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COVID-19 UPDATE A SCIENCE-BASED OVERVIEW & DISCUSSION

December 17, 2020 MEET YOUR PRESENTERS

Martina Vosteen, PhD Andrea Pegoli, PhD Sandra Sulsky, PhD Health Sciences – Global Senior Consultant Principal Division Director • Overview of main • Distribution and tracking • COVID-19 numbers COVID-19 vaccine types • Herd immunity • Vaccine testing, • Frontrunner candidates evaluation and approval

2 COVID-19 IN NUMBERS

Table 1: COVID-19 vs seasonal COVID-19 (2018-2019) in the USA1 SARS-CoV-2 Financing vaccine and support 73.6 million cases Seasonal candidates worldwide COVID-19 influenza Unprecedented support from 1.64 million deaths governments and regulatory bodies Approximately 250 to boost the development of Cases 16.7 million 36 million candidates are being COVID-19 treatments: evaluated as Deaths 303,872 34,000 for SARS-CoV-2 • USA: Operation Warp-Speed (USD 10 billion) • ~ 150 candidates in 2.3% Mortality ~ 2% ~ 0.09% preclinical evaluation • WHO: COVAX - equitable access to COVID-19 vaccines (EUR 500 • ~80 candidates in million) clinical evaluation (~ 40 candidates in • Accelerated approval procedure of total cases Ph 2 / Ph 3 studies) from FDA and EMA

1 Centers for Disease Control and Prevention (seasonal influenza); John Hopkins University (COVID-19) 3 THE VACCINE TESTING PROCESS

Preclinical trials Before being tested in humans, the efficacy of a vaccine to trigger an is tested on cells (in-vitro tests) and then given to animals (in-vivo tests).

Clinical trials

Phase Participants Goal Normal duration

1 < 100 Collect first data on safety, immune response and dosing regimen < 1 year

Collect information about safety and immune response among a bigger 2 < 1,000 Up to 2 years group of participants

Investigate efficacy of the vaccine in a placebo-controlled, randomized, 3 > 10,000 Up to 4 years blinded and multicenter study

Regular Vaccinovigilance by regulatory bodies once the vaccine is 4 Vaccine is approved Vaccine lifetime approved to monitor effectiveness and safety profile

4 EVALUATION PROCESS FOR VACCINES

Standard vaccines COVID-19 vaccines

Vaccine available for use Vaccine available for use

Pharmaceutical quality Pharmaceutical quality

Non-clinical research Non-clinical research

Human pharmacology studies Phase I Phase I: Human pharmacology studies Clinical Clinical Therapeutic exploratory studies Phase II Phase II: Therapeutic exploratory studies trials trials

Clinical efficacy and safety studies Phase III Phase III: Clinical efficacy and safety studies

Scientific evaluation and authorization Scientific evaluation and authorization

Large-scale production Large-scale production

Studies after authorization Studies after authorization

~ 10 years ~ 1 year

Source: EMA website (COVID-19 vaccines: development, evaluation, approval and monitoring | European Medicines Agency (europa.eu)) 5 VACCINE APPROVAL PROCEDURE DURING COVID-19

01 02 03 An Emergency Use A vaccine efficacy of 50% Regarding safety, the FDA Authorization (EUA) is a efficacy is the benchmark for expects an EUA submission mechanism to facilitate the requesting a EUA. will include: availability and use of • Phase 1 and Phase 2 safety medical countermeasures, data during public health • Phase 3 safety data with a emergencies, such as the median follow-up of at least current COVID-19 pandemic. 2-months • A Phase 3 safety database with over 3,000 vaccine recipients

6 OVERVIEW ON MAIN COVID-19 VACCINE TYPES

• Inactivated SARS-CoV-2 • Non-replicating viral vectors • mRNA-based vaccines • DNA-based vaccines • -based vaccines • Replicating viral vectors • Virus-like particles

7 OVERVIEW ON MAIN COVID-19 VACCINE TYPES What is a spike protein?

The Spike protein (or S-protein) is a specific protein expressed on the surface of the SARS-CoV-2 envelope. It plays a main role in the cycle SARS-CoV-2 and helps the virus to enter in the cell. spike protein The S-protein is able to trigger a response from our . The S-protein alone is not able to start an infection and it is not dangerous. Once we are vaccinated and we enter in contact with the virus, the immune system recognize the spike protein expressed on the virus’ surface and mediates a prompt immune response. In this way we are protected against the virus. OVERVIEW ON MAIN COVID-19 VACCINE TYPES Inactivated virus

