Bloomberg Intelligence Covid-19 Vaccine Phase III Data Read Research Report: Covid-19 Vaccine Race Novavax Is Next as Moderna's Covic+19 Vaccine Hits 100% Efficacy (Bloomberg intelligence) ~ Novavax's U.K. trial has a good chance of showing strong etficacy, based on preclinical and clinical data and the design ofits vaccine candidate. Moderna and Pfizer- BioNTech have shown more than 90% efficacy, with 100% efficacy In preventing severe Covid-19 In Moderna’s tral. We await AstraZeneca's published data to judge its potential, while we remaln concerned about J6j's US. tral, 273020 1. Novavax Stands Out as Early Data Paints 2 Hopeful Picture Phase Il data suggest that all late-stage vaccines should work to some degree, though trial design Issues, such as Astra's UK trial, could impact the outcomes. They induce similar levels of virus neutralizing antibodies (Nabs}, though Novavax stands out with higher levels, while Astra is at the lower end, but methodological variables may explain some of the differences, All vaccines activate CD4 T-cells, which support antibody-producing B-cells. Some also activate CD8 T:cel's, which kill infected cells. Antibody and T-cell levels are mostly within/above the range in convalescent patients, 18] and Novavax use a modified spike-protein sequence different to that used by Astra and others, Inducing the best antibody response in a study by Prot. Florian Krammer. Which vaccine becomes, dominant may come down to ease of shipping. 11/2920 Early Human Vaccine Data 2. Caveats Apply to Our Positive View on Novavax While we believe that Novavax is developing one of the more-promising Covid-19 vaccine ‘candidates, the way It produces the vaccine and its US. trlal design are reasons to be cautious. Novavax seems to be having trouble getting the FDA over the ine to start its U.S. and Mexico Phase Ill trial, I now expects Phase Il startin the “*coming weeks." The issue is in getting a ‘manufacturing site for commercialscale production of its vaccine through the regulatory process We also wonder whether it will need to redesign its Phase Ill tral to include an “active” arm using either Phizer-BioNTech or Moderna vaccines, instead of placebo, This may impact upcoming Phase ll rials. I's also not clear why data from its U.S. Phase I trial, which