Rapid Response Vaccines to Stop the COVID19 Pandemic

Phil & Sandra Nudelman Endowed Lecture

November 16, 2020

Deborah Fuller, PhD

Professor, Department of Microbiology

University of Washington

Division Chief, Infectious Diseases and Translational Medicine

Washington National Primate Research Center

Disclosures

I am a co-founder of Orlance, Inc. a biotechnology company that aims to commercialize gene gun delivered DNA and RNA vaccine technologies that will be presented.

I do not have financial interests in HDT Bio, the biotechnology company that aims to commercialize the novel LION/repRNA-CoV2S vaccine that will be presented.

Stopping COVID-19

Social distancing & masks

• Slow transmission

Testing• Quarantine the infected

Vaccines are coming• Stop the pandemic by

providing immunity to the population

November 19, 2020

https://coronavirus.jhu.edu/map.html

Vaccines are:

A way of priming the immune system (immunization) to provide protection from disease caused by a

pathogen without subjecting that person to the disease

Vaccines: An ounce of prevention, a pound of cure

It is estimated that vaccines have saved more lives worldwide than all other medical interventions combined

Herd immunity is achieved(70-90% of population immune)

Herd Immunity

Measles vaccine

Vaccines induce immune memory to a specific pathogen

• Deliberate exposure to Ag that will not produce disease

• Stimulate primary immune response

• Memory cells produced

• Rapid, longer lasting secondary response when we encounter thesame pathogen later (specificadaptive immunity).

Most vaccines protect us from an infection by inducing antibody responses

How will vaccine-induced antibody responses protect us from COVID-19?

ACE2 is a molecule on human cells and it’s what SARS-CoV-2 attaches to in order to infect our cells

SARS-CoV-2 is the virus that causes COVID-19

The virus binds ACE2 via it’s receptor binding domain (RBD) on the viral spike protein

Vaccines aim to induce antibodies that bind the RBD, block viral binding to ACE2 and prevent infection

Vaccines under development for COVID-19

RNA

Candidate COVID-19 vaccines include traditional and new approaches

• mRNA• DNA • Inactivated• Live viral vector• Rec. protein

SinophramSinovac

NovavaxMedicagoClover/GSKU of Queensland

Oxford/AstraZJ&JCanSino

ModernaPfizer/BioNtecHDT/UWInnovioCureVacSanofi

U of Melbourne

https://www.nature.com/articles/d41573-020-00073-5

Current landscape of leading vaccines in phase 3 clinical trials

• The current high rate of transmission is accelerating this timeline

• Timelines for public rollout are moving up by about 3-4 weeks.

Limits of the lead vaccines

• Cold Chain may limit distribution world-wide• Pfizer’s vaccine requires storage at ultra-cold (-80C)

• Limited demographics• Adenovirus-based vaccines (J&J, AstraZeneca and the lead vaccines in Russia and China) are generally

less potent in the elderly

• Short durability• All the lead vaccines are focused on antibody responses that may wane quickly, requiring frequent

booster doses to sustain immunity• Adenovirus-based vaccine induce responses that compromise potency of booster doses.

• Multiple doses• Need to manufacture more doses• Takes longer to induce immunity (at least 6 weeks)

Key attributes for an effective pandemic vaccine

Induces immunity quickly

(Ideally with one dose but two is ok)

Induces antibody and T cell responses

(Antibody, Killer T cells, Type 1 T helper cells)

Effective across different demographics

(Elderly, immune-compromised, co-morbidities)

Fast and cost-effective scale-up, stable at room temperature

We are designing the next generation vaccines to address limits of the 1st wave of vaccines.

• Stable at room temperature

• More effective in the elderly

• Long-term immunity

• One dose

• Needle free - self administration could increase vaccine coverage

“New” kids on the block: DNA and RNA vaccines instruct our own cells to produce vaccine antigens

DNA vaccine RNA vaccine

DNA & RNA vaccines can be rapidly designed and produced: Only need the genetic sequence of a pathogen

They induce both antibody and T cell responses – two weapons of the immune system

Antibodies and T cells work together to fight against SARS-CoV-2 infection

Cytotoxic T cells find and kill cells that become infectedAntibodies block the virus from infecting a cell

Helper T cells help B cells make antibody and activate killer T cells

2nd generation vaccines under development at the University of Washington

Vaccine platforms• Replicating RNA vaccines delivered IM

by LION (HDT Bio Corp)

• DNA and RNA vaccines delivered to the epidermis by needle-free gene gun (Orlance, Inc.)

• Nanoparticle recombinant protein vaccines delivered by IM (Neil King, David Veesler)

Nucleic acids (DNA and RNA) are new rapid response vaccine platforms for pandemics

Traditional vaccinesRequire pathogen and cell-based

manufacturing processes before they can be injected

DNA vaccines insert a code into cells to instruct them

to make vaccineRequires delivery into cell

AND the nucleus

RNA vaccines insert a code into cells to instruct them

to make vaccinerequires delivery into cell

Requires only gene sequence of the pathogen to design (Fast!) Rapid scale-up (Fast! Low cost) Stable at room temperature (DNA, certain formulations of RNA) (helps worldwide distribution) Induces both antibody and T cell responses (two weapons of defense against the virus)

Second generation RNA vaccine: Self-amplifying replicon RNA vaccines (repRNA)

Amplifies amount of antigens and the immune response

DNA is easily manipulated Viral RNA is immunogenic

More immunogenic More effective in the immunocompromised and elderly More durable immunity

