UPDATED: NOVEMBER 25, 2020 COVID-19 : Visit www.racap.com/covid-19 for latest version. Anything wrong/outdated? Please contact [email protected]. This map is a compilation of the biotech Strategic Overview & Instructions on How to Use This map TOLERABILITY COVID-19 (CORONAVIRUS) VACCINES industry's effort to rid the world of COVID-19. placebo Our visualization aims to convey not only individual innovations from specific companies but also the collective mild and moderate severe LOCAL PAIN SWELLING FEVER DISEASE SEVERITY AND effort and sheer hustle of the entire industry. Shingrix (70+) SHINGRIX PBO COVID-19 SHINGLES The legacy of COVID-19 will hopefully include not only new treatments for an acute viral illness but also a greater PROGRESSION TIMELINE appreciation of what society can accomplish when we unite against a common foe. We've already achieved Sanofi Fluzone (single dose) ONSET OF TWO MONTHS SANOFI FLUZONE PBO NR NR NR SYMPTOMS ONGOING INFECTION/INFECTIVITY RECOVERY RESOLVED INFECTION/POTENTIAL IMMUNITY remarkable innovations in many diseases: hepatitis C, HIV, melanoma, breast cancer, and cystic fibrosis, to DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 DAY 22 DAY 23 DAY 24 DAY 25 DAY 26 DAY 20 DAY 27 DAY 28 DAY 29 DAY 30 DAY 31 VACCINES Sanofi Flublok (single dose) name a few. What we need now is a sustained, collective effort to make medical advances SANOFI FLUBLOK PBO RNA INFLUENZA SENSITIVITY OF KEY To save lives, we need vaccines to prevent infection and drugs to treat people who become infected. Novavax Ph1 Flu (single dose) BIOMARKERS FOR COVID-19 available to everyone instead of overburdening patients with excessive out-of-pocket IgG ANTIBODIES Fortunately, many of both are in development, though we don’t yet know what works. The first vaccines are likely to become NOVAVAX PH1 FLU PBO NR NR NR SOURCE: https://diagnostics.roche.com/us/en/products/params/elecsys-anti-sars-cov-2.html costs that discourage them from receiving appropriate care. This will require fundamentally RNA peaks at day 3-4 ANTIGEN available towards the end of 2020 for front-line workers and for masses in 1H21. Novavax (5ug) ANTIGEN peaks at day 1-2 reforming America’s insurance system, building on the recent patches put in place after peaks between day 7-14 NOVAVAX PBO IgM ANTIBODIES Drugs to treat may already be available if existing ones we have for other diseases turn out to DOSE 1 IgG ANTIBODIES peaks after day 14 work for COVID-19 (e.g. remdesivir, Actemra), but if we do need new ones (as we likely will), then those probably won’t be payers initially refused to cover COVID-19 testing and the uninsured were overwhelmed by Moderna (100µg) PATHOGEN PRESENCE PATHOGEN IgM ANTIBODIES IMMUNE RESPONSE available until September 2020 or later (need to run tests and manufacture). the cost of hospitalization. MODERNA PBO NR NR NR

COVID-19 BioNtech BNT162b2 (30µg) US (18-55) NR INCUBATION PERIOD RECOVERY/IMMUNE The Biotech Social Contract, as described in The Great American Drug Deal, affirms BioNtech BNT162b2 (30µg) US (65-85) OF THE POPULATION 1 100% 5-14 DAYS AFTER INFECTION COVID-19 COVID-19 SYMPTOMS BIONTECH PBO - US 40% 40% OF INFECTED PATIENTS that we do not have to choose between innovation and affordability. We as a society can ASYMPTOM- RECOVERY CAN RANGE BETWEEN ATIC AZN 5E10 0-6 WEEKS FEVER 88% PATIENTS rise to the challenge of tackling all human diseases just as we have COVID-19, making depending on severity p e t e r ko l c h i n s k y DISEASE LOSS OF SMELL/TASTE* 79% investments that will permanently upgrade our health and that of future generations. DRY COUGH 68% 60% MILD SYMPTOMS Shingrix (70+) DIAGNOSTIC/CLINICAL SIGNIFICANCE FATIGUE 38% SYMPTOMATIC 5-14 DAYS AFTER INFECTION PATIENTS SOURCE: Genalyte COVID Investor 200404.pdf SHINGLES SHINGRIX (70+) PBO OVERVIEW SPUTUM PRODUCTION 33% 40% 80% OF SYMPTOMATIC PATIENTS REMAIN ASYMPTOMATIC no symptoms PCR IgM IgG Novavax (5ug) SEVERE SYMPTOMS SIGNIFICANCE SHORTNESS OF BREATH 19% (Ag) (Ab) (Ab) SYMPTOMS: NOVAVAX PBO HOSPITALIZATION REQUIRED TWO WEEKS MAP LEGEND 48% in hospital SORE THROAT 14% DEVELOP MILD SYMPTOMS ONLY AFTER ONSET OF SYMPTOMS Patients may be in the “window period” of SARS-COV-2 infection Fever, dry cough, fatigue, and shortness of breath are no or mild pneumonia 7 DAYS Moderna (100µg) 14% 14% OF SYMPTOMATIC PATIENTS the major symptoms associated with COVID-19. The CDC HEADACHE Preclinical Trial EUA Emeregency Use Authorization Patient may be in the early stage of infection, and the body’s immune response first produced the MODERNA PBO NR NR NR antibody IgM, but no IgG was produced or the IgF content did not reach the detection limit of the CRITICAL SYMPTOMS also includes loss of taste or smell, chills, muscle pain, MUSCLE/JOINT PAIN 15% RCT Randomized Controlled Trial

diagnostic treatment. COVID-19 8% ICU REQUIRED BioNtech BNT162b2 (30µg) US (18-55) PROGRESS TO SEVERE SYMPTOMS THREE WEEKS headache, and sore throat as symptoms to watch for. DOSE 2 HOSPITALIZATION REQUIRED difficulty breathing (dyspnea), low CHILLS 11% in hospital/ICU Approved Therapeutic IST Investigator-Sponsored Trial oxygen (hypoxia), and/or lung involvement on imaging 10.5 DAYS AFTER ONSET OF SYMPTOMS Patients may be in late or recurrent stage of infection. While other symptoms have been reported, they occur BioNtech BNT162b2 (30µg) US (65-85) 6% OF SYMPTOMATIC PATIENTS NAUSEA/VOMITING 5% 4% Patient is in the active phase of infection, but the human body has developed some immunity to Repurposed Therapeutic ORAL Oral Delivery PROGRESS TO CRITICAL SYMPTOMS much less frequently. BIONTECH PBO - US ICU REQUIRED respiratory failure, shock, or multiorgan dysfunction SARS-COV-2 (the persistent antibody IgG has been produced). DEATH NASAL CONGESTION 5% P Prophylaxis Treatment SUBQ Subcutaneous Delivery <1% Patient may be in the acute phase of SARS-COV-2 infection. At this time, nucleic acid test results AZN 5E10 PROGRESS TO DEATH ~18 DAYS AFTER ONSET need to be considered (PCR may be false negative). DIARRHEA 4% Therapeutic Treatment Regardless of Hospitalization IV Intravenous Delivery OF SYMPTOMS Patient may have been infected with SARS-COV-2 in the past, but the patient recovered or the virus 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 0% 20% 40% 60% 80% 100% ID <1% OF in body has been cleared. DISEASE PROGRESSION: Treatment In Hospital Setting Only Intradermal Delivery SYMPTOMATIC Patient has recently been infected with SARS-COV-2 and is in the recovery stage. Or the nucleic 2,3,4 *Weighted average 1D INTRANASAL PATIENTS acid test result is false negative and the patient is in the active infection stage. One Dose Intranasal Delivery PRE-INFECTION 2D Two Dose Vaccine INHALED Inhaled Delivery INFECTION (5-14 DAYS BETWEEN INFECTION & ONSET OF SYMPTOMS) ONSET OF SYMPTOMS WEEK ONE WEEK TWO WEEK THREE WEEK FOUR TWO MONTHS COVID-19 can be prevented through the use of + BARDA In collaboration with BARDA IM Intramuscular COVID-19 US CASES, BY AGE placebo basic precautions and (in the future) an effective + CEPI In collaboration with CEPI CHANGES HIGHLIGHTED IN YELLOW mild and moderate vaccine. CASES BY TYPE NUMBER OF CASES HEADACHE FATIGUE MUSCLE PAIN WARP Recognized by Operation Warp Speed (OWS) CLICK TO SEE MAP UPDATE LOG > severe ages Novavax/Emergent BioSolutions + CEPI (NVX-CoV2373) ≥85 Shingrix (70+) Novavax reported Ph1/2 RCT data for two doses (5 ug and 25 ug) of NVX-CoV2373 + 50 ug of its Matrix-M adjuvant. Neutralizing antibody titers were the highest produced by any vaccine candidate to date POST-EXPOSURE (3906 GMT, assessed by a stringent 100% inhibition live virus assay) and the tolerability profile was largely superior to other published COVID vaccine candidates, as well as common marketed common flu vaccines. SHINGRIX PBO The Ph2 portion of trial started August 2020 and data from this study demonstrated that NVX-CoV2373 is well tolerated in an expanded adult population, including elderly patients. Novavax was ages SHINGLES awarded $1.6B from Operation Warp Speed to support large-scale manufacturing of candidate NVX-CoV2373 by FUJIFILM Diosynth Biotechnologies and fund clinical development. A Ph3 RCT started recruiting Novavax/Emergent BioSolutions CEPI & BARDA 2D + Pure Full-length Spike nanoparticles: After exposure to SARS-CoV-2, it takes several days 75–84 September 2020 in the UK and a second Ph3 RCT is expected to start in the US/Mexico November 2020, with efficacy data expected early 1Q21 followed by rapid submission. Together with their acquisition of (NVX-CoV2373) WARP Sanofi Fluzone (single dose) NR Novavax’s platform is promising because it was well tolerated and generated strongest immunogenicity data in their Ph1 COVID-19 trial to date (see data tables on the map). Additionally, their quadrivalent candidate (NanoFlu) has seen success in a large Ph3 trial with adults aged 65 years and older. Novavax uses its own unique Cyrus Poonawalla Group, Novavax is guiding to having 100M doses ready by late 2020 and reach 1B doses/year run rate by YE21. The company recently entered an exclusive licensing agreement with the Serum LIKELY TO BE PART OF THE FIRST WAVE OF for symptoms to develop. During this incubation Institute of to support an additional 1B doses for India and low- and middle-income countries, a partnership with Takeda to support the production of over 250M annually for Japan, a development and supply adjuvant called Matrix M for both their COVID-19 and influenza programs. ages SANOFI FLUZONE PBO NR NR NR agreement with SK Bioscience for global manufacturing of the antigen component and vaccine supply for South Korea, an agreement with the UK government to purchase 60M doses, and agreements in principle to period, the infected person is able to transmit the 65–74 supply up to 76M doses to Canada and up to 40M doses to Australia. Combinable with flu vaccine in the same Sanofi Flublok (single dose) adjuvant system virus despite being unaware of their illness. This is University of Queensland/CSL Behring + CEPI ages SANOFI FLUBLOK PBO

why basic protective measures like social distancing, CASE-FATALITY INFLUENZA This technology leverages a molecular clamp to stabilize the viral antigen. Ph1 trials started 3Q20, with data expected by YE20 before initiation of a large scale Ph3 study. The program has multiple additional 55–64 % OF CASES BY AGE 2D University of Queensland/CSL Behring Truncated Spike protein trimers: ICU ADMISSION COVID-19 VACCINES: partners (Cytiva, Viroclinics Xplore, Lonza, and Thermo Fisher Scientific) and recently announced an agreement with the Australian government to supply 51M doses. CSL expects the first doses to be available MY21 + CEPI % OF POPULATION BY AGE Novavax Ph1 Flu (single dose) hand washing, and mask wearing are critical. HOSPITALIZATION with capacity for up to 100M doses YE21. LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS The University of Queensland’s (UQ) partnership with CSL to develop a COVID-19 vaccine provides access to Seqirus’ proprietary adjuvant technology MF59, which is used in their quadrivalent seasonal influenza vaccine (FluAd). UQ is also comparing GSK’s vaccine with Dynavax’s. Most ages NR NR NR Programs with marketed people develop symptoms between 2-14 days post-infection, NOVAVAX PH1 FLU PBO or clinically advanced 5 45–54 Sanof + BARDA with the majority developing symptoms by 5 days . Novavax (5ug) quadrivalent seasonal Sanofi guided to producing 600M vaccine doses between YE20 and 2H21, and then scaling up to 1B doses annually by YE21. However, since protection requires 2 doses this is enough to vaccinate only 50M-300M FLOW CYTOMETRY: Truncated Spike protein trimers influenza vaccines that can be ages NOVAVAX PBO DOSE 1 people. Sanofi was recently awarded $2.1B by Operation Warp Speed to supply the US with 100M doses in 2021 with the option for up to 500M doses. Similarly, Sanofi has entered agreements with the UK to 2D If we had a therapy that was safe, efficacious, and DOSE 1 supply up to 60M doses, with Canada to supply 72M doses, with the EU to supply up to 300M doses in 2021, and with the World Health Organization to supply 200M equitable doses. Ph1/2 testing launched Sanofi + BARDA WARP Sanofi has recently accelerated its timeline and is guiding to starting trials September 2020 with the goal of having a licensed product by July 2021, which is half a year behind other lead programs.However, Sanofi makes the common seasonal quadrivalent flu vaccine and could easily drop in the SARS-CoV-2 subunit antigen in with the flu antigens combined with their COVID-19 20–44 LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS NR September 2020, with data expected December 2020 and the initiation of a Ph3 trial shortly thereafter, with possible regulatory approval 1H21. Early data showing the minimum dose needed to achieve protective to create a single pentavalent vaccine that people will get seasonally. Therefore, while all eyes are now on the vaccines that will be first to market or even can be most rapidly scaled to give everyone their first , a juggernaut like Sanofi might best address the seasonal market over the long run. All other companies would have to bring their candidate easy to administer, it could be given to people who Moderna (100µg) immunity will be critical to determine how quickly Sanofi could make a dent in global vaccine need. own flu vaccines to the market, which is hard. Sanofi is comparing their own adjuvant with GSK’s adjuvant. have come into contact with infected individuals (such ages CD4+ CELLS MODERNA PBO NR NR NR Sinovac (PiCoVacc) 0–19 as caretakers or hospital workers) to try to prevent COVID-19 NR NR NR candidate for which preliminary Ph2 data were recently reported and demonstrated induction of neutralizing antibodies in above 90% of volunteers. Preclinically, NHP challenge experiment Inactivated vaccines: likely requires 2 doses, so strong immunity takes 6 weeks from frst injection, but potentially less regulatory risk relative to live viruses since chemical treatment renders virus Flow cytometry - CD4+ cells BioNtech BNT162b2 (30µg) US (18-55) 35% 30% 25% 20% 15% 10% 5% 0% 0% 5% 10% 15% 20% 25% 30% 35% for SARS-CoV-2 demonstrated protection without enhancement, though doses seemed too high for efficient manufacturing. This program is run by the Chinese government and entered into a collaboration with the incapable of propagation *BNTX/PFE is taking BNT162b2 Brazilian Institute to initiate a Ph3 trial (committing 60M-100M doses through this agreement), in addition to a supply deal with Indonesia (committing 40M doses). Although immunogenicity data from this trial have 2D Sinovac (PiCoVacc)* Not yet combinable with flu vaccine in the same them from becoming infected. This kind of treatment into their Ph2/3, not BNT162b1 1.0 BioNtech BNT162b2 (30µg) US (65-85) not yet been published, this vaccine candidate was granted emergency use authorization in China August 2020, with an efficacy readout expected November 2020, and entry into a Ph1/2 pediatric trial shortly LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS • This strategy is used for vaccination against hepatitis A, , and rabies. adjuvant is called post-exposure prophylaxis, and while there thereafter. The Ph3 recently resumed after a temporary suspension due to a serious adverse event that was later found to be unrelated to the vaccine. Sinovac currently has the capacity to produce ~100M doses INFg *with adjuvant from Dynavax • Importantly, the Sinovac vaccine used this approach and showed protection against infection in monkeys without immune enhancement. However, the chemical inactivation process that Sinovac uses appears to make the vaccine less effective, requiring fairly high doses. BIONTECH PBO - US annually and is aiming to triple capacity to ~300M doses largely for domestic supply in 2021. are currently many ongoing trials in this space, no IL-2 • Sinovac has a quadrivalent seasonal influenza vaccine (Anflu) marketed in China formulated with an aluminum hydroxide adjuvant. They are comparing their own adjuvant with Dynavax’s and will likely be limited to the Chinese domestic market in a seasonal setting. Younger people make up majority TNFa AZN 5E10 Medicago/Mitsubishi Tanabe medications are yet approved for this purpose. Those Any Th1 response Leveraging a plant-based vaccine production platform. Medicago recently released Ph1 data demonstrating modest neutralizing antibody titers (811 GMT with a low stringency 50% inhibition live virus assay) with the of the cases, while older people 0.8 3.75-ug dose for which they plan to move forward in clinical trials. Ph2 trials are expected to start in November with Ph3 following shortly thereafter in December. The company has guided to supplying 120M doses 2D Medicago/Mitsubishi Tanabe Full-length spike within VLPs who believe they have been exposed to the virus should self- annually by 2021, with plans to double production capacity in 2022, and ultimately achieve greater than 1 billion doses of COVID-19 vaccines per year in 2023 after they complete building their large-scale factory *comparing adjuvant from GSK vs. Dynavax Medicago has a plant-based quadrivalent VLP seasonal influenza vaccine candidate. While development has been discontinued in the US, a NDS is under review by Health Canada with possible approval coming 2021. Medicago’s vaccine will contain GSK’s AS03 adjuvant. disproportionately get serious in Quebec. The company recently signed an agreement with the Government of Canada to supply 76M doses of its vaccine and will also receive $173M in funding to support research and development. quarantine for 14 days to prevent spreading it to others. SpyBiotech / covid-19 and die. Shingrix (70+) A Ph1/2 study has been initiated in Australia. This platform uses a proprietary SpyCatcher/SpyTag “superglue” technology to display the Spike protein on the surface of surface antigen VLPs.

