COVID-19 Vaccine Overview Immunisation Coalition Annual Scientific Meeting Sunday 7Th Feb 2021

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COVID-19 Vaccine Overview Immunisation Coalition Annual Scientific Meeting Sunday 7th Feb 2021

Associate Professor Paul Griffin FRACP FRCPA Director of Infectious Diseases, Mater Medical Director and Principal Investigator, Nucleus Network Immunisation Coalition Director and Scientific Advisory Board Member COI/Disclosures

Employed by Nucleus Network as the Principal Investigator on numerous vaccine clinical trials including the following SARS-CoV-2 vaccines; UQ Novavax Serum Institute of India Symvivo Member of Novotech IBC (Institutional Biosafety Committee) AstraZeneca International Medical Advisory Board Member Outline

History of Coronavirus Vaccines Clinical Trials for COVID-19 Vaccines COVID-19 Vaccine Tracker Vaccines: mechanism Leading vaccines Comparison of leading vaccines Vaccines trialled in Australia Vaccines by approval status Australian supply Conclusion History of Coronavirus vaccines

• No licenced human coronavirus vaccine previously • Many currently in use for animals including; IBV (Infectious bronchitis virus) vaccine for chickens (live attenuated and inactivated) Bovine coronavirus (live attenuated) • Many candidates for SARS A number of different platforms, recombinant and inactivated Many animal models (small animals and NHP) suggested high levels of immunogenicity Complicated by • Immunopathology

TH2 based • Enhanced disease (ADE) Ultimately eradicated with infection control measures • More severe disease • Total cases 8422 with case fatality rate 11%

• Wang, Qidi, et al. "Immunodominant SARS coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates." ACS infectious diseases 2.5 (2016): 361-376. • Bolles, Meagan, et al. "A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge." Journal of virology 85.23 (2011): 12201-12215. Clinical trials for COVID-19 vaccines -Objectives

Phase 3 Primary: Prevention of COVID-19 (often symptomatic PCR proven disease) Safety, tolerability and reactogenicity Secondary: Many laboratory correlates of protection: neutralising antibodies, antibody titre, cellular responses More detailed clinical responses including: asymptomatic infection, severe disease, emergency visits, admissions, mortality (all cause and COVID-19 related) Phase 2 Primary: Focus on laboratory correlates whilst still closely monitoring safety Secondary: Includes prevention but not sufficiently powered for this to be primary outcome Phase 1 Primary: Safety, tolerability and reactogenicity (laboratory correlates also measured) Secondary: Extensive additional safety parameters in addition to those in primary, detailed immunological assessments, infections still monitored

https://www.scimex.org/newsfeed/explainer-vaccine-clinical-trial-phases, Paul Griffin. Clinical trials for COVID-19 vaccines -Speed How is everything happening so fast Not by skipping any key clinical trial components Funding Lead candidates have access to ample funding Not iterative funding based on results of clinical trials CEPI: coalition for epidemic preparedness innovations Funding 11 of the lead candidates Over 1 billion USD Also generous government funding and advanced purchasing deals Operation Warp Speed around 10 billion USD Bconcen of naionalim

Nicole Lurie, Melanie Saville, Richard Hatchett, and Jane Halton. Developing Covid-19 Vaccines at Pandemic Speed May 21, 2020 N Engl J Med 2020; 382:1969- 1973. DOI: 10.1056/NEJMp2005630 Clinical trials for COVID-19 vaccines -Speed

Preclinical data Same tox data required Often submissions commence prior to report being ready Provided available prior to dosing Some leniency in efficacy data Animal challenge studies occurring in parallel to clinical trials Hastened regulatory processes Essentially real time approvals Study design Most commence with phase 1/2 studies As soon as phase 1 data supports from safety perspective, phase 2 commenced Many with expanding groups e.g. elderly cohorts Scaling of manufacturing Given access to funding Scaling of manufacturing occurred in parallel with early phase trials

Vaccines: mechanism Nucleic acid Viral vector Protein Inactivated or attenuated Nucleic acid mRNA Pfizer-BioNTech: BNT162b2, 95% Efficacy, Approved Moderna: mRNA-1273, 94.5% Efficacy, Approved Curevac: CVnCoV, Phase 3 Arcturus/Duke, Phase 2 Genova/HDT: HGC019, Phase 2