Inactivated SARS-CoV-2

“Classic” methodology for developing vaccines. SARS-CoV-2 is inactivated via physicochemical treatments making the virus not able to infect the cells. Coronavirus spike protein MoA The immune system recognizes the spike on the surface of the inactivated virus which trigger the immune response

Examples presenting cell Immune Polio, HepA, response Candidates Wuhan Institute of Biological products / Sinopharm; SinoVac

MoA: mode of action OVERVIEW ON MAIN COVID-19 VACCINE TYPES Non-replicating

Coronavirus spike gene

Non-replicating viral vectors Viral genes (some inactive) Viral vector genetically modified to make it replication-defective. Adenoviruses (Ad) are being investigated for this use. Coronavirus spike protein MoA Once infected, the cells use the gene carried by the viral vector to produce the spike protein

Examples Ebola, Rabies (in animals) Antigen presenting cell Immune Candidates response AstraZeneca / Oxford University (ChAd), Janssen, Sputnik V (HAd).

MoA: mode of action; ChAd: Chimpanzee adenovirus; HAd: Human adenovirus OVERVIEW ON MAIN COVID-19 VACCINE TYPES RNA vaccine

RNA mRNA-based vaccines

Messenger RNA (mRNA) encapsulated in a lipid nanoparticle. mRNA molecules are degraded by Viral proteins Antigen presenting cell enzymes in the body ().

Coronavirus MoA spike protein The mRNA contains encoded information for the production of SARS-CoV-2 spike protein

Examples No mRNA-based vaccines approved so far

Immune Candidates response BioNTech / Pfizer and

Nucleus Cell

MoA: Mode of action COVID-19 VACCINES IN PHASE 3 CLINICAL STUDY

Candidate Sponsor Trial phase

Messanger-RNA (mRNA) based vaccines

BNT162 Pfizer, BioNTech Phase 3 (completed)

mRNA-1273 Moderna Phase 3 (completed)

Non-replicating viral vectors

AZD1222 The University of Oxford; AstraZeneca Phase 3 (completed)

Ad5-nCoV CanSino Biologics Phase 3

JNJ-78436735 Johnson & Johnson (Janssen) Phase 3

Sputnik V Gamaleya Research Institute Phase 3

Inactivated vaccines

CoronaVac Sinovac Phase 3

Covaxin Bharat Biotech; National Institute of Virology Phase 3

N/A Wuhan Institute of Biological Products; Sinopharm Phase 3

Authorized vaccines in the EU and/or in the USA are reported in red 16 THE FRONTRUNNER CANDIDATES

Only three candidates completed the Phase 3 clinical studies:

BioNTech / Pfizer Moderna AstraZeneca (AZ) / 01 (BNT162b2) 02 (mRNA-1273) 03 Oxford University (ChAdOx1-S)

Approval Dosing Reported AVRs Storage Costs Candidate Type Efficacy Data available timeline [day] (> 2%) conditions [°C] [dose]

Authorized: UK, Canada BioNTech / Pfizer and US - Fatigue (3.8%) Ph 3 study mRNA 0, 21 95% - 70 °C ~ $20 (BNT162b2) - Headache (2%) (n ~ 43,000) EU: Dec 21 (expected)

FDA: Dec 18 - Fatigue (9.7%) (expected) - Myalgia (8.9%) Moderna Ph 3 study mRNA 0, 28 94% - Arthralgia (5.2%) - 20 °C ~ $30-40 (mRNA-1273) EMA: Jan 12, (n ~ 30,000) - Inj. site pain (4.2%) 2021 - Erythema at inj. site (2%) (expected)

Non- Ph 3 study, AZ / Oxford Univ. replicating N/A 0, 28 70% - Paresthesia (3%) + 2-8 °C interim data ~ $3-4 (ChAdOx1-S) viral vector (n ~ 23,000)

17 EQUITABLE DISTRIBUTION OF SAFE, EFFECTIVE VACCINES

Maintain healthcare capacity After EUA: • Phased delivery – scientific and ethical principles • At first, supply << demand • Define and select priority groups – Ensure Save recommendations still being discussed equity lives • High risk of serious illness or death Age threshold? Which pre-existing conditions?