0.6 SHINGLES SHINGRIX (70+) PBO ExpreS2ion Biotechnology/AdaptVac/Bavarian Nordic MILD Partnered with Bavarian Nordic A/S, Europe’s largest independent vaccine developer, and sponsored by EU’s PREVENT-nCoV vaccine research consortium, this program is expected to start Ph1 trials in December Novavax (5ug) 2020 with early data available 2021. It is unlikely that this vaccine candidate will factor into global supply until the end of 2021 or even 2022. 2D SpyBiotech / Serum Institute of India Most patients who develop COVID-19 have a mild disease course and are able to manage their NOVAVAX PBO iBio (IBIO-200) Small company not funded to scale their VLP vaccine, although they estimate they could make about 500M doses annually once their vaccine candidate is approved (unclear timeline). Unlikely to contribute large 2D ExpreS2ion Biotechnology/AdaptVac/Bavarian Nordic symptoms at home using over-the-counter medications that relieve pain and/or reduce fever 0.4 Moderna (100µg) NR scale production before 2022.

2D (e.g., Tylenol/acetaminophen or Advil/ibuprofen). %CD4+ T Cells iBio (IBIO-200) Full-length (not truncated) Spike protein trimers: potentially If you are diagnosed with COVID-19, please follow the NR NR NR Saiba/AGC Biologics MODERNA PBO 2D Saiba/AGC Biologics Spike within VLPs: no news about large investments in scaling up advantageous since displaying full-length protein shows the Part of a Swiss consortium that aims to get the entire Swiss population (8.5M people) inoculated by 4Q20. Recently partnered with AGC biologics to manufacture and distribute at national scale. Currently not advice of your healthcare professional. manufacturing, suggesting that these programs may provide proof of concept immune system more of the Spike protein against which to COVID-19 focused on global development. BioNtech BNT162b2 (30µg) US (18-55) 2D Imophoron/Bristol University This version of RA Capital’s DOSE 2 (ADDomer) data but will be late in getting to large scale develop antibodies (trimer is a cluster of 3 spike proteins that 0.2 Imophoron/Bristol University (ADDomer) 2D Akers Biosciences/Premas Biotech form the characteristic crowns decorating the virus) Some “asymptomatic” patients with COVID-19 may not develop any noticeable symptoms and BioNtech BNT162b2 (30µg) US (65-85) UK academic spin-out in preclinical testing. Currently looking for partners to further development past PC stage. 2D VBI Vaccines/National Research Council of Canada may not realize they have been infected. Because these individuals can still spread the virus, everyone BIONTECH PBO - US Akers Biosciences/Premas Biotech should employ basic protective measures like social distancing, hand washing, and mask wearing (obviously none of Very early VLP vaccine prototype. Unclear clinical timelines and manufacturing capacity indicate that this program will not be impactful before 2022. NOT REPORTED AZN 5E10 VBI Vaccines/National Research Council of Canada those are necessary if you live by yourself and never see anyone else, though washing hands is still nice). 0.0 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 Enveloped VLP pan-coronavirus vaccine candidate targeting COVID-19, SARS, and MERS. VBI was recently awarded CAD $56M by the Canadian government to accelerate vaccine developments efforts through Ph2 Novavax Moderna BioNTech/Pfizer AstraZeneca/ testing. VBI selected two lead candidates to take into Ph1/2 YE20 that generated robust neutralizing antibody titers in mice. (NVX-CoV2373) (mRNA-1273) (BNT162b1)* University of Oxford HOSPITALIZATION 5mcg 100mcg all doses Germany (AZD 1222) 5E10 vp Clover Biopharmaceuticals This program recently published preclinical data in a nonhuman primate challenge model demonstrating that Clover’s vaccine candidate elicited strong neutralizing antibody titers (in the 1000s), which reduced viral load in the lungs and nasal canal after challenge, but did not confer sterilizing immunity. Interestingly, GSK’s adjuvant elicited a superior antibody response relative to Dynavax’s adjuvant in this head-to- Some patients who develop COVID-19 symptoms become seriously ill (1 out of every 6 timepoint D29 D43 D29 head comparison. Ph1 clinical trials started 2Q20 with initial data expected 4Q20. They have in-house 2x2000L bioreactor capacity, which could translate to “hundreds of millions of doses” annually. CEPI Subunit vaccines (loose protein or particle-based) that direct the immune response against viral diagnosed, but a lower rate amongst all, including undiagnosed, who are infected), develop recently expanded its partnership with Clover by investing up to $328M (including $69.5M previously announced) to fund the company’s vaccine through licensure, including a global Ph2/3 starting by YE20 and Spike protein (likely 2 doses, so strong immunity takes 6 weeks from frst injection) days post manufacturing scale up. 2D Clover Biopharmaceuticals* + CEPI boost 7 days 14 days 7 days • Antibodies that bind the receptor binding domain (RBD) region of Spike block it from binding the ACE2 receptor on cells, neutralizing the virus and preventing difficulty breathing, and must be admitted to the hospital to manage these symptoms. Older placebo *comparing GSK vs Dynavax adjuvant Kentucky Bioprocessing, Inc it from infecting cells. While this approach is the most plausible vaccine strategy for COVID-19, narrowly focusing on this ‘Spike-only’ approach could put ‘too mild and moderate many eggs in the same basket.’ Still, vaccines that train the immune system against only Spike will likely be sufficient; this is supported by lab work showing that people (≥65 years old) and those with other medical issues are most at risk of developing serious CHILLS TENDERNESS JOINT PAIN Kentucky Bioprocessing is a wholly owned subsidiary of British American Tobacco leveraging a plant-based vaccine production platform. It is currently awaiting FDA approval to begin Ph1 testing for COVID-19 and 2D Kentucky Bioprocessing, Inc Larger companies: more likely to both have larger-scale production capacity severe have guided to having the capacity to produce 1M-3M vaccine doses/week. vaccines targeting the other two external proteins, Envelope (E) and Membrane (M), did not protect animals from infection; however, vaccines for Spike (S) did, illness. Some identified risk factors include cardiovascular disease, diabetes, high blood pressure (hypertension), 2D Covaxx to start with and ability to increase production in parallel with early testing, demonstrating that vaccination against Spike was ‘necessary and sufficient.’ Covaxx which would facilitate production of large numbers of doses in 2021. chronic lung disease, cancer, and chronic kidney disease (CKD). Typically, hospitalized patients have difficulty Shingrix (70+) NR NR 2D • Manufacturing at large scale has been worked out for these ‘tried and true’ types of vaccines, but it is expensive and time consuming, which means that small Covaxx is a spinout company of United Biomedical Inc developing a synthetic RBD-Fc vaccine formulated with T-cell epitopes and a proprietary adjuvant. They achieved high neutralizing antibody titers in guinea pigs Baylor College of Medicine/Biological E 6,7 ( >32,000) and entered Ph1 testing September 2020 in Taiwan. They have guided to producing 100M doses by 1Q21 with the capacity to scale up to 1B by YE21 and have entered a global distribution partnership companies need large partners and big capital infusions. Those without such resources are unlikely to make a dent in the world’s need for billions of doses in breathing and decreased levels of oxygen in their blood, requiring administration of supplemental oxygen . SHINGRIX PBO NR NR with Maersk. 2021. COVID-19 VACCINES: SHINGLES Baylor College of Medicine/Biological E Acute respiratory distress syndrome (ARDS) is a serious complication in patients with severe Sanofi Fluzone (single dose) NR NR Ph1/2 trial started in Nov 2020 with results expected Feb 2021. Baylor College of Medicine licensed their candidate to Biological E to help manufacture and develop. Biological E expects to NR manufacture hundreds of million doses annually, although little information about this program is available within the public domain. disease and is associated with a high risk of respiratory failure. These patients must be carefully SANOFI FLUZONE PBO NR NR managed in the intensive care unit, often with the use of mechanical ventilation, and have the Sanofi Flublok (single dose) NR NR Anhui Zhifei Longcom Biopharmaceutical/ Institute of Microbiology, Chinese Academy of Sciences highest risk of death from COVID-19. ARDS is common for hospitalized patients with COVID-19 (20-42%) and TITERS Little information is available publicly about this program’s clinical timeline or manufacturing scale. The company will likely focus on the domestic Chinese market in 2021. SANOFI FLUBLOK PBO NR NR initial labored breathing can quickly progress to ARDS and ICU admission. In addition to lung injury, ARDS is also INFLUENZA Vaxine Pty/Medy-Tox/Oxford Expression Technologies NR NR Truncated Spike protein trimers: may not train the immune COVID-19 Vaccines map8,9,10 Novavax Ph1 Flu (single dose) Small, Australian biotech company leveraging its proprietary adjuvant (Advax-CpG55.2) and its previous experience developing a SARS-CoV1 vaccine candidate to develop COVAX-19. They are partnered with Human Convalescent Sera (HCS) Vaccine Candidates system to recognize all the vulnerabilities that the full-length associated with kidney, liver, and heart complications, which can also increase the risk of mortality . South Korea’s Medy-Tox and the UK’s Oxford Expression Technologies to develop this program. Unclear clinical timelines or manufacturing scale. NOVAVAX PH1 FLU PBO NR NR NR protein would display. Although nearly all other viral vaccines Mild Moderate Severe Prime Boost HCS 1 “Report of the WHO-China Joint Mission on Coronavirus ....” 28 Feb. 2020, https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf 10000 10000 Medigen/NIAID/Dynavax ( including mRNA, adenoviral, nanoparticle, and inactivated) 7457 NR 2 “International Forum of Allergy & Rhinology - Wiley Online Library.” 12 Apr. 2020, https://onlinelibrary.wiley.com/doi/abs/10.1002/alr.22579. 7280 Novavax (5ug) Ph1 testing is expected to start September 2020. The company plans to finish the preclinical development and CMC by Fall 2020 to proceed with clinical trials to be done by June 2021. Concurrently, manufacturing display the full-length Spike protein trimer -- there is still a 3 “Alterations in Smell or Taste in Mildly Symptomatic Outpatients ....” 22 Apr. 2020, https://jamanetwork.com/journals/jama/fullarticle/2765183. 3906 and scale-up are planned to provide up to 200M doses by YE21. This program recently entered a partnership with Vaxess Technologies to develop a combination COVID-19 + seasonal influenza microneedle patch Anhui Zhifei Longcom Biopharmaceutical/Institute of NOVAVAX PBO NR DOSE 1 vaccine. 2D good chance that vaccinating with a truncated Spike protein 4 “Olfactory and gustatory dysfunctions as a clinical presentation ....” 6 Apr. 2020, https://link.springer.com/article/10.1007/s00405-020-05965-1. DOSE 1 Microbiology, Chinese Academy of Sciences will be good enough 5 “The Incubation Period of Coronavirus Disease 2019 (COVID-19).” 10 Mar. 2020, https://annals.org/aim/fullarticle/2762808/incubation-period-coronavirus-disease-2019-covid-19-from-publicly-reported. Accessed 20 Apr. 2020. Xiamen Innovax Biotech (XWG-03) Moderna (100µg) NR NR NR 2D Vaxine Pty/Medy-Tox/Oxford Expression Technologies 6 “Hospitalization Rates and Characteristics of Patients ... - CDC.” https://www.cdc.gov/mmwr/volumes/69/wr/mm6915e3.htm. Accessed 20 Apr. 2020. 983 Chinese company with no declared timeline to enter the clinic. They have previously reported bulk capacity to produce 20M doses/year. They would therefore need to scale up to meet even domestic demand. Programs that have not yet 1000 837 1000 been seriously explored for 7 “Management of Patients with Confirmed ....” https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Accessed 20 Apr. 2020. 671 654 MODERNA PBO NR NR NR MIGAL Galilee Research Institute/MigVax 2D Medigen/NIAID/Dynavax influenza. It is unlikely that 8 “Management of Patients with Confirmed ....” https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html. Accessed 20 Apr. 2020. * 9 “Coronavirus disease 2019 (COVID-19 ... - UpToDate.” https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19--virology-clinical-features-diagnosis-and-prevention/abstract/39. Accessed 20 Apr. 2020. 522 COVID-19 NR Company is guiding that they could be in the clinic ‘in a couple of months.’ Recently raised a $12M round for the development of this vaccine candidate led by OurCrowd. Their manufacturing capacity is currently 2D Xiamen Innovax Biotech (XWG-03) Standard Injection into the muscle BOOST AFTER D21 14 DAYS DAYS AFTER D21 372 BioNtech BNT162b2 (30µg) US (18-55) NR they will bring a seasonal flu BOOST unclear. 10 “Coronavirus disease 2019 (COVID-19): Critical care issues ....” 1 Apr. 2020, https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-critical-care-issues. Accessed 20 Apr. 2020. 254 361 256 158 214 *in collaboration with GSK vaccine to market now just to 149 NR 100 BioNtech BNT162b2 (30µg) US (65-85) IMV combine with their COVID-19 100 100 94 94 2D MIGAL Galilee Research Institute/MigVax NR Plans to begin Ph1 trials in Canada in MY20 and Ph2 by YE20. They have recently been granted CAD $10M by the Canadian government to progress their candidate DPX-COVID-19 through Ph1. candidate. 60 BIONTECH PBO US 2D IMV AFTER D28 BOOST 14 DAYS University of Pittsburgh (PittCoVacc) 29 AZN 5E10 Microneedle delivery platform that plans to enter the clinic in 3Q20 on the back of serological studies in mice. Does not appear scalable at the moment. Smaller companies and academic groups: may quickly initiate early trials of AFTER PRIME 28 DAYS 2D University of Pittsburgh (PittCoVacc) AFTER PRIME 28 DAYS

14 BOOSTD28 AFTER 28 DAYS 12 DAYS AFTER PRIME 21 DAYS a small number of vaccine doses but cannot easily scale up manufacturing, BOOST AFTER D21 7 DAYS Intravacc/EpiVax/CimCure/Celonic Group 10 10 2D Intravacc/EpiVax/CimCure/Celonic Group DAYS AFTER D21 BOOST AFTER D21 7 DAYS This collaboration will leverage Intravacc’s intranasal OMV technology platform to deliver COVID-19 antigens optimized by EpiVax. The program plans to be in the clinic in 2021, and has recently entered a research increasing the time needed to produce meaningful numbers of doses Virus (Log10) Live Neutralizing GMTs agreement with Celonic Group (CDMO), although the manufacturing capacity of this joint venture is unclear. 2D EpiVax/University of Georgia (EPV-CoV19) 3.2

EpiVax/University of Georgia (EPI-CoV19) AFTER D28 BOOST 28 DAYS NR