DNA AnGes: AG0302-COVID19, Phase 3 Zydus: ZyCoV-D, Phase 3 Skin patch Inovio: INO-4800, Phase 2 Delivered into the skin with electrical pulses GeneOne, Phase 2

Symvivo, Phase 1 (underway in Brisbane) Oral Nucleic acid-mechanism of action

mRNA: Instruction to make proteins Cellular machinery (ribosome) translates these instructions into proteins In this case, the protein is the spike protein Given mRNA is inherently unstable Need to be coated in oily bubble or lipid nanoparticle to prevent degradation Need to be kept very cold The mRNA helps to boost the immune response so no adjuvant required But still require multiple doses Fast, but not yet licenced technology Safe

• Wang Jieliang e al The COVID- Vaccine Race Challenge and Ooniie in Vaccine Fomlaion AAPS PhamSciTech ol 1,6 225. 5 Aug. 2020, doi:10.1208/s12249-020-01744-7 • Calina, D., Sarkar, C., Arsene, A.L. et al. Recent advances, approaches and challenges in targeting pathways for potential COVID-19 vaccines development. Immunol Res (2020). • NCIRS Vaccine Platforms: http://ncirs.org.au/vaccine-platforms Viral vector

Gamaleya: Gam-Covid-Vac or Sputnik V, 91.6% Efficacy, Early use Ad5 and Ad26 Oxford/AstraZeneca: ASD1222, 82.4% Efficacy, Emergency Use ChAdOx1 CanSino: Convidecia/Ad5-nCoV, Limited use Ad5 Johnson & Johnson: Ad26.COV2.S, 57% to 72% Efficacy, Phase 3 Ad26 Single dose Viral vector-mechanism of action

Gene for the target, in this case spike protein, inserted into a benign unrelated virus In this case most commonly an Adenovirus Oxford-AstraZeneca is a modified chimpanzee adenovirus ChAdOx1 The virus is capable of entering cells but not replicating Typically, some are able to replicate Once inside, DNA to mRNA to protein Spike protein produced The vector virus also aids in the generation of an immune response so no adjuvant required And typically potent cellular and humoral responses generated However, pre-existing or newly generated immunity against the vector may impact efficacy

Bektop: EpiVacCorona, Phase 3/Early use in Russia Viral peptides Novavax: NVX-CoV2373, 89.3% 57% to 72% Efficacy, Phase 3 Spike protein, nanoparticle, Matrix-M adjuvant ZFSW/Chinese Academy of Medical Sciences: ZF2001, Phase 3 Receptor Binding Domain, adjuvanted Medicago: CoVLP, Phase 2/3 Plant based, adjuvanted (GSK) Clover: Phase 2/3 Protein-based S-Time ih Dnaa CPG adjan Protein-mechanism of action

Components of target antigen produced in laboratory Now often associated with additional technologies Nanoparticles/Virus Like Particles/Molecular Clamp etc Po Ea o manface fom eence no live virus, well established platform, specifically targeting essential antigens can reduce reactogenicity Con can hae high odcion co ofen require adjuvant and or multiple doses

Sinopharm: BBIBP-CorV, 79.34% 57% to 72% Efficacy, Approved Cultured virus inactivated with beta-propiolactone, adjuvanted Sinovac: CoronaVac, 50.38%, Emergency Use Cultured virus inactivated with beta-propiolactone, adjuvanted Bharat Biotech: Covaxin/BBV152 A, B, C, Emergency use Cultured virus inactivated with beta-propiolactone, adjuvanted

Codagenix, Phase 1 Live attenuated, intranasal proprietary deoptimization technology Hundreds of silent mutations using codon pairs underrepresented in human cells therefore de-optimized for translation in human cells 100% identical to circulating viral strain at amino acid level Inactivated or Attenuated -mechanism of action Vaccines created from weakened coronaviruses or coronaviruses that have been killed (often with chemicals) Lead candidates use variants that multiply quickly in cell culture (monkey kidney cells) Attenuation can include Chemical: most commonly beta-propiolactone bind gene o can elicae proteins, including spike, remain intact Po Scalable and ineenie eeience ed for over a century) Con Ofen ill need adjan no eeing ame levels of efficacy as other platforms

bioRxiv 27th Jan 2021

bioRxiv 19th Jan 2021 Moderna (mRNA) Moderna (mRNA): Evidence Oxford-AstraZeneca (Viral Vectored) Oxford-AstraZeneca: Evidence Oxford-AstraZeneca: Evidence