• High risk of exposure Front-line health care workers essential workers; unable to work remotely Minimize social and economic disruption due to COVID-19

18 DISTRIBUTION LOGISTICS

Define Monitor Track delivery Hybrid of phases/priorities stocks/availability centralized and Issuing reminders for local oversight second dose in EU, UK, US

Cold chain requirements Implement pharmacovigilance Production Storage, handling, (US CDC has issued guidance) ramp-up training, use interval Passive reports by medical care providers

Active safety follow-up by outreach to vaccinated individuals via text messages and phone calls

Manufacturer responsibility

19 US MAY BEGIN VACCINE DELIVERY 1ST QUARTER 2021

Oversight by CDC and Department of Defense 60 jurisdictions (states, territories, some large cities Allocation based on models within jurisdictions accounting for • Population size and structure • Vaccine effectiveness and uptake Deployment at medical offices; mass sites; pharmacies; long term care facilities

20 DISADVANTAGED POPULATIONS

• Uptake expected to be low • Suffered from the pandemic disproportionately • Severe and fatal disease more common • Large and economic impact • Valid historical reasons to mistrust the vaccine and medical research • Engage community leaders as trusted messengers • To participate in developing distribution plans • To develop and deliver accurate messaging • To encourage participation/cooperation

21 HERD (COMMUNITY) IMMUNITY

An Epi Curve for propagated outbreak Cases in the USA Last updated December 16, 2020

200,000

150,000

100,000 Number of cases

50,000

0 Apr 1 May 1 Jun 1 Jul 1 Aug 1 Sep 1 Oct 1 Nov 1 Today

https://covidactnow.org/ Day of onset

Epidemics recede when a sufficient proportion of the population is resistant to or no longer susceptible to an infectious agent Susceptibles are protected if a sufficient proportion of the community is immune, but outbreaks can still occur Eradication occurs when no one in the population is susceptible (this is rare)

22 ACHIEVING HERD IMMUNITY

• Most estimates place the If mostonly someget vaccinated,get vaccinated, spreading the virus is contained. spreads. threshold between 60% and 90% • Based on serology studies, about 10% of the global population has been infected with SARS-CoV-2 • Duration of immunity after infection not yet known • Risk of reinfection with SARS-CoV-2 mutations not yet known

Healthy, non-vaccinated Healthy, vaccinated Not vaccinated, sick, contagious

What Would Happen If We Stopped ? | CDC | Covid Herd Immunity Threshold Is Difficult to Determine – Bloomberg (Justin Fox) 23 Spencer J Fox, Pratyush Potu, Ravi Srinivasan, Michael Lachmann, View ORCID ProfileLauren Ancel Meyers. The COVID-19 herd immunity threshold is not low: A re-analysis of European data from spring of 2020. medRxiv preprint server. doi: https://doi.org/10.1101/2020.12.01.20242289,https://www.medrxiv.org/content/10.1101/2020.12.01.20242289v1 WILL THE PANDEMIC END ONCE A VACCINE IS AVAILABLE?

Infections avoided with 30-day lag in vaccine effectiveness; 12-month outlook*

Scenario A: 0.5% Pace, 50% Coverage

Vaccine efficacy Reduction in

25%

50%

75%

*Paltiel AD et al. Health Affairs 40, 1(2021): Clinical Outcomes of a COVID-19 Vaccine: Implementation over Efficacy. Appendix exhibit 7A 24 Clinical Outcomes Of A COVID-19 Vaccine: Implementation Over Efficacy (healthaffairs.org) I’VE BEEN VACCINATED. NOW WHAT?

Until infectivity and duration of immunity after vaccination are known, and vaccination coverage is high (enough), behavioral interventions such as mask use, physical distancing, and practicing good hygiene remain crucial for reducing the spread of COVID-19, limiting disability and death, and protecting health care capacity

25 DISCUSSION

OPEN QUESTIONS SOCIAL ISSUES  How long will the vaccine be protective?  Fair and equitable access to vaccines  Are vaccinated individuals contagious?  Impact of misinformation (e.g. fake  Efficacy / safety in special populations news) on vaccination campaign (e.g. pediatric, elderly)?  Long term adverse reactions?  Approval procedure for later candidates?  Can governments mandate specific groups to get vaccinated?  Employer responsibility: internal policies, recommendations / mandates?  Could there be restricted access for people that didn’t get vaccinated e.g. airplanes?

26 Stay safe.