AFTER NR PRIME Shingrix (70+) DAYS AFTER PRIME 21 DAYS DAYS AFTER PRIME 21 DAYS 2D Vaxil BioTherapeutics NOT NOT 28 DAYS NOT NOT Preclinical mouse and ferret challenge experiments are set to readout in MY20. No guidance on clinical timelines yet. n=42 n=8 n=3 n=25 n=4 n=25 n=25 n=32 n=13 n=3 n=12 n=12 n=38 n=12 n=12 n=38 n=10 n=10 n=5 n=10 n=10 n=49 n=32 0 REPORTED 0 REPORTED REPORTED REPORTED NR Validated approach: SHINGLES SHINGRIX (70+) PBO NR Vaxil BioTherapeutics 2D AJ Vaccines HCS HCS Novavax Moderna BioNTech/Pfizer BioNTech/Pfizer AstraZeneca/ AstraZeneca/ JnJ Vaxil has recently entered a cooperative research and development agreement with USAMRIID to test its vaccine candidate (CorVax) in mice. They are assessing several contractors to develop a scaled GMP process. generate antibodies PREVENT INFECTION (HK panel) (NVAX panel) (NVX-CoV2372) (mRNA-1273) (BNT162b2) 30 ug (BNT162b2) 30 ug University of University of (Ad26.COV2.S) NR 5ug 100 ug US (age 18-55) US (age 65-85) Oxford Oxford 5E10 vp Novavax (5ug) 2D AJ Vaccines WRAIR/USAMRIID (ChAdOx1 nCoV-19) (ChAdOx1 nCoV-19) NR against SARS-CoV-2 (and 5E10 vp 5E10 vp NOVAVAX PBO No useful information in the public domain. Company focuses on manufacturing standard vaccines without a track record of developing new ones. 2D VIDO-InterVac at the University of Saskatchewan Assay Used potentially induce T-cell MN 50% MN 100% MN 100% PRNT 80% VNT 50% VNT 50% VNT 100% MN 50% VNT 50% NR NR NR WRAIR/USAMRII % inhibition Moderna (100µg) 2D OncoGen Research Center COVID-19 Vaccines Have Short-Term and Long-Term Value: How Vaccines Work: Generating Neutralizing Antibodies Key Risks: Immune Enhancement least stringent stringent stringent moderately stringent least stringent least stringent stringent least stringent least stringent US Department of Defense-sponsored research effort whose lead COVID vaccine (SpFN) expects to be in the clinic by December 2020. Historically focused on vaccines for military applications and has limited immunity, which may be MODERNA PBO NR NR NR manufacturing. is out ofThe vaccine candidates on this map thatdate. prove to be safe and efficacious will have immediate short- Vaccines train the immune system to recognize pathogens like viruses by introducing a piece of the The vaccine field must demonstrate that SARS-CoV-2 vaccines, both generally and for each vaccine helpful)

COVID-19 NR VIDO-InterVac at the University of Saskatchewan • All known effective vaccines work by stimulating the immune term value as part of our global pandemic response: they will help prevent SARS CoV-2 infection and, virus or the entire virus after inactivating or weakening (attenuating) it. A vaccine for a different virus, like individually, do not paradoxically worsen disease if a person later becomes infected, a phenomenon BioNtech BNT162b2 (30µg) US (18-55) DOSE 2 VIDO-InterVac was awarded $23M by the Canadian government to accelerate COVID-19 vaccine development and the University of Saskatchewan was awarded another $3.6M. Recently partnered with Dalton system to generate antibodies that bind and neutralize a given for those who become infected, reduce the risk of serious infection and/or transmission to others; this influenza, cannot be simply repurposed to protect against COVID-19; to protect against infection the called “immune enhancement.” This has occurred with one vaccine in humans (for RSV in 1960s) NR Pharma and Biodextris for manufacturing and fill-finish. Clinical trials are expected to start by Jan 2021. pathogen -- these vaccines employ this validated approach. Nearly can help protect unvaccinated people or those who don’t develop a strong immune response to the vaccine must introduce the SARS-CoV-2 virus (or parts of it) to train the immune system to recognize and in animals with some vaccines against two other diseases caused by novel (new) coronaviruses: BioNtech BNT162b2 (30µg) US (65-85) all are injected. In some cases, these vaccines may also stimulate NR OncoGen Research Center a T-cell response against infected cells, though the relevance of vaccine through a phenomenon called “herd immunity.” and destroy it. However, established techniques such as virus inactivation or attenuation used for flu SARS and MERS; these vaccines induced the production of antibodies that helped the virus infect BIONTECH PBO US NR Romanian research institute with micro-scale (<10K doses) capacity. this is unclear since vaccines that only generate antibodies without vaccines can be applied towards making COVID-19 vaccines. Newer vaccine technologies are not yet immune cells, leading to overactivation of the immune system and ultimately causing organ damage. T-cell immunity also work. However, there’s reason to believe that COVID-19 will continue to circulate with us for a while and AZN 5E10 become endemic, so we have recently restructured this map to teach the longer-term value that extends broadly used in the clinic, but they have been shown to work in clinical trials evaluating vaccines against Determining whether a vaccine causes immune enhancement requires developing animal models Sinopharm Group/Wuhan Institute of Biological Products/Beijing Institute of Biological Products • Most vaccines are likely going to have to be given as 2 doses, other viruses. of COVID-19, which some laboratories have only just managed to create in hamsters and monkeys. typically 4 weeks apart. The first dose “primes” the immune system beyond the initial pandemic response. Even after a successful vaccine is developed, we’ll likely need 0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100 Inactivated vaccine sponsored by the China National Pharmaceutical Group that entered Ph1/2 testing in April 2020. Early data from this trial demonstrated that participants generate relatively low levels of and generates some antibodies, and the second dose “boosts” the Scientists are now beginning experiments to see if certain vaccines cause enhancement, in parallel with neutralizing antibodies (121-250 GMT with a low stringency PRNT50 assay), although they did not have a human convalescent comparator arm to benchmark these results to. The company has guided to supplying Sinopharm Group/Wuhan Institute of Biological Products/ to boost people’s immunity to COVID-19 for multiple reasons: 1) immunity wanes over time, 2) some All known effective vaccines work by stimulating the immune system to generate antibodies that 2D immune response and helps improve the quality and quantity of initial human clinical trials. Companies will have to show lack of enhancement in animals before they 1B doses in 2021. Initiated a Ph3 trial in the UAE enrolling up to 15K volunteers. In September 2020, the UAE granted Emergency Use Authorization for this vaccine candidate before clinical trials are complete, Platforms that can support Beijing Institute of Biological Products neutralizing antibodies. So far, all signs point to each SARS-CoV-2 people have compromised immune systems (particularly older individuals, who are most vulnerable bind and neutralize a given pathogen -- these vaccines employ this validated approach. Nearly all are becoming the first program to be granted approval by a foreign country. LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS can start larger clinical studies and file for FDA approval. seasonal boosting together vaccine developer planning on using 2 doses of their own vaccine. to COVID-19), 3) vaccines may not provide sterilizing immunity, and 4) some people may refuse injected. In some cases, these vaccines may also stimulate a T-cell response against infected cells, Chinese/Indian programs Chinese Academy of Medical Sciences with influenza vaccines. However, it does not have to be that way. Vaccination courses vaccination and serve as reservoirs for the virus, enabling it to spread. Thus we may need seasonal though the relevance of this is unclear since vaccines that only generate antibodies without T-cell 2D COVID-19 VACCINES: IST sponsored inactivated initiated MY20 that demonstrated relatively low levels of neutralizing antibodies (43-55 GMT), lagging behind both Sinovac and Sinopharm. Chinese Academy of Medical Sciences will likely focus on domestic can include one type of priming dose (e.g., adenoviral vector) and markets in 2021 Inactivated virus: likely requires 2 doses, so strong immunity takes 6 weeks from frst injection, but potentially another type of booster (e.g., protein subunit or MVA vector). Also, against COVID-19, similar to how we already get seasonal boosters for influenza. In this immunity also work. 2D Additional Considerations: Combining Disparate Vaccines Bharat Biotech International () Bharat Biotech International (Covaxin) less regulatory risk relative to live viruses since chemical treatment renders virus incapable of propagation prime and booster doses do not always require the same amount scenario we believe it makes the most sense to combine the two: to develop a combined COVID-19 of vaccine. For example, Oxford is testing a that is A vaccine may turn out to be effective enough to stop a person from becoming infected. That would Recently entered Ph3 clinical testing and will use ViroVax’s Alhydroxiquim-II adjuvant. They reported that this vaccine has a “positive” reactogenicity profile and are collecting sera to study immunogenicity. The • This strategy is used for vaccination against hepatitis A, polio, and rabies. half of the prime dose. This helps to make additional vaccine doses plus seasonal influenza vaccine called a pentavalent vaccine that everyone could receive. Most vaccines are likely going to have to be given as 2 doses, typically spaced 3 or 4 weeks apart. The company expects their vaccine to hit the market summer 2021 and has guided to producing 200M doses annually Whole virus vaccines (not just Spike protein): these could provide a hedge against failure of prevent the virus from spreading throughout the population and so would protect even people who • Colorado State’s vaccine unit uses photochemical inactivation that does not modify proteins (only destroys the viral RNA genome) and may have a very potent SARS-CoV-2 antigen. available and to provide doses as quickly as possible. It’s not a foregone conclusion that this will be necessary. But we think it’s likely enough that we should weren’t vaccinated (i.e., it would facilitate herd immunity). However, a vaccine might also turn out to first dose “primes” the immune system and generates some antibodies, and the second dose “boosts” BASIC PROTECTIVE Spike-only vaccines (e.g., in case those caused immune enhancement or failed to generate Therefore, it may not cost much or take long to scale up to hundreds of millions of doses. However, no one has yet stepped up to fund the scale-up of this vaccine, possibly because protective immunity), though very few are focusing on this approach • EXAMPLE OF COMBINING DISPARATE VACCINES: be looking ahead. Seasonal flu vaccines currently make up a $4.5B/year market and this could grow protect a person from developing severe illness (or any illness) but not stop the virus from infecting the immune response and helps improve the quality and quantity of neutralizing antibodies. So far, all Valneva well-intentioned but counter-productive academic policies preclude any company from licensing the technology exclusively (the exact opposite of what the Bayh-Dole Act charged Animal studies of other adenoviral (Ad) vaccines for different signs point to each SARS-CoV-2 vaccine developer planning on using 2 doses of their own vaccine. Valneva expects to enter clinical studies by YE20 with potential regulatory approval 2H21. They have recently reached an agreement with the UK to provide 60M doses 2H21 (purchased for 470M euros), with universities with doing). Therefore, it will require either an act of generosity on the part of a company or a grant from CEPI or BARDA to scale up and test this approach. We think it pathogens, such as Ebola and HIV, have shown that Ad vectors substantially if transformed into a pentavalent vaccine market, making it attractive to vaccine developers and replicating in a person’s nose (upper respiratory tracts), in which case the virus might still spread options for an additional 130M doses 2022-2025, which will be manufactured at its facilities in Livingston, Scotland and Solna, Sweden. Dynavax will supply its adjuvant for this agreement. Valenva has a marketing 2D Valneva would be a worthy program to include in our collective armamentarium because of how quickly billions of doses could be generated. Colorado State already has data demonstrating can be boosted with other vaccines. Ideally, companies with such to compete for a share. This would require developing a flu and COVID antigen on the same platform throughout a vaccinated population (i.e., not providing herd immunity) and universal vaccination would However, it does not have to be that way. Vaccination courses can include one type of priming dose and distribution agreement for Seqirus’ quadrivalent seasonal influenza vaccines in Austria. This prior relationship provides possible access to MF59 and discussions are ongoing. US/EU program would likely neutralizing titers in hamsters and will soon have data from challenge studies. potentially complementary vaccines would conduct animal studies (e.g., adenoviral vector) and another type of booster (e.g., protein subunit or MVA vector). Also, prime MEASURES be needed to serve their (e.g., all mRNA or, if protein based, using the same adjuvant) to create a vaccine that is well tolerated on be required to protect everyone from COVID-19. SOCIAL DISTANCING Colorado State University 2D Colorado State University and clinical trials together to look for such synergies. For example, and booster doses do not always require the same amount of vaccine. For example, Oxford is testing own markets in 2021/2022 if JNJ has made 200M doses of their Ad26 vaccine by the time it first dose and redosable (meaning it does not use a viral vector). delay outbreak peak Social distancing means staying a safe distance away from other people (CDC recommends minimum of 6 feet, 10 better) to mitigate community spread of SARS-CoV-2. Academic initiative led by the Infectious Disease Research Center. They will not be in the clinic for another year, but they offer access to relevant animal models to assess key vaccine enhancement safety concerns. is approved and Novavax has 100M doses of their nanoparticle a booster dose that is half of the prime dose. This helps to increase the total number of vaccine doses While there are no approved medications to prevent the spread of COVID-19, They have $3.1M in NIH grant funding but are not partnered/funded for scaled-up manufacturing. Ideally, you should stay home as much as possible. Social distancing slows the spread of disease (ie. “flattening the curve” of infections) by reducing the chance that an infected person infects someone vaccine, each of which needs to be given twice, then it might available and to provide doses as quickly as possible. turn out that the best use of their vaccines would be to give one THE FOLLOWING BASIC PROTECTIVE MEASURES else before recovering, reducing the so-called “R0” (pronounced “R-not”) value, ideally to below 1 so that each person infects less than 1 person and the infection burns itself out. Some small countries like