Preprint Lancet 2nd Feb Johnson & Johnson (Viral Vectored) Johnson & Johnson: Evidence

Jan 29th Press Release Novavax (protein) Novavax (protein): Evidence Comparisons of leading vaccines Pfizer-BioNTech Moderna Oxford-AstraZeneca Johnson & Johnson Novavax Comparisons of Leading vaccines

Pfizer-BioNTech Moderna Oxford-AZ Janssen Novavax Efficac 95% 94.1% 82.4% 72% (US) 89.3% Severe 90% 100% 100% 85% 28 days 100% COVID19 100% 49 days protection Doses 2 (3 weeks) 2 (4 weeks) 2 (4+ weeks) 1 2 (3 weeks) 82.4% was 12 Age 16+ 18+ 18+ 18+ 18+ Storage Ultra-cold Ultra-cold - C 1 - C - C -70C 6 months -C monh - C da - C da Room temp 12 hours

endoin micobiologicall oen momaic COVID-19 Comparison of Leading vaccines-variants

Pfizer-BioNTech Moderna Oxford-AZ Janssen (J & J) Novavax Efficacy (old 95% 94.1% 82.4% 72% (US) 89.3% variants) B.1.1.7 (UK) Predicted to not Predicted to not cenl no 85.6% variant impact have impact on have impact on evidence that efficacy efficacy the vaccine does not work against he ne ain B.1.351 (South 0.81-1.46 fold 6 fold decrease 57% efficacy 60 % HIV neg African) variant decrease in in neutralising 49.5% HIV + / - impact neutralising antibodies (not antibodies (not efficacy) efficacy) Contingency Not developing Developing Developing Developing plan for new booster yet booster updated vaccine updated vaccine variants Vaccines trialled in Australia Novavax UQ Clover Vaxine Serum Institute of India Symvivo COVID-19 Vaccines in Australia-Clinical Trials

Novavax NVX-CoV2373 (PI) First vaccine to commence human trials in southern hemisphere, 26th May Recombinant Spike protein nanoparticle with matrix M adjuvant Results of phase 1 published in NEJM Many phase 2 sites in Australia and elsewhere Phase 3 commenced September 24 1 of 4 3 vaccines with supply agreements for Australia 51 million doses COVID-19 Vaccines in Australia-Clinical Trials

University of Queensland Sclamp (PI) Recombinant spike protein with molecular clamp First dosed 13th July Rapid response project commenced around 2 years earlier CEPI funded predominantly Phase 1 still going Excellent preclinical data Safe and effective Was 1 of 4 vaccines with supply agreements for Australia Diagnostic interference COVID-19 Vaccines in Australia-Clinical Trials

Clover S-trimer vaccine Chinese based clinical stage biotech Phase 1 Linear in Perth

Vaxine/Flinders University Spike protein using plant sugar with insect cell expression system Reported to have completed phase 1 with 30 actives that supported progressing in the middle of last year Not able to find published results as yet COVID-19 Vaccines in Australia-Clinical Trials

Serum Institute of India (PI) Receptor Binding Domain attached to Hep B sAg (spycatcher/spytag- bioconjugation) Virus Like Protein Phase 1 commenced 1st September 2020 30 subjects 18 to 59 Additional studies using multiple dose/adjuvant combinations to follow soon COVID-19 Vaccines in Australia-Clinical Trials

Symvivo (PI) First oral vaccine in clinical trials bacTRL Gene Therapy Platform Genetically Modified Bifidobacteria B. longum Engineered to deliver plasmids containing synthetic DNA encoding SARS-CoV-2 spike protein Technology already in use intravenously for oncology indication Delivers IL-12 via IV administration selectively to tumours Phase 1 commenced late last year Also stable at room temp Vaccines: by approval status Approved Authorised Not yet approved/authorised Abandoned Approved Sinopharm Inactivated, quoted efficacy 79.34% Approved in China, UAE, Bahrain Emergency use in Egypt, Pakistan, Hungary.

