As a consequence, 75% of

Chinese patients with seasonal influenza are prescribed antibiotics despite a lack of efficacy

US antibiotic consumption per person annually China antibiotic consumption per person annually

Building immune defence against respiratory tract infection

Accumulating evidence indicates antibiotic use perturbs immune defence against influenza

Microbiota regulates immune defence against influenza virus infection

Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. PNAS 2011; 108(13):5354-5359 Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T et al. Immunity. 2012;37(1):158-170.

Gut microbiota is necessary for antibody responses to seasonal influenza vaccination

Oh JZ, Ravindran R, Chassaing B, Carvalho FA, Maddur MS, Bower M, et al. Immunity 2014; 41(3):478-492

US antibiotic consumption per person annually China antibiotic consumption per person annually

• Influenza

epidemics

• ccurring

virtually every year

• Link between reduced productivity

and cognitive impairment well recognised

• As a consequence, 75% of Chinese

patients with seasonal influenza are prescribed antibiotics despite a lack

• f efficacy
• Accumulating

evidence now indicates that antibiotic use perturbs immune defence against influenza

Commercial opportunity

Change the “antibiotic panacea” to F&B solutions that build immune defence against respiratory tract infection

Acetate Butyrate Propionate

Foodstuff Metabolites

Tryptophan/ tyrosine metabolites Fibre succinate

GPR43 GPR41 GPR109A GPR35 GPR91

Receptor

Citric acid cycle

Main role in immunity

Gut homeostasis, regulation of inflammation Macrophage/DC biology Metabolic control Gut homeostasis Regulation of some inflammatory conditions

Medium chain fatty acids Omega-3 fatty acids

GPR84 GPR120 GPR40 ? Pro-inflammatory Role unclear Type 2 diabetes related receptor Anti-inflammatory properties, Inhibition of TNF, IL-6 Anti-inflammatory properties, Role still unclear ? Pro-inflammatory

Nicotinic acid Kynurenic acid Slide courtesy of Charles Mackay

• Vaccination responses provide insight into the overall

efficacy of the co-ordinated function of a wide range of immune processes

• Increased numbers of individuals attaining acceptable

antibody titres is an appropriate nutrition responsive biomarker

• Immune responses vary widely from person to person

Nakaya, HI et al. Nature Immunology 2011 12 786-795. Tsang, JS et al. Cell 2014 157 499-513

• Non-heritable factors have the greatest contribution to

immune health and wellbeing

Brodin, P et al. Cell 2015 160 37–47 Carr, EJ et al. Nature Immunology 2016 in press Baxter, AG et al. Genome Medicine 2015 7:29

• Immune response to vaccination depends on baseline

immune status

Tsang, JS et al. Cell 2014 157 499-513 Carr, EJ et al. Nature Immunology 2016 in press

• Baseline immune status is stable over an extended

sampling period

Orrù, V. et al. Cell 2013 155 242-256 Tsang, JS et al. Cell 2014 157 499-513 Brodin, P et al. Cell 2015 160 37–47 Carr, EJ et al. Nature Immunology 2016 in press

Building immune defence against influenza exploratory study

Day 0 Day 28

125 participants 18-64yrs

Wk 26 Day 7 Day 3

Day -7 – Day -1 Day -4 – Day 0 Day 21 – Day 27 Day 24 – Day 28

• Started 01/04/16; as at 11 am today ~40 participants will have

completed day 0

• 24/06/16: 500 visits and 750 samples

(~26L blood and 250 faecal samples)

HAI

  

Microbiota + food diaries

 

Gene expression

  

Cell subset flow

 

TIV-B cell ELISpot

  

ELISA

 

Day 0 Day 3 Day 7 Day 28 Wk 26

Building immune defence against influenza exploratory study

Building immune defence against influenza exploratory study

Outcomes: Intra-individual responses as compared to baseline Inter-individual diversity Stool community types in NZ cohort Association to vaccine response > High/Low responder profile > Identify low responders > Identify biomarkers that predict immune response

Measures immune response in broad and unbiased fashion

• Cell populations
• Gene expression
• Antibody response
• Baseline signatures
• Stool community type

Systems Immunology approach

Pre-clinical models to examine food-health relationships

Pre-clinical model of modern-day dysbiosis

Poor diet Stress Early-life antibiotic treatment

Measure immune responses Seasonal flu vaccine Nutritional intervention Positive control/benchmark food Lead food candidates

Acknowledgements

• H-VN Management Team
• Science Leadership Team and Gut and Immune Expert

Panel

• Building Immune Defence Team
• Consumer Insights and Science of Food Teams
• Immune Defence Industry Reference Group