Altimmune (AdCOVID)/Vigene Biosciences/UAB dose of the JNJ vaccine followed by half of a dose of the Novavax New Zealand have employed social distancing and testing (to know where to isolate people even more carefully) so successfully that they have stamped out their infections, aka “crushing the curve”. While Altimmune (AdCOVID)/Vigene Biosciences/UAB one. In other words, the 2 vaccines working together could result CAN HELP PREVENT INFECTION: Ph1 set to start 4Q20 with topline safety and serology data expected 2021. The company is scaling up manufacturing to reach 100M doses annually with Vigene Biosciences and Lonza. They recently presented 1D INTRANASAL Intranasal in vaccination courses for 200M people total instead of 150M if it’s now too late to stamp out SARS-CoV-2 in large countries and the world, social distancing helps ensure that we avoid a rapid increase in cases that would overwhelm our healthcare system. preclinical data at the World Vaccine Conference, demonstrating the generation of neutralizing titers in mice. reduction in peak *Phase 1 start 4Q20 Adenovirus (Ad) vector administered separately (100M people receivingJNJ vaccine and CASES 50M people receiving Novavax vaccine. WITHOUT of outbreak You can practice social distancing by avoiding large gatherings and minimizing time spent in public settings. We have a collective responsibility to participate in social Vaxart/Emergent Biosolutions/Kindred Biosciences Some oral/intranasal programs currently in development are based on the Ad5 vector, and early clinical data suggest that unliked injected vaccines, the mucosal route of administration can PROTECTIVE Vaxart announced FDA clearance of their COVID-19 vaccine candidate IND in September 2020 and have released hamster challenge study data demonstrating no systemic weight loss, an indicator of protection Vaxart/Emergent Biosolutions/ bypass pre-existing antibodies to this common vector type, which would otherwise make the vaccine less effective. Whether or not this platform is truly redoseable will be borne out by MEASURE distancing as much as possible. The extent of social distancing will vary for each person and household - for example, a healthcare worker won’t be able to proactively isolate themself at home 1D Oral/intranasal vaccines: easier to administer but associated with limitations that have so far against COVID-19 in this animal model. They have a development agreement with Emergent BioSolutions to prepare bulk cBMP oral COVID-19 vaccine. Vaxart has also contracted KindredBio to manufacture its lead Kindred Biosciences ORAL these programs. CLEANING prevented major vaccine funders from placing much stock in these approaches SOCIAL WEARING the way someone who can easily work remotely via their laptop can. But all of us can be aware and do what we can to reduce person-to-person transmission. In households at risk of infection because vaccine candidate at a large scale. Selected by Operation Warp Speed to participate in a NHP challenge study Oral YOUR HANDS • Theoretically, oral and intranasal vaccines would train the immune system to generate the special IgA types of antibodies that protect our mucus membranes from DISTANCING A FACE MASK CASES NUMBER OF DAILY someone is an essential worker, that person must take precautions such as wearing a mask around others, stripping off HEALTH CARE SYSTEM CAPACITY Codagenix/Serum Institute of India infection. FREQUENTLY potentially contaminated clothing ideally before entering the home (being mindful not to contaminate themselves and WEEKLY EXCESS DEATH RATE FROM SEPTEMBER 8, 1918 - FEBRUARY 22, 1919 1D Codagenix/Serum Institute of India* ST. LOUIS, MO Currently running preclinical challenge experiments and could be in the clinic by late summer 2020. Their partnership with the Serum Institute of India provides manufacturing capacity on the scale of hundreds of • In addition, oral and intranasal vaccines for other viruses, including the approved intranasal flu vaccine Flumist, tend not to work well, either because they induce CASES WITH millions of doses. CLEANING YOUR HANDS surfaces in the home), and clean themselves and any surfaces they touch (car, home) thoroughly. Even then, they should *Phase 1 likely start by July 2020 Live-attenuated virus: likely only need 1 dose so immunity could kick in more quickly, but could face only local immunity in the nasal passages or because the vaccine is just not very strong. Oral is thought to be much better than a non-replicating Please visit: SOCIAL DISTANCING can prevent WEARING A FACE MASK, even PROTECTIVE MEASURE 70 Viral deoptimization platform addresses both safety and scalability additional scrutiny from FDA and other regulators since live virus is replicating in people receiving it vector but it does not induce lasting immunity. SARS-COV-2 consider wearing a mask in the home and sleeping in a separate room to reduce the chance of spreading the virus to Meissa Vaccines (MV-014-210) the spread of COVID-19 by reducing FREQUENTLY, avoiding touching a less advanced one, can help Weekly excess death rate • Still, these programs are worth watching since they could offer a means of vaccination without injections. TIME SINCE FIRST CASE family members. Social distancing can be difficult and ultimately carries risk of its own adverse events, such as social 60 Meissa’s COVID-19 vaccine candidate, MV-014-210, was derived by modifying the company’s RSV LAV candidate, MV-012-968, and replacing the RSV glycoproteins with a functioning SARS-CoV-2 Spike protein. This 1D Meissa Vaccines (MV-014-210) • This approach introduces a live and replicating (but weakened) virus that gives the • Likely not suitable for immunocompromised or otherwise high-risk patients (as they can the number of people an infected your face, and disinfecting “high reduce both the risk of infection and 2 x baseline mortality platform offers potential advantages for global deployment and clinical trials are expected to begin early 2021. Intranasal immune system a more realistic sense of what to expect from the real thing and may also potentially cause disease). isolation and depression, which must be weighed against the risks of COVID-19 for each person and those around them. First pneumonia and influenza case 1D Indian Immunologicals/Griffith University generate a strong T-cell response (though the benefit of this response is not yet clear). Alternative routes of administration to improve upon standard injection person comes into contact with. touch” surfaces can reduce infection potentially the severity of illness since 50 Indial Immunologicals/Griffith University • Technology is potentially rapidly scalable but, because the virus is replicating, the FDA These approaches are easier to administer but have been logistically challenging to develop and bring to market. Should the long-term cost-benefit of *Viral deoptimization platform • This strategy is used for vaccination against measles, mumps, and rubella (MMR), and other regulators might be more cautious and therefore it could come to market after following contact with an infected in some cases the amount of virus No clear development timeline. IIL and Griffith have collaborated before to develop a . IIL has the manufacturing capacity to produce hundreds of millions of doses/year. these next-gen vaccines prove superior to traditional injectables, they could replace our current mode of seasonal immunizations. REPLICATION AND TRANSMISSION smallpox, chickenpox, and yellow fever. subunit, mRNA, and vectorized vaccines (e.g., from JNJ). SEE "SOCIAL DISTANCING" surface. that starts an infection correlates 40 Vaxess Technologies/Medigen FOR MORE DETAIL. with the severity of disease (more RISK OF OPENING TOO EARLY MIMIX platform allows for combination of multiple antigens (COVID and Flu) for the development of a pentavalent, single dose, self-applied vaccine. Vaxess recently announced a partnership with Medigen to use The virus that causes COVID-19 is called SARS-CoV-2. We don’t currently know how long social distancing will be required before it is considered “safe” to re-integrate. Ultimately, some degree of social distancing will be 30 their COVID-19 vaccine candidate for this combination patch. Their microneedle technology is silk-based and the antigen is room temperature stable. It is unlikely that this program will contribute to the first wave of SARS stands for “severe acute respiratory syndrome,” which can virus at the time of initial infection COVID vaccines. A more likely market is for future seasonal vaccine cycles. 1D Vaxess Technologies/Medigen important until there’s been widespread vaccination. What is clear is that social distancing combined with widespread, rapid testing and early and aggressive social isolation of infected people Microneedle patch involve shortness of breath, pneumonia and/or respiratory distress, and the virus is so named because it closely resembles the gives the virus a head start over the 20 Verndari Inc as well as those they came in contact with (contact tracing) can be effective. The more piecemeal or inconsistent the measures, the less effective it will be. Because contact tracing involves a lot of manual 1D Verndari Inc Using a microneedle patch to intradermally deliver vaccines is dose-sparing and more convenient to administer. However, there are no microneedle patch vaccines virus (SARS-CoV) that caused the SARS outbreak of 2002/2003. Both viruses come from the coronavirus (CoV) family. immune system). To help prevent the RATE DEATH EXCESS WEEKLY Early stage company spun out of UC Davis developing VaxiPatch (protein subunit + adjuvant + medical grade stainless steel patch) as a single dose, room temperature stable, self-administrable vaccine. Recently currently on the market despite these potential benefits, because significant challenges exist around the cost and QC to scale up manufacturing for large-scale effort (an army of people chasing down each infection), it’s easier to implement contact tracing if a country has first reduced the number of infections dramatically with widespread social distancing. When 10 announced a collaboration with NIAID to develop a intranasal Ad4 prime + VaxiPatch boost COVID-19 vaccine solution (would require two separate regulatory paths). 1D University of Pittsburgh (PittCoVacc) supply. spread of COVID-19, wear a mask in SARS-CoV-2 is enclosed by a protective lipid (fatty) membrane containing proteins that give the virus The virus may be able to there are still thousands of new cases every day, it’s not feasible to switch from social distancing to contact tracing and selective isolation as a means of keeping the curve flat.. University of Pittsburgh (PittCoVacc) public settings (e.g., grocery stores or POPULATION PER 100,000 NUMBER OF DEATHS 0 Cellulose-based microneedle delivery platform that plans to enter the clinic in 3Q20 on the back of serological studies in mice. Does not appear scalable at the moment. structure and allow for infection.The membrane is a weak point that makes it easy to kill with soap, bleach, SURVIVE FOR Ad26 vector pharmacies). When considering when to reopen the country and ease social distancing mandates, we should be aware of potentially eliciting a second wave of cases if doing so SEP 8 OCT 6 NOV 3 DEC 1 JAN 5 FEB 2 FEB 23 JNJ is manufacturing at large scale and said that production will be running at 600M-900M or alcohol. UP TO 72 HOURS prematurely. The example to the right, straight out of the history books, describes what happened during the 1918 influenza pandemic in St. Louis. Once the death rate due to the virus began to trend 1918 1919 JNJ/Emergent Biosolutions + BARDA Inside the virus there is a single strand of ribonucleic acid, or RNA, that contains the virus’s genetic information. The doses/year by 1Q21, scaling to 1B/year and reaching >1B/year by end of 2021; we estimate on surfaces such as plastic and SEE "MASKS" FOR MORE DETAIL SCHOOL CLOSURE While their lead candidate failed to provide sterilizing immunity in an NHP model, it did provide protection from severe disease. Ph1/2 trial started July 2020, the Ph2 portion initiated the first week of September then that JNJ might be able to launch their vaccine around March/April 2021 with 150-300M down, schools were reopened and public gathering bans were lifted. However these orders resulted in a second, much larger wave of deaths. Had St. Louis continued their strict social distancing and coat of the virus consists of several structural proteins, including the spike protein (S), which allows the virus to attach to host cells stainless steel. PUBLIC GATHERING BAN in Europe and the Ph3 started in late September after positive Ph1/2a interim results and is planned to enroll up to 60K participants across 3 continents. BARDA has committed $454M to support the ongoing Ph3 courses, depending on whether they need to give 1 or 2 doses. If the US were to secure a 1D JNJ/Emergent Biosolutions + BARDA WARP school closures, they would likely have avoided the second wave of deaths. BUSINESS HOURS RESTRICTED, trial. This trial has resumed after being put on pause due to the unexpected illness in one participant, although details from this case have not been disclosed. A concurrent Ph3 trial of a 2-dose regimen started in large fraction of that supply, which BARDA has likely negotiated, that could start to open and gives the virus its distinctive shape. STREETCARS’ CAPACITY LIMITED LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS November. Ad26 is less common than Ad5 so risk of pre-existing immunity is lower. They have a large manufacturing capacity and are targeting 1B doses on a not-for-profit basis (with 100M doses pledged to the US up the economy rapidly since it would be enough to vaccinate everyone in America with TO HELP PREVENT and 200M pledged to the EU with an option for 200M additional). Recently signed a $480M, five-year manufacturing agreement with Emergent Biosolutions to manufacture its COVID-19 vaccine. risk factors for COVID-19. However, keep in mind that the combined US and EU population SARS-CoV-2 enters host cells by binding a specifc protein, called “ACE2,” on the cell surface; once inside, the is close to 1.1B people, the world has 8B people, and big pharmaceutical companies are INFECTIONS: global. virus hijacks the host’s cellular machinery to replicate and assemble more viral particles.After the virus binds

Astrazeneca/Vaccitech/University of Oxford (AZD1222) + BARDA the cell, enzymes produced by the host (TMPRSS2) activate the viral spike protein (S), which allows the virus to enter the cell (see ChAdOx1 vector: 1,2 Ph3 clinical trials for this vaccine candidate resumed everywhere after a clinical hold was triggered by a possible case of transverse myelitis. Although AstraZeneca has not released any medical details about this Program will have clinical data first (by June 2020) but still needs to be scaled up, so large- schematic below) . Once inside the cell, the virus rapidly makes more copies of its genetic material (RNA) as well as the proteins situation, they do report that an independent review deemed the safety signal was not likely associated to the vaccine itself, although there is insufficient evidence to say for certain. Recent topline data from this Ph3 1 2 3 AstraZeneca/Vaccitech/University of Oxford scale manufacturing is unlikely before 2H21 (pending massive investment that AstraZeneca efficacy trial demonstrated that Astrazeneca’s vaccine was 70% effective on average, 90% in a subpopulation of volunteers (n = 2,741) who received a half dose followed by the full dose of the vaccine 1 month 1D needed to create new viral particles. The RNA is packed into new particles, which are released into the body to infect surrounding later and 62% effective (n = 8,895) in the population who received two full doses. It is not immediately clear why the lower dose regimen generated superior vaccine efficacy, but it is unsurprising that these data on + CEPI & BARDA (AZD1222) WARP will presumably provide). A recent NHP challenge experiment using this vaccine candidate WASH AVOID TOUCHING DISINFECT average appear inferior to mRNA vaccines based on the Ph1 immunogenicity profiles of these programs. AstraZeneca’s vaccine has a logistical advantage (can be shipped at stored at 2-8oC) and the company has LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS demonstrated that while all 6 vaccinated monkeys were protected from severe disease, cells. signed agreements to provide hundreds of millions of doses to be delivered starting YE20 (100M UK, 300M US, 400M Serum Institute of India to provide for poorer countries, 300M CEPI/GAVI, and 300M EU). neutralizing antibody levels were low and this did not prevent viral replication in the nose YOUR HANDS YOUR FACE SURFACES They also reached a licensing deal with Chinese firm BioKangtai for 200M doses annually. Recognized by Operation Warp Speed (OWS) as one of five vaccine candidates most likely to work. (upper respiratory tract). It is possible that other vaccine candidates will elicit higher titers Vectors seemingly unaffected by pre- of neutralizing antibodies and shut down nasal replication, which would make them better existing immunity: these are more SARS-CoV-2 is thought to frst infect the cells of the nose and throat, from where it can spread, but it does candidates for protection via herd immunity. likely to be effective than Ad5 Adenovirus (Ad) vector (mostly injected) not cause signifcant symptoms until it progresses into the lung. During the first stage of infection patients are ReiThera/Leukocare/Univercells DISINFECT SURFACES THAT • These viruses already regularly cause infections in people (e.g., common cold) and therefore many people already have antibodies against REGULARLY AND AVOID TOUCHING YOUR FACE European Consortium developing a vaccine candidate that entered the clinic August 2020 in Italy. The consortium will start manufacturing and stockpiling the vaccine in parallel with clinical development, with 6M 1D ReiThera/Leukocare/Univercells adenoviruses, though some “strains” or “serotypes” of adenovirus are more common (e.g., Ad5) than others (e.g., Ad26, ChAd). A key distinction Vectorized vaccines: more likely solution for more likely to spread the virus to others by coughing or breathing, even before they start to show symptoms (referred to as ARE COMMONLY TOUCHED doses available early 2021 for healthcare and high-risk individuals. Simian adenovirus vector between adenoviral vector vaccines is the impact that pre-existing antibodies have on their ability to function as vaccines. While Ad5 vectors THOROUGHLY WASH YOUR to prevent accidental transfer of the the masses since easier to scale and potentially “asymptomatic”) or while their symptoms are too mild to distinguish from a harmless cold. Once the virus makes it way into the (phones, remote controls, counters, have been shown to be inhibited by pre-existing antibodies against them, Ad26 and ChAd vectors are not significantly impacted when a person require only a single dose HANDS virus to your eyes, nose or mouth. has antibodies to the vector. Therefore, vaccines based on Ad5 might require higher doses to overcome those antibodies, which might make it with soap and water • These are non-replicating, non-integrating vectors (deliver vaccine code but do lungs, more notable symptoms (coughing, fever, and/or shortness of breath) start to become more prevalent. SARS-CoV-2 also tabletops, doorknobs, etc.) ImmunityBio/NantKwest (Ad5COVID-S/N) harder to get to large scale production of vaccine doses. and/or clean your hands with not copy themselves the way a real virus would and don’t alter a cell’s DNA). uses additional mechanisms to slow down the response of the immune system, meaning that the infection can linger for longer and with household cleaners such First dual antigen (both spike and nucleocapsid proteins) vectorized vaccine candidate. They launched a US Ph1 trial in October and plan to have capacity for 100 million doses of vaccine by YE20. There were no 1D ImmunityBio/NantKwest (Ad5COVID-S/N) • Making sure a vaccine works at low doses is critical to stretching manufacturing capacity to generate as many effective vaccinations as possible. an alcohol-based hand sanitizer • If only 1 dose is required then immunity would kick in faster (likely within 2 as diluted bleach solution (1/3 SAEs observed during an initial safety review of the low-dose Ph1 cohorts. Second generation hAd5 Vector We do not yet know what doses will be required of these vaccines, but doses in the 1010-1011 range are commonly tested. Nor do we know the host can infect more people. In contrast, SARS-CoV and MERS-CoV primarily and quickly infect lung cells, which are deeper in (must be >60% ethanol or >70% whether these vaccines will require giving 1 or 2 doses to achieve high levels of neutralizing antibodies to SARS-CoV-2. Finding this out will be weeks of ) than if protection required 2 doses spaced 28 days Programs that cannot be re-dosed because initial vaccination elicits apart (immunity would likely kick in within 6 weeks of the first shot). cup bleach per gallon of water), CanSino Biologics (Ad5-nCoV) critical to knowing how many doses will be manufactured and how quickly. However, JNJ has committed to generating 1B doses of vaccine immunity against the viral vector itself the respiratory tract and cause an earlier onset of serious symptoms, so patients can be identified and quarantined sooner before isopropanol) to kill any virus that TYPES OF MASKS AND WHEN TO USE THEM in 2021, knowing that they might have to give higher doses. Therefore, if it turns out that their vaccine only needs to be given once and at low alcohol solutions (>60% ethanol Publication of Ph1 trial results demonstrated that ~50% of participants have pre-existing immunity to Ad5, which greatly impedes immunogenicity and makes this vaccine candidate less relevant for the broader • Early clinical immunogenicity data from candidates have may be on your hands. There are several different face masks that can help prevent transmission of SARS-CoV-2: doses to achieve good protection, then it would mean that JNJ’s manufacturing capacity will stretch a lot further than their base case plans. population. Low levels of neutralizing antibodies were reproduced in their expanded Ph2 cohort, signaling that this vaccine may not provide strong protection. The company started a Ph3 trial in Mexico in November been underwhelming and generated low neutralizing antibody (nAb) titers, they spread the virus, making it easier to stamp out the original SARS and MERS cases before they triggered a pandemic. or >70% isopropanol), or other and plans to soon expand in Russia, Pakistan, Brazil, and Chile. China has approved this vaccine for military use and while current in-house manufacturing capacity sits at 80M doses annually, a new factory under • Interestingly, people may develop some immunity to the adenovirus vector after the first dose, which one would think would require higher sometimes even less than human convalescent sera controls (see data tables EPA-recommended household construction in China will allow the production of 100-200M doses/year starting 1H21. Cansino has a 35M dose advance purchase agreement with Mexico. In August the National Research Council of Canada subsequent doses of the same vector if/when people need a booster shot. However, booster shots of Ad26 and ChAdOx vectors appear to still on the map). While it is still possible that these vaccine candidates will provide (https://www.epa.gov/pesticide- SURGICAL MASKS are loose-ftting masks that protect the wearer from large droplets that could contain viral announced that collaboration with CanSino ended upon delays in vaccine shipments. At the same time, CanSino has entered talks with several countries to get emergency use authorization for its COVID-19 1D CanSino Biologics (Ad5-nCoV) work. In one of its clinical trial arms, Oxford’s ChAdOx1 booster dose is half of its prime dose, suggesting that they are not worried about the some level of protection against COVID-19 (perhaps by preventing severe disinfectants Wearing a face mask, even a less advanced one, can help reduce both the risk of candidate. Concurrently, they are initiating a Ph1 trial of a two-dose regimen for this vaccine after concerns were raised by the scientific community about the limited efficacy of this vaccine. WWW.RACAP.COM/COVID-19 registration/list-n-disinfectants-use-against-sars-cov-2) LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS prime dose driving neutralization of the booster dose. However, should the prime dose interfere with the effectiveness of the booster, then one disease) they are unlikely to provide sterilizing immunity, as demonstrated by particles; their main role is to prevent contamination of the surrounding area when a person coughs, sneezes, non-human primate challenge experiments. infection and the severity of illness. While ideally masks would protect us from infection, the Gamaleya Research Institute could use a different vaccine for the booster (e.g., prime with Ad26 and boost with ChAdOx1 or even an entirely different modality such as mRNA or even just talks. or a nanoparticle). This could make manufacturing capacity stretch to help more patients. BARDA and CEPI are best positioned to encourage Healthy people can help reduce their exposure to SARS-CoV-2 by wearing a surgical mask, particularly if they Gamaleya started Ph1 trials 2Q20 for their adenovirus based vaccine (now called Sputnik V) and applied for conditional registration on August 12th, before any efficacy data was presented. Based on Ph1 1D Gamaleya Research Institute reality is that all but the most advanced masks let some droplets through (or around edges). However, by immunogenicity data, neutralizing antibody titers are similar to other adenovirus vaccines. However, a global group of scientists have called into question the reliability of these data after highly unlikely data patterns such collaborative vaccine development among the companies they have funded. are participating in activities that increase their risk of infection (e.g., caring for an infected person, visiting a crowded area, etc). 1D Greffex reducing the number of droplets, masks can also reduce the amount of virus that someone is exposed were identified throughout the publication. Russia recently announced that this vaccine has achieved 92% vaccine efficacy in a Ph3 trial on the basis of 20 COVID cases and has submitted a certification request to the Less efficient due to pre-existing neutralizing antibodies: may not work as well as other ad vectors, WHO. While Russia expects between 2 and 10 million doses of this vaccine to be produced by the end of the year, manufacturing projections for 2021 are premature at this time and Russia is in early negotiations to, which can reduce the severity of the resultant disease if they do become infected. The more virus 1D with other countries to license the use of this vaccine.. Memgen (MemVax) which will make it harder to manufacture as many vaccine courses 1 Spike protein on the virion binds to ACE2, a cell-surface someone is infected with, the more of a head start the virus has on their immune system. So wearing Greffex protein. TMPRSS2, an enzyme, helps the virion enter N95 RESPIRATORS are tight-ftting protective masks that flter out ≥ 95% of very small (0.3 micron) particles masks may help reduce the severity of disease even if people still get infected. Underfunded small company, not clearly differentiated, and unlikely to be part of large-scale supply of vaccines. from the air, which includes bacteria and viruses, and therefore protect the wearer by reducing inhalation of Memgen (MemVax) 2 The virion releases its RNA In addition to the the measures listed above, viral particles. These specialized masks are in short supply and should currently be worn only by healthcare personnel due to their FOR A VISUALIZATION OF HOW DROPLETS SPREAD BETWEEN PEOPLE, SEE company leveraging their MEM40 (CD40L transgene) tech as an adjuvant together with their Ad5 COVID vaccine candidate. Preclinical development is underway with partners. They plan to be in the THE FOLLOWING CAN HELP REDUCE THE SPREAD OF DISEASE IF YOU ARE SICK OR clinic 2H20. Spike protein (S) increased risk of exposure. or search online for “COVID microdroplets video”. 3 Some RNA is translated into proteins by the cell’s machinery THINK YOU MAY BE INFECTED: Envelope protein (E) Production of N95 and surgical face masks has greatly increased and availability for German Center for Infection Research (DZIF) 4 Some of these proteins form a replication complex with the This program has entered Ph1 clinical testing in Germany, which is the third COVID-19 vaccine trial to launch in that country after BioNTech and CureVac. HOMEMADE CLOTH MASKS are a surrogate for surgical masks (which are still in short supply and may need both healthcare professionals and the general public should increase substantially in 1D German Center for Infection Research (DZIF) viral RNA genome to make more copies of the genome, to be prioritized for healthcare workers) if they ft snugly over the nose and mouth, allow for unrestricted Geovax/BravoVax MVA (vaccinia) vector (injected) RNA the coming months. 3M, Honeywell, and Kimberly-Clark are the major US manufacturers of face 1D Geovax/BravoVax a process that introduces some mutations. breathing, and can be secured with ties or ear loops. Vaccine developer BravoVax in Wuhan will provide testing and manufacturing support as well as interactions with Chinese authorities to enable GeoVax to pursue regulatory paths in both China and the US. GeoVax MVA is believed to produce a weaker immune response than adenovirus and therefore seems unlikely to be effective against SARS-CoV-2. The CDC recommends the use of a facemask, including homemade masks. 3M in particular is massively expanding its production and aims to make 1B+ face masks by has secured a patent license agreement with the NIH for a stabilized spike protein. Although the virus has proof-reading cloth masks, to help prevent the spread of SARS-CoV-2 when people must go into public settings (e.g., grocery stores or Nucleocapsid (N) STAY HOME PRACTICE RESPIRATORY YE20. Massachusetts Eye and Ear/ pharmacies). 