Nucleic acid vaccines can rapidly respond to new pandemics

Metagenomicanalysis

Full genome sequence available Jan 10, 2020

Ag design, cloning, &

pilot DNA or RNA lots

7 days

Preclinical down selection

(animal studies)14-120 days

GLP/Tox, Formulation and manufacturing

30-90 days

Human clinical testing (HDT301)

Phase I

FAST! We designed, produced and started testing a candidate replicating RNA vaccine within 7 days after the sequences of SARS-CoV-2 were published

Nov 2020-Jan 2021Jan 2020 Feb-May 2020 June-Oct 2020

Getting RNA into cells: LION and Lipo-nanoparticles (LNP)

LION (our vaccine) LNPs (Moderna, Pfizer, J&J)

Formulation RNA on particle surfaceSimple mixing process – Rapid scale up

RNA inside particleComplex process – Slower scale up

Scale up No cholesterol – all components easily sourced Uses cholesterol – limited supply

Stability Longer shelf life - room temp stable Short shelf life – needs a freezer

Promising pre-clinical results in nonhuman primates with our LION/repRNA vaccine

• Protective levels of antibody are sustained for 4+ months (and counting) after a single shotRapid immunity to block the virus

• T cell responsesClear virus if some gets past antibody

• Strong responses in aged animalsElderly are highly vulnerable but

respond poorly to vaccines

Immune responses induced by the repRNA/LION vaccine in nonhuman primates are durable

Getting DNA and RNA into cells – another way

Formulate DNA or RNA ontoMicroscopic 1-3 uM Gold Particles

Helium Gas Jet Acceleratesthe Particles to Supersonic Speed

into Skin

Penetration of the micron-sized particles is painless

Research Device Clinical Device

DNA needs to get in nucleus.Not all cells that get a gold particle

will express antigen but the ones that do express protein longer

RNA

DNA

RNA only needs to get into cytoplasm.

All cells that get a gold particle will express antigen

Gene gun (Orlance)

Needle-free delivery – pain-free, self-administration Stable at room temperature – supports worldwide distribution

Clinical development of a new vaccine: How long does it take?

A new vaccine requires multiple phases of development and clinical testing to:

• Make sure it works• Make sure it’s safe

6 COVID-19 vaccines to date have been rapidly advanced to phase I clinical trialsSome vaccine platforms were in pre-clinical development for a related viruses (MERS) at the time of the outbreak

But this still takes at least 5 years!

Accelerated timeline to get a vaccine into the population as soon as possible

License or BustMassive

scale-up

SAFETY FIRST! No safety checkpoints are skipped

Where are we now?

LION/repRNA vaccine

• Sinopharm (China) – 2 inactivated vaccines• Sinovac (China) –inactivated• Moderna (US) – mRNA• Oxford/AstraZeneca (UK) – ChAd5• Pfizer/BioNTec (US/Germany) – mRNA• CanSino (China) – Ad5• J&J – Ad26• Novavax – recombinant protein

CanSino (China)-Ad5Gamaleya (Russia) – Ad5/Ad26Sinopharm (China) – 2 inactivated vaccinesBektop (Russia)Sinovac (China) -inactivated

Three ways a COVID-19 vaccine can protect

From infection From disease From transmission

Hodgson et al, Lancet Infectious Disease 2020

FDA requirements for COVID-19 vaccine

EFFICACY• Minimum 50% efficacy

• Document a minimum number of cases (130-160)

• Positive for COVID19 AND positive for 1-2 symptoms

• Efficacy in protection from disease• Pfizer and Moderna report > 90%!

• Document a minimum number of severe cases (at least 5)

• Protection from severe disease

SAFETY• Minimum 2 months follow-up

• Mild/moderate reactogenicity• This is normal – indicates the vaccine is

working!

• No vaccine-associated adverse events

• No evidence of enhancement of disease

Once we have vaccines, how will they be used to stop the pandemic? Who will get it first?

Once we have vaccines, how will they be used to stop the pandemic? Who will get it first?

Getting an effective vaccine into billions of people is the next hurdle

Emergency Use Authorization (limited roll-out)High risk groups (elderly)

Medical teams

First responders

Ring vaccination – used when vaccines are in short supply

• Identify cases & vaccinate close contacts.

• Close contacts are protected

• Chain of transmission is broken

Vaccinating the rest of us

• Even a highly effective vaccine (i.e. > 80% efficacy) will require 55-60% of the population gets immunized to stop the pandemic.

• Social distancing + masks + vaccination are need to accelerate the timeline to stop the pandemic

• The coming mass vaccination campaign will be unprecedented.

No single silver bullet (or arrow)

Induces immunity quickly (single shot)

Effectiveacross

demographics(i.e. elderly)

Fast, cost-effective scale-up

Stable at room temperature

Strongest antibody and

T cellsLong-term immunity

5-7 effective vaccines that work together will likely be needed to stop the pandemic

Acknowledgments

Megan O’Connor

Fuller lab (UW)Patience MurapaJim FullerThomas LewisKevin DravesSamantha Randall

Michael Gale Jr. (UW)Emily Hemann

David Veesler (UW)Alexandra (Lexi) Walls

Washington National Primate Research CenterKathryn Guerriero

HDT Bio CorpAmit KhandharMalcolm DuthieDarrick CarterSteven ReedPeter Berglund

NIH Rocky Mountain LabsHeinz FeldmanDavid HawmanShanna LeventhalElizabeth Fischer

FundingNIH ORIPNIH NIAIDCIIIDCEIRSFAST grantsPew Biomedical ScholarsWashington Research FoundationHDT Bio Corp

Jesse Erasmus