Pfizer-BioNTech mRNA, quoted efficacy 95% Approved in Bahrain, Saudi Arabia, Switzerland Emergency use in U.S., E.U., many other countries

Moderna mRNA, quoted efficacy 94.5% Approved in Switzerland Emergency use in U.S., U.K., E.U., Canada, Singapore. Authorised

Gamalea Snik V Viral vectored (Ad26, Ad5), quoted efficacy 91.6% Early use in Russia Emergency use in many other countries

Oxford-AstraZeneca Viral vectored (ChAdOx1), quoted efficacy 62-90% (82.4) Emergency use in UK, EU, other countries

CanSino Viral vectored (Ad5) Limited use in China Other leading vaccines not yet approved/authorised

Johnson & Johnson Viral vectored (Ad26), quoted efficacy 57-72%

Novavax Protein, quoted efficacy 89.3% Abandoned

UQ/CSL Poein molecla clam Dec 10, first vaccine to be abandoned after entering clinical trials HIV test interference Merck Institut Pasteur developed with Austrian firm Themis Bioscience Viral vector (Measles) Abandoned Jan 25 Response weaker than natural infection Merck With IAVI Viral vector (vesicular stomatitis virus) Same as approach as first approved Ebola vaccine Abandoned Jan 25 Response weaker than natural infection Imperial College With Morningside ventures Self amplifying RNA vaccine Abandoned Jan 27 Not the right time to start new efficacy trial for a further vaccine in the UK Australian supply COVID-19 Vaccines in Australia-Supply

Australian supply 3 vaccines Pfizer-BioNTech mRNA, 2 doses 10 million doses now 20 million doses Minus 70 storage, so logistics challenging Oxford/Astra Zeneca Adenoviral vectored ChAdOx1 3.8 million doses initially, delivered to Australia hopefully soon 50 million doses manufactured by CSL Commenced last year COVID-19 Vaccines in Australia-Supply

Australian supply 3 vaccines Novavax Nanoparticle/matrix M 51 million doses

Total therefore: 20+53.8+51 = 124.8 million doses

University of Queensland Sclamp protein, 2 doses Was to be 51 million doses manufactured by CSL Now 0 In Conclusion Questions that are still asked frequently I i e he accine ial on ell abo eenion of mild dieae o more severe disease etc. No Most phase III trials have been designed to look at a complete spectrum of disease Including using surrogates to look at all disease severities including ED presentations, all cause and COVID-19 related mortality, hospital admission, ICU admission, ventilation etc Also include regular virological assessment, even in asymptomatic participants I i e ha cen accine on edce anmiion No Efficacy discussed relates currently to reductions of symptomatic microbiologically proven cases Reducing symptoms in those infected reduces ability to shed viral containing droplets and therefore ability to transmit (at least to some degree) Many vaccines studied have shown reductions in viral shedding, at least in animal studies This is a challenging endpoint to measure in clinical trials The absence of evidence is not evidence of absence However reduction in asymptomatic PCR positivity (e.g. of 67%) may be an indication this Outstanding questions

Longevity and requirement for boosting The more boosters required and the shorter the interval, the lower our probability of achieving sufficient coverage May be addressed by second (or later) generation vaccines Heterologous boosting also may be a solution If we have multiple generations of vaccines, how will we know which are compatible, which combinations are potentially beneficial vs otherwise Still outstanding questions on first generation vaccines How effective they will be/new variants/duration of protection/requirement for boosting etc. This is work is now underway May be that certain combinations give the best protection e.g. prime with mRNA or viral vectored and boost with protein/subunit (a guess) Ongoing challenges

Perhaps the biggest challenge; Uptake A highly effective vaccine will have little impact if few receive it Safety concerns; many reports misconstrued as evidence of lack of safety Speed: commonly reported that speed coming at the cost of safety and insufficient testing Conspiracy theories: virus created for some agenda Other common misunderstandings Illness is mild, therefore why would we vaccinate Sain and maion mean accine on ok Summary

Vaccine development/clinical trials progressing faster than ever before Without omitting any critical steps All vaccine platforms have been applied to COVID-19 Many exceptional candidates Many now approved Development of new later generation vaccines continues Potentially with properties to address limitations (relatively) of first generation candidates The scaling of manufacturing that occurred early is facilitating relatively rapid roll out Some supply issues It will still likely be a lengthy process with complex logistics Given above, and uncertainty around transmission blocking The vaccine in itself is a key intervention, but not the whole story Need ongoing testing, therapies, technological solutions to aid contact tracing etc. And ongoing mitigation strategies But can hopefully begin to gradually ease as coverage increases