1D Massachusetts Eye and Ear/Novartis proteins that try to correct the IF YOU FEEL UNWELL HYGIENE The AAVCOVID program is run by a consortium led by MEE, MGH, Penn, and Mass General Brigham and in a manufacturing collaboration with AveXis/Novartis AAV vector encoding either full-length Spike or RBD region If it proves highly potent, then this vector may have the manufacturing scale (thanks to many existing AAV gene therapy programs) to generate a large supply of doses. It likely will not have clinical data until the end of 2020 at the earliest. mistakes, some slip through Viral envelope STAY HOME IF YOU FEEL UNWELL TO PREVENT PRACTICE RESPIRATORY HYGIENE TO HELP Bharat Biotech International/Thomas Jefferson University 5 Proteins and RNA are 1D Bharat Biotech International/Thomas Jefferson University SPREAD TO OTHERS AND CONSULT WITH YOUR MINIMIZE INFECTION OF OTHERS. WEAR A This program initiated Ph2 testing September 2020 and is the first domestic vaccine in India to enter the clinic; Bharat Biotech can produce hundreds of millions of doses/year. Rabies vector (injected) This is a novel, unvalidated platform using a recombinant, deactivated, non-replicating rabies vector. While this vaccine candidate could provide immunity to both Rabies and SARS-CoV-2, it has no prior clinical experience and is thus considered riskier. assembled into a new Membrane protein (M) DOCTOR OR HEALTHCARE PROVIDER, IF NEEDED. FACE MASK WHEN YOU ARE AROUND OTHER Moderna/Lonza (mRNA-1273) + CEPI and BARDA virion and People who are mildly ill with COVID-19 are able to recover PEOPLE AND COVER YOUR MOUTH AND NOSE Moderna released topline data from their Ph3 efficacy trial and reported 94.5% vaccine efficacy 14 days after the second dose (in 95 COVID cases, with 11 severe cases in the placebo group, 15 older adults, and at home. Do not leave, except to get medical care. Call WITH YOUR BENT ELBOW OR TISSUE WHEN YOU 20 participants from diverse communities). At this time, these data look equivalent to the efficacy generated by Pfizer/BioNtech’s vaccine candidate (95% vaccine efficacy 7 days after the second dose) and we 6 released Moderna Therapeutics/Lonza CEPI & BARDA your doctor’s office in advance of coming in and tell them COUGH OR SNEEZE (EVEN IF WEARING A MASK). await further data readouts to assess durability of protection, protection after the first or second dose, and granular safety/efficacy breakdown between different subgroups. The biggest differentiating factor here is 2D + COVID-19 VACCINES: Moderna’s cold chain storage advantage, as their vaccine can be stored at -20C, while the Pfizer/Biontech candidate requires -70C storage. Moderna has guided to supplying 500M - 1B doses annually (20M by (mRNA-1273) WARP Testing 100-μg dose that would generate 500M-1B you may have COVID-19. This will help everyone in the SARS-CoV-2 spreads through droplets in the air. You can YE20) and has committed 100M to the US (with the option of an additional 400M), 80M to the EU, and 50M to Japan. They were awarded $56M by DARPA to develop a small-scale, mobile platform to enable fast, LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS in-field automated manufacturing and deployment and are recognized by Operation Warp Speed (OWS) as one of five vaccine candidates most likely to work. Moderna has initiated rolling submissions with the UK doses in 2021 office protect themselves and other patients. Listen to the reduce contamination of surfaces and prevent disease and Canada and intends to file for EUA with the FDA after completing their final analysis (151 COVID cases, and a median follow-up of more than 2 months) instructions of your healthcare provider. spread by trapping these virus-containing droplets in a well- * fitting mask. (DATA AS OF NOVEMBER 25) BioNTech/Pfzer (BNT162) 1 SARS-CoV-2 MILESTONES Pfizer/BioNtech completed the final efficacy analysis of their Ph3 trial and demonstrated that their vaccine is 95% efficacious 7 days after the second dose (in 170 COVID cases, 9 severe cases in the placebo group and 1 in the vaccine arm). These results provide validation for vaccines targeting the Spike protein and greatly surpass the benchmark set by the FDA (50% vaccine efficacy). Pfizer/BioNtech are the first cel vaccine developer to submit a EUA request to the FDA, which could be granted as early as 3-4 weeks from submission. The FDA will host an Adcom early in December to assess these data for approval. Pfizer/ l mem New BioNtech are guiding to manufacturing 50M doses by YE20, scaling up to 2B doses in 2021 with the recent acquisition of a GMP facility in Germany and manufacturing supply agreements with the UK (60M), the US bran 6 (100M-600M), the EU (200M), and Japan (120M). Recognized by Operation Warp Speed (OWS) as one of five vaccine candidates most likely to work and awarded 375M euros by the German Federal Ministry e SARS-CoV-2 NUMBER OF VACCINES COURSES/QUARTER 2020 2021 2022 of Education and Research to advance vaccine development. The company initiated rolling submissions for BNT162b2 for both the EMA and Canada in October, with formal submissions to follow demonstration of 2D BioNTech/Pfizer (BNT162) Company (Drug) PR Geography vaccine efficacy and safety from Ph3 analysis. 4Q20 1Q21 2Q21 3Q21 4Q21 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS 2 CureVac SS *Phase 1 started April 2Q20 PR NANO- This program is in Ph1 testing in Germany and Belgium and initiated a Ph2a trial September 2020 in Panama and Peru. Based on interim immunogenicity data generated from their Ph1 trial, the 12-ug dose of their M RNA replication PARTICLE WARP 2D CureVac + CEPI Testing doses ranging from 1-100μg; if low doses work E2 T 4 vaccine candidate (which they intend to take into Ph2/3 possibly YE20) generates neutralizing antibodies equivalent to a panel of human convalescent control sera (1:113, microneutrlaization assay). The company Major players (Spike antigen only) C assuming 2 doses Novavax/Emergent Biosolutions (NVX-CoV2373) 250 275 350 375 1/21 3 1Q21 announced that they are in advanced talks with the EU to supply 225M doses of their vaccine candidate MY21, with an option for 180M more. Recently awarded 252M euros by the German Federal Ministry of LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS then could potentially generate 1B doses by early A until data suggests Education and Research to advance vaccine development. 2021. otherwise + CEPI & BARDA 2D Translate Bio/Sanofi 2 5 ExpreS2ion Biotechnology/AdaptVac/ Translate Bio/Sanof LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS 2Q22 Bavarian Nordic 1 Sanofi recently doubled down on a $425M commitment to fund Translate Bio’s mRNA vaccine, with a trial to start November 2020. The company recently released preclinical NHP data demonstrating peak neutralizing antibody titers of 1,877, which places this vaccine in the middle of the pack for RNA candidates, between Pfizer/BioNTech (GMT 962) and Moderna (GMT 3481) which both used similar assays to Sanofi COVID-19: (50% inhibition live virus assay) and observed similar neutralizing antibody levels in human convalescent serum (GMT 41-94). Translate Bio has established 100-g single-batch production with its clinical-stage mRNA VLP Medicago 25* 25* 1 3 YE21 therapeutics platform. Build-out of dedicated manufacturing space is underway through a contract manufacturing partner to accommodate at least two 250-gram batches/month. Depending on the final human dose, they’re guiding to 90-360M by 1H21. Saiba/AGC Biologics 10 1 YE20 Ntx (multivalent mRNA) to view the latest version of the map Could help others scale-up their mRNA programs with 2D VACCINES WARP mRNA encoding full-length Spike combined with additional mRNA encoding other viral antigens. Although behind other programs, this is the only other program in development besides inactivated and attenuated Ntx (multivalent mRNA) more efficient mRNA synthesis. viral proteins 50* 100 150 1 2Q21 viral vaccines to include more than just Spike protein. 3 Sanofi/GSK BARDA However, time to integrate this technology to make a difference for 2021 production is Standard modifed mRNA: can be RNA + running short. engineered to stimulate a stronger Vaccines are a type of medication used to prevent an infection in healthy individuals by teaching the immune system to recognize the Clover Biopharmaceuticals MY21 China CDC/Tongji University/Stemirna Therapeutics immune response infectious agent (e.g., bacteria or virus) and destroy it. Vaccines can stimulate the immune system and protect against disease-causing pathogens but + CEPI 1 Chinese academic/small biotech initiative without clear scale-up and will likely serve the domestic Chinese market in 2021. generally do not cause infection themselves because they use weakened or killed pathogens or only fragments of the pathogens. Vaccines have successfully reduced University of Queensland/CSL Behring/Seqirus Fudan University/Shanghai JiaoTong University/RNACure Biopharm 1 YE21 2D China CDC/Tongji University/Stemirna Therapeutics the impact of serious diseases such as influenza, chickenpox, and Hepatitis A and B. Traditional vaccines consist of 1) an “antigen”, which is a protein or other piece + CEPI 25 25 Chinese academic/small biotech initiative without clear timelines or scale-up and will likely serve the domestic Chinese market in 2021. *Phase 1 start April 2020 of a pathogen or even the whole pathogen (inactivated or weakened so that it is less likely to cause disease) together with 2) an immune stimulant called an adjuvant. Fudan University/ Shanghai JiaoTong University/ People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech 2D TRANSMISSION: Together, they provoke an immune response in healthy individuals. Newer vaccine platforms deliver the genetic code for the antigen using a harmless viral vector or SUBUNIT MIGAL Galilee Research Institute/MigVax 1 YE21 RNACure Biopharma encoded in genetic material (DNA or mRNA), which make a person’s own cells produce the antigen. These vaccines can be injected into the muscle, subcutaneously, assuming 2 doses The first mRNA vaccine candidate to enter clinical testing in China (supported by the highest level research institute of the People’s Liberation Army). This program will serve the domestic Chinese market. until data suggests People’s Liberation Army (PLA) Academy of Military SARS-CoV-2 is spread from person to person mainly through respiratory droplets that are created when a or intradermally or more rarely taken orally or intranasally. Vaccines typically are given as 2 doses, the first to “prime” the immune system into making some antibodies otherwise IMV YE21 BioCad 2D (DPX-COVID) 1 Sciences/Walvax Biotech and the second, usually 4 weeks later, to “boost” the quantity and quality of the antibodies. Besides prompting the immune system to make antibodies, vaccines Very little publicly available information about this program; no follow-up or guidance on timelines since its initial announcement. person coughs, sneezes, or talks (similar to how influenza spreads). These droplets are thought to travel no more can also, to varying degrees, elicit a T-cell response, which can mobilize these cells to help kill infected cells. All vaccines elicit antibodies whereas only some also YE21 Abnova/PharmaJet 2D BioCad EpiVax/University of Georgia (EPV-CoV19) 1 Small/early players mRNA vaccines: fast to develop and immunogenic. This platform is useful for responding rapidly than six feet, thus this distance is reflected in current social distancing rules, though research shows microdroplets can travel elicit a T-cell response. There are no marketed Unclear clinical development timeline. PharmaJet is providing its needle-free injection technology for Abnova’s mRNA vaccine. Manufacturing based in Taiwan. 2D Abnova/PharmaJet vaccines that only work by eliciting a T-cell to a new pandemic (especially for the next one when there will be larger-scale manufacturing further and therefore 6 feet should be considered a minimum. 10 feet apart is better. Wearing masks in public places can help Medigen/NIAID/Dynavax YE21 eTheRNA INFLUENZA 1 2D eTheRNA capacity from the start). However, mRNA is both antigen and adjuvant and highly reactogenic prevent both the spread of these droplets to others if you are infected and at least partially reduce inhalation of these droplets from response. TriMix mRNA technology is designed to enhance T-cell responses (caTLR4, CD40L, and CD70) to its vaccine candidate. Recently granted 35M euros ($38M) to fund its mRNA platform, including its Covid-19 (painful, hard to tolerate), so not a good ft for creating a pentavalent seasonal booster (i.e., Programs that are too reactogenic (pain, fever, etc) for even just COVID program. They won’t be in the clinic until 2021. 2D University of Tokyo/Daiichi-Sankyo people will learn to really fear their seasonal shot). to be used at even higher doses for an annual pentavalent influenza + Platforms that may be others if you are well. Some vaccines contain adjuvants, Covaxx 1 YE21 University of Tokyo/Daiichi-Sankyo Early Ph1 immunogenicity data from both Moderna and BioNTech/Pfizer demonstrated that this platform is able to generate neutralizing antibody (nAb) titers multiple which are substances that boost the COVID vaccine suitable for contributing to EASY TO DEVELOP NEW STRAINS Early academic program supported by Daiichi Sankyo that won’t reach the clinic until 2Q21. fold greater than their respective human convalescent sera controls (see data tables on the map). While the correlate of protection for nAbs is not yet known, it is immune response against an antigen. 1. The multiple genomic segments of influenza can easily be re-assorted Sinovac Biotech (PiCoVacc) SARS-CoV-2 may also spread by touching an infected surface followed by subsequent contact with the eyes, KNOWN 2. The lack of a proofreading enzyme increases the number of mutations NOVEL 25 25 25 25 1 3 1Q21 better for a vaccine candidate to generate as high a titer as possible. The reactogenicity profile of for mRNA vaccines is even less tolerable than that of Shingrix (one COVID pandemic recovery but Adjuvants are most commonly used in vaccines INFLUENZA INFLUENZA of the most painful adult vaccines on the market), which can partly be attributed to the lipid nanoparticle that is formulated to deliver the mRNA. It is thus unlikely for STRAINS STRAIN BioNTech/Pfzer (BNT162) nose, or mouth. Sinopharm Group/Wuhan Institute of Biological Regular hand washing and disinfection of commonly touched surfaces can help reduce this type of spread. that deliver fragments of protein and thus need this platform to support the addition of four influenza components for use in a flu plus COVID-19 pentavalent vaccine. are very unlikely to be useful Began Ph1/2 trials in Germany at the end of April 2020 and in the US in early May 2020 with small cohorts of patients to identify dose and schedule; will expand to larger cohorts in July 2020. They are testing INACTIVATED 10 50 100 150 200 1 3 YE20 RE-ASSORTED Products/Beijing Institute of Biological Products doses between 1-100 mg and, depending on which doses work, have guided to producing millions of doses by YE20 and hundreds of millions of doses in 2021. Recognized by Operation Warp Speed (OWS) as one an extra “boost” to ensure a strong immune RNA replication + MUTATED assuming 2 doses 2D BioNTech/Pfizer (BNT162) WARP for creating a pentavalent of five vaccine candidates most likely to work. There is no evidence that SARS-CoV-2 can spread through food (different from foodborne viruses like response; they are used less commonly in until data suggests otherwise Bharat Biotech International * * LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS (influenza + COVID) seasonal 50 50 1 3 2H21 Arcturus Therapeutics/Duke University norovirus or hepatitis A) or through mosquitoes (different from mosquito-borne viruses like Zika or West whole virus or vector preparations that elicit

Completed preclinical studies demonstrating that a single 2-μg dose of their LUNAR-COV19 vaccine provided immunity (seroconversion in 100% of animals vs 0% at this dose for standard mRNA). They announced a booster vaccine due to poor a strong immune response on their own. 2D Arcturus/Duke University Self-replicating mRNA: potentially much more potent such that low scale manufacturing might generate more doses; however, self-replicating mRNAs are Nile). Valneva * * Ph1/2 clinical trial to begin 3Q20 in Singapore and topline results from this trial demonstrated that a single dose of their vaccine candidate generates neutralizing antibodies in the same range as human convalescent SARS-CoV-2 causes respiratory symptoms that increase its spread to others, unlike foodborne viruses that cause ce 25 25 1 3Q21 Examples of adjuvant ingredients used in ll LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS tolerability, difficulty redosing, m longer, harder to make, and may not be as inherently immunogenic as modifed mRNA e control (GMT 1:147). Arcturus signed a partnership with Catalent to help them scale up to 100M doses in 2021. Recently signed an agreement with CDMO Recipharm to support manufacturing, but have not m b gastrointestinal symptoms and spread primarily through contact or sharing food or utensils. Furthermore, in contrast to mosquito- US vaccines today include aluminum salts, r a provided additional dosing guidance. and/or complexity (i.e. would n LIVE 2D Imperial College London monophosphoryl lipid A, squalene oil, and e Codagenix/Serum Institute of India 1 2Q21 borne viruses, the spread of SARS-CoV-2 occurs directly from person to person and not through an animal host. ATTENUATED Imperial College London be too little too late for these cytosine phosphoguanine (CpG). A number Secured £22.5 ($28M) in funding from the UK government. The funding will help them move through Ph1 trial, which started in June 2020. Unclear what partnerships they would seek to scale up manufacturing. programs to start creating a of proprietary adjuvants (such as Dynavax’s JNJ/Emergent Biosolutions BARDA SARS-CoV-2 could theoretically be transmitted by blood transfusions, but viral transmission has not been RE-ASSORTMENT & MUTATION WARP + 400 300 300 1 3 2Q21 Inovio/Beijing Advaccine Biotechnology (INO-4800) + CEPI flu vaccine from scratch just CpG 1018 and GSK’s AS03) have been made Announced that they should have 1M doses available by YE20 and that they are working to scale up to hundreds of millions in capacity pending future funding and investment. Recent data from an NHP challenge linked to blood transfusion for SARS-CoV-2, SARS, or MERS. Viral genomic material has been detected in the blood freely available to vaccine developers through WARP Inovio/Beijing Advaccine to combine with their COVID model demonstrated that INO-4800 did not provide complete protection in the lungs or nasal cavity against COVID-19, which is a weak signal moving into clinical trials. From the Ph1 trial, 94% (34/36) volunteers 2D of ~15% of patients hospitalized with COVID-193, but not in patients with milder disease4. For COVID-19, we do not yet know the Coalition for Epidemic Preparedness AstraZeneca/Vaccitech/University of Oxford/ 100 450 400 550 600 1 2/3 4Q20 seroconverted but no additional data have been released. A Ph2/3 trial is expected to start late summer, but has been put on partial hold by the FDA due to additional questions around the CELLECTRA 2000 Biotechnology + CEPI (INO-4800) INTRADERMAL vaccine) Innovations (CEPI) in an effort to support the Serum Institute of India (AZD1222) delivery device. While the Ph2 portion of Inovio’s Ph1/2 has been cleared to start, this program remains on partial hold and Inovio must await FDA partial hold clearance and Ph2 results before initiating the Ph2/3. LIKELY TO BE PART OF THE FIRST WAVE OF VACCINATIONS NO RE-ASSORTMENT & LOW MUTATION RATE BARDA & CEPI Inovio was granted $71M from the DoD to support manufacturing of their intradermal DNA delivery device. Selected by Operation Warp Speed to participate in a NHP challenge study Comparatively major players (more likely to invest in development and delivery meaningful number of whether these patients have infectious viral particles in their blood or only (noninfectious) genomic material. Both SARS and rapid development of a vaccine against SARS- + doses) CoV-2. Zydus Cadila 2D Zydus Cadila MERS, two other related respiratory diseases caused by novel coronaviruses, were also associated with detectable virus particles Reithera/Leukocare/Univercells 1 1H21 5 6 Large Indian pharmaceutical company that was awarded funding by the Indian Department of Biotechnology to develop a COVID-19 vaccine. Initiated a Ph2 trial 3Q20 and guiding towards 100M doses annually in the blood during infections, particularly SARS (~75% of patients with SARS and ~33% of patients with MERS ). Additionally, An effective vaccine against SARS- ADENOVIRUS starting 2Q21. VECTOR * 7 PROOF- CanSino Biologics (Ad5-nCoV) * * * 1Q21 CoV-2 would greatly increase our READING assuming 1 dose 25 25 50 50 2 3 replicating coronavirus particles have been detected in the blood of mice infected with SARS . We also know that non-human ENZYMES Genexine/Binex (GX-19) ability to manage COVID-19. Without a until data suggests DNA vaccines: would likely require multiple doses to generate protection (at least 2 and possibly 3) but should be able to scale up manufacturing primates can be infected with the virus that causes SARS (SARS-CoV) via blood transfusions and that these animals also develop otherwise Small Korean biotech companies without the manufacturing capacity to supply beyond the Korean domestic market. Initiated Ph1/2 trials in June and expects data 4Q20. The company has recently guided that Ph2/3 vaccine, the only way to become immune is ImmunityBio/NantKwest 50* 50* 50* 50* 1 2Q21 efficacy trials could start 1H21, which would make 2H21 the earliest timeframe for approval. quickly if successful Programs that have relatively low immunogenicity, so we expect them 8 • The key limitation for DNA vaccines is the need to use a special device to get the DNA into human cells (e.g., via electroporation, using electricity to zap cells into opening pores via which DNA can get inside). SARS symptoms . While it is encouraging that none of these diseases have been linked to human blood transfusions, there are to catch the disease and then recover. Given Osaka University/AnGes/Takara to have low utility in a pandemic and seasonal setting 9 reasons to remain vigilant: SARS and MERS had very different infection numbers (~8,000 SARS infections and ~2,500 MERS the risks of COVID-19, we can only fully lift Gamaleya Research Institute 1/21 4Q20 2 1Q21 This Japanese program will enter the clinic in summer 2020. They are ready to supply vaccines to 200K people this year, and are focused on the Japanese domestic market with approval projected for MY21. • Inovio could have 1M doses by the end of 2020 but needs to invest in manufacturing to get to 10-20M doses/month sometime in 2021, which is still not enough for the world; to make a dent in global demand, Inovio would need to scale up Early clinical immunogenicity data from these programs are hard to interpret because they do not report internal human convalescent sera controls RNA replication 2D Genexine/Binex (GX-19) 10 the numerous social distancing restrictions production of hundreds of thousands of electroporation devices and billions of disposables. or even neutralizing antibody titers. However based on non-human primate experiments, these candidates will not likely be able to provide robust UNCHANGED Takis Biotech/Applied DNA Sciences infections worldwide) and almost no asymptomatic infections (greatly reducing the risk of infected patients donating blood). currently in place once a vaccine is available to WARP 2D Osaka University/AnGes/Takara • Because manufacturing DNA vaccines is going to require a concerted effort, it does not make sense to spread our bets too widely across this space: once it is clear which 1 or 2 DNA vaccines work well,it will be important to fund large-scale protection or sterilizing immunity. YE21 Ph1 trials to begin in Italy late 2021; their manufacturing capacity is currently unclear. The company has recently announced the launch of a veterinary trial to study the immune response in companion felines of 1 manufacturing capacity across many manufacturers that work with E.coli to produce plasmids. Inovio has historically been the best funded of this group. protect high-risk individuals (e.g., elderly and/ Vaxart/Emergent Biosolutions/Kindred Biosciences humans. 2D or immunocompromised) and manage any KNOWN SAME Takis Biotech/Applied DNA Sciences 1 Understanding SARS-CoV-2 and the drugs that might lessen ....” 12 Mar. 2020, https://www.economist.com/briefing/2020/03/12/understanding-sars-cov-2-and-the-drugs-that-might-lessen-its-power. Accessed 14 Apr. 2020 CORONAVIRUS DIFFICULT TO DEVELOP NEW STRAINS CORONAVIRUS STRAINS Altimmune/Vigene Biosciences (AdCOVID) Entos Pharmaceuticals/EpiVax future outbreaks. Once a large percentage of STRAINS 1. The single genomic segment of coronavirus prevents re-assortment 1 YE21 2 “The spike protein of SARS-CoV — a target for ... - Nature.” 9 Feb. 2009, https://www.nature.com/articles/nrmicro2090. Accessed 14 Apr. 2020. 2. The proofreading enzyme corrects mutations * Lead candidate selected 2Q20. Entos announced receiving a $4.2M award from the Canadian government to support development of its vaccine candidate through Ph1/2 trials, which will begin late July 2020. They 2D Entos Pharmaceuticals/EpiVax 3 Clinical features of patients infected with 2019 ... - The Lancet.” 24 Jan. 2020, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Accessed 9 Apr. 2020. the population is vaccinated and immune to are working with Applied Pharmaceutical Innovation (API) in scaling up in-house development and manufacturing capacity to provide millions of doses of an approved product within 1 year. Minor players (unlikely to be relevant in 2021 without major investment, though unclear this is good use WARP *Fusogenix platform 4 “Virological assessment of hospitalized patients with ... - Nature.” 1 Apr. 2020, Virological assessment of hospitalized patients with COVID-2019. Accessed 9 Apr. 2020. SARS-CoV-2, spread of disease will be greatly of resources at this point). Moderna Therapeutics/Lonza (mRNA-1273) 4Q20 Immunomic/EpiVax/PharmaJet 2D Immunomic/EpiVax/PharmaJet 5 “Antibody response and viraemia during the course of severe ....” Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)-associated coronavirus infection | Microbiology. Accessed 9 Apr. 2020. reduced and even unvaccinated persons will 10 50 75 100 125 1 3 6 “Viral RNA in Blood as Indicator of Severe Outcome in ... - CDC.” 20 Sep. 2016, Viral RNA in Blood as Indicator of Severe Outcome in Middle East Respiratory Syndrome Coronavirus Infection. Accessed 9 Apr. 2020. + CEPI & BARDA No clear timeline to enter the clinic. Immunomic plans to explore grant initiatives through the US government, NPOs, and other companies/institutions but at the moment they are not at the scale required to advance have indirect protection, a phenomenon known CORONAVIRUS their COVID-19 program for global distribution in 2021. 2D BioNet Asia 7 “A Mouse-Adapted SARS-Coronavirus Causes ... - NCBI - NIH.” 12 Jan. 2007, A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice. Accessed 9 Apr. 2020. 8 “Cynomolgus Macaque as an Animal Model for Severe ... - PLOS.” 18 Apr. 2006, Cynomolgus Macaque as an Animal Model for Severe Acute Respiratory Syndrome. Accessed 9 Apr. 2020. as “herd immunity.” BioNTech/Pfizer (BNT162) 4Q20 BioNet Asia 2D Karolinska Institute/Cobra Biologics 50 115 115 165 215 1 2/3 DEVELOPMENT TIMELINE 9 “Summary of probable SARS cases with onset of illness ... - WHO.” Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003. Accessed 9 Apr. 2020. Part of a consortium with several health organizations in Thailand. Ph1 testing started in Australia, sponsored by the University of Sydney in collaboration with Technovalia and Pharmajet. Their production capacity is Currently marketed vaccines (e.g. for if no specific guidance, assumes 15 2D University of Waterloo 10 “Middle East respiratory syndrome coronavirus (MERS-CoV).” Middle East respiratory syndrome coronavirus (MERS-CoV). Accessed 9 Apr. 2020. mRNA * * * somewhere between 50M-100M doses/year and they will likely focus on supply to southeast Asia in 2021. flu, measles, hepatitis B, etc) are safe and efficacious but novel vaccines (e.g. SARS-CoV-2) must be tested to ensure they are safe and assuming 2 doses CureVac + CEPI 150 150 150 1 2Q21 months for clinical development until data suggests Karolinska Institute/Cobra Biologics effective.There are risks associated with developing a novel vaccine, including one against SARS-CoV-2. One such risk is enhanced disease, which is thought to otherwise Translate Bio/Sanofi 2Q21 1 PHASE 1 START DATE Part of an EU focused consortium called OPENCORONA. First trials in humans will not begin until 2021 at the Karolinska University Hospital, so this has limited application before 2022. occur when the body produces antibodies against the virus that help the virus infect cells instead of neutralizing the virus. This phenomenon has only been seen once 10 50 100 1 University of Waterloo before in humans (with a vaccine from the 1960s against an unrelated respiratory virus called RSV) and the risk is low. Vaccine platforms that induce large amounts of 2 PHASE 2 START DATE Canadian academic effort to develop an intranasal DNA-based vaccine candidate that will still be in R&D until later this year. Could be in the clinic 2021 with limited application before 2022. antibodies that can neutralize infectivity and strongly activate immune cells (specifically T-cells) are thought to have a lower risk of causing enhancement. References Imperial College London 1 MY21 to the importance of skewing the vaccine response towards TH1 vs. TH2 (which are specific types of T-cells) refers to the theory that certain types of antibodies that 1/2 PHASE 1/2 START DATE

Merck/Institut Pasteur/University of Pittsburgh + CEPI are made when the immune system has a stronger TH1 response are less likely to cause immune enhancement than the kinds of antibodies made when the immune Arcturus/Duke University * * * 50 50 100 1 2Q21 2/3 PHASE 2/3 START DATE Consortium headed by the Institute Pasteur and backed by CEPI. The University of Pittsburgh will develop a candidate, while Merck (which acquired Themis) is responsible for supporting the clinical trial and system skews to a TH2 response (e.g., antibodies more likely to cause allergic reactions). The earliest studies from animal model experiments with SARS-CoV-2 manufacturing. Ph1 dosing has started in Belgium September 2020. 1D Merck/Institut Pasteur/University of Pittsburgh + CEPI Measles vector vaccines have so far shown them to be safe and effective, protecting animals from challenge with the virus without causing enhanced disease. WARP Inovio/Beijing Advaccine Biotechnology APPROVED Zydus Cadila 0.5 5* 10 * 15 * 20* YE20 1D Zydus Cadila Using this vector to deliver SARS-CoV-2 would be advantageous since it would also provide strong immunity against measles; however, overcoming pre-existing immunity would Replicating but non-integrating (INO-4800) + CEPI 1 Large Indian Pharmaceutical company that was awarded funding by the Indian Department of Biotechnology to develop a COVID-19 vaccine. No clinical timelines provided but previously reported capacity of 20M require large doses, which might pose a manufacturing challenge. vectors: activate a stronger immune In the best case scenario, we will see low-scale production of a SARS-CoV-2 vaccine by 4Q20, which will likely be reserved for front-line doses annually. response but also introduce and essential workers and maybe some vulnerable populations, followed by large-scale production for the broader population in the Zydus Cadila 15 * 15 * 15 * 2Q21 potential safety risks for high-risk frst half of 2021; we will know if any of the frst wave of vaccines are showing efficacy in clinical trials during the June-October 2020 DNA 1 University of Hong Kong + CEPI DISCLAIMER assuming 2 doses 1D University of Hong Kong + CEPI Influenza vector patients, making it a questionable until data suggests Awarded $620K by CEPI. Set to start a Ph1 trial in July 2020. No partners declared yet but will likely rely on manufacturers in mainland China. timeframe and can make better time estimates once those data read out. It will take time to understand the efficacy and risks of these vaccines in otherwise Genexine/Binex (GX-19) University of Wisconsin–Madison/FluGen/ • This would be a novel approach with poorly understood benefits. • Also, pre-existing immunity to flu might necessitate taking large doses. technology for vaccinating billions development: this should not be viewed as a race but rather a concerted effort to understand whether these approaches can provide real benefit to our society. 1 YE21 University of Wisconsin–Madison/FluGen/Bharat Biotech (CoroFlu) 1D of people against SARS-CoV-2 Bharat Biotech International (CoroFlu) • Even a live attenuated flu vaccine like Flumist generates a modest immune response • De-risking this technology would take too long if we aim to have a vaccine at scale by While the goal is to have a significant portion of the population vaccinated, it will take time for the vaccine to be produced and available in sufficient quantities. Thus, Clinical trials expected to start Fall 2020. Bharat Biotech can produce 300 million doses/year. RA Capital Management, LP (“RA Capital”) is an investment adviser registered with against flu. 2021. Activate a stronger immune response but this also introduces we might see more vulnerable/high-risk people (e.g., healthcare workers, the elderly, those with pre-existing conditions) receive the vaccine before it can be made potential safety risks for high-risk patients, making it a Osaka University/AnGes/Takara 1 MY21 questionable technology for vaccinating billions of people the Securities and Exchange Commission (“SEC”) under the Investment Advisers Act of available for the general population. Some vaccine doses, maybe millions of doses twidely throughout the US and world over during the first half of that year. There against SARS-CoV-2. is a real concern that vaccines will first be made available to nations that sponsored their production, with secondary supply made available to other countries. That Merck/Institute Pasteur/Univ. of Pittsburg Center Tonix/Univeristy of Alabama Birmingham (TNX-1800, TNX-1810, TNX-1820, TNKS-1830) Tonix/Univeristy of Alabama Birmingham/University of Horsepox vector YE21 1D MEASLES for Vaccine Research 1 No development timeline has been provided for this program since its announcement. Unlikely to make an impact in 2021. Alberta (TNX-1800, TNX-1810, TNX-1820, TNKS-1830) • This is a novel platform related to the smallpox virus family, which as a vaccine rarely • While the company presents horsepox as the safest replicating pox vector, other In addition, most people have been immunized to measles 1940, as amended (“Advisers Act”). may happen (AstraZeneca partnered with Oxford and specifically said that they would prioritize vaccinating the UK population; BARDA is funding programs with + CEPI causes disease in humans but will likely lag behind better validated approaches. approaches would likely be validated for safety and efficacy for SARS-CoV-2 ahead of and flu, and thus vaccines using these vectors will need to conditions that favor vaccinating Americans), but CEPI and WHO are working to make sure that innovations coming out of the research and development for a SARS- this novel vaccine platform. overcome pre-existing immunity, requiring a high dose of From time to time, RA Capital may hold long and/or short positions in companies which are included in this map. The information contained CoV-2 vaccine will hopefully become widely available in all countries quickly. Until a vaccine becomes broadly available, people should continue to practice good FLU VECTOR University of Hong Kong + CEPI 1 YE21 the vector to achieve sufficient levels of SARS-CoV-2 Spike Likely better: show the immune system the whole viral protein Merck/International AIDS Vaccine Initiative (IAVI)/Batavia Biosciences hand hygiene, mask wearing, and social distancing when possible. protein to trigger an immune response. This established method involves inserting the viral DNA into a vector and delivering the vector to cells. Cells that have taken up the virus would then produce the in this map should not be interpreted or construed as investment or other professional advice. All information about the individual companies DNA In the early stages of developing a candidate. Recently announced a collaboration with Merck and is expected to start human trials sometime 2020. Recognized by Operation Warp Speed (OWS) as one of five Symvivo 1D Merck/International AIDS Vaccine Initiative (IAVI) WARP Vesicular stomatitis virus (VSV) vector: SARS-CoV-2 protein. assuming 1 dose 2022 vaccine candidates most likely to work. • Additionally, Merck’s VSV platform poses safety risks (arthritis/replication in joints long referenced in this map is presented for the purpose of progressing a strategic approach to the Coronavirus Disease 2019 (“COVID”) crisis, based on clinical (Novel oral probiotic bacterial delivery platform) 1 • While Merck used this VSV platform to make a licensed (Erbevo), the after vaccination, risk to immunocompromised individuals) not associated with other We have not yet seen clinical or non human primate immunogenicity data from these candidates. However some programs have credibility signals from funding design University of Western Ontario 1D University of Western Ontario neutralizing titers were not as high nor as durable as what could be achieved with, for and is in no way inclusive of all the factors that should be considered when making an investment decision. Such considerations include, but safe approaches, and physicians and patients may not want to take the chance. agencies and large pharmaceutical partners make them worth tracking. A vaccine against SARS-CoV-2 could provide lasting protection or may need to be given periodically to boost immunity, but Academic initiative awarded $1M by the Canadian Institute of Health Research (CIHR). Unlikely to have the manufacturing capacity to provide global supply. example, Novavax’s protein nanoparticle vaccine. TOTALS 181M 970M 1.75B 2.35B 2.71B are not limited to, the financial condition of a firm, the skill of the management team, the evolving competitive landscape, and other revenue the virus is unlikely to mutate away from our frst generation of vaccines the way flu does each year. Mutating away from sources outside of COVID-related projects. Therefore, nothing herein should be used to partially or fully inform an investment decision. The map US 61M 305M 865M 915M 1.10B Sensei Biotherapeutics the vaccine is unlikely because coronaviruses are much more stable than influenza viruses, which can mutate through a 2D Sensei Biotherapeutics Complex but could provide a hedge against ADE: protein-based, phage display Programs using more complex approaches, potentially associated with Could be in the clinic as early as Summer 2020 and would have to scale up to reach 100M doses/year is provided for informational purposes only, and nothing contained herein constitutes a solicitation, recommendation, endorsement, offer or an process called “re-assortment” that does not apply to coronaviruses, which actually try to correct their genetic mutations. CUMULATIVE VACCINES This vaccine candidate is very similar to VLP and uses non-infectious lambda bacteriophage viruses to display multiple immunologically reactive SARS-CoV-2 target epitopes (full length, S1, S2, N, M, and E). Each vaccine “cohort” will contain a cocktail of several greater risk and thus less likely to work to even make a COVID vaccine EU 60M 100M 380M 600M 700M phages (all containing the S2-E backbone) to generate effective neutralizing antibodies while hedging against RBD associated ADE. Influenza’s genome consists of eight independent segments that can easily mix with other strains when they pass through the same host; as a MANUFACTURED BY -- let alone be used to create a flu vaccine from scratch just to combine inducement to invest with RA Capital or its funds, or to buy or sell any securities or other financial instruments in any jurisdiction. The factual result, new strains of flu that emerge each year can be vastly different from the strains circulating in previous years, and these “shifts” have led to COUNTRY INDIA 50M 450M 315M 515M 515M ShenZhen Geno-Immune Medical Institute (LV-SMENP-DC) with a COVID vaccine to create a seasonal pentavalent booster. information contained within this map is publicly available. The analysis of such data represents the views held by RA Capital and its employees 1D ShenZhen Geno-Immune Medical Institute (LV-SMENP-DC) Integrating vectors: because lentiviral vectors (like HIV) can integrate into the human genome, they can also introduce risky mutations several major flu pandemics. In contrast, the SARS-CoV-2 genome contains just one segment, so it cannot recombine as easily and will not undergo <1M 1-99M 100-499M 500-999M >1B No additional information provided since program announcement at the time of publication and is subject to change without notification. Nothing in this map should be considered medical advice or guidance on CHINA 10M 100M 150M 225M 275M This approach is based on an HIV-like vector encoding multiple antigens and could potentially generate a broader immune response. However, the gratuitous risk of integration into the human genome outweighs these benefits. the drastic changes that are relatively common with influenza viruses. In addition, influenza can change its genetic material in a second way through 100* (unbolded, in italics) = our speculation. the treatment or prevention of COVID. JAPAN 15M 40M 65M 90M Generex/EpiVax (il-key platform) a process called “drift,” in which small errors are introduced to the viral genome each time the virus copies its RNA. This can result in slightly 100 (bolded, without *) = based on public guidance. Sources are linked. This company recently submitted a vaccine development proposal to several US agencies (including BARDA) but has not disclosed its clinical timelines or target manufacturing capacity. They recently announced an different influenza viruses over time; however, our immune system is often partially prepared due to exposure to similar influenza strains, and this agreement with Bintai Kinden to advance the development and commercialization of their vaccine candidate for Malaysia. 1D Generex/EpiVax (il-key platform) Only show the immune system pieces of viral proteins • This unproven approach involves delivering viral proteins linked with immunostimulatory factors. can reduce the severity of the illness caused by new strains that have only slightly “drifted” from those we’ve seen in past years. SARS-CoV-2 also Heat Biologics/University of Miami (gp-96 platform) 1D Heat Biologics/University Miami (gp-96 platform) No clinical timeline provided since program announcement. The company is applying for several large grants to support clinical development of this COVID-19 vaccine program, and does not expect to use significant • These 2 small companies do not have prior experience developing infectious disease vaccines with their technologies and are not funded to manufacture at scale. Both approaches may trigger T-cell immune responses, which can be complementary to other makes small errors when copying its genome, but unlike influenza it has an extra proof-reading enzyme to correct these errors and reduce “drift.” vaccines (similar to Flow Pharma). This in itself is an unproven approach and neither company states this as their goal. resources to advance it. *Milestone dates are approximated based on the estimated primary completion date as reported on clintrials.gov or our best estimate for when we could see data Likely worse: unproven approaches Because influenza can change itself substantially through these two processes - shift and drift - we need a new flu vaccine each year. In contrast, SARS-CoV-2 is much less likely to change in these ways, thus we could likely use the same SARS-CoV-2 vaccine for several years once one is Symvivo discovered. This company launched a Ph1 clinical trail in 2Q20 and will beginning enrolling <100 patients by the end of the quarter. They have received funding of up to $2.8M from the National Research Council of Canada 1D Symvivo Unvalidated delivery platform Industrial Research Assistance Program (NRC IRAP). This approach uses orally delivered bacTRL (live Bifidobacterium longum) to deliver plasmids containing synthetic DNA encoding SARS-CoV-2 Spike protein. Similar to traditional probiotic supplements, the delivery efficiency and scalability of this approach is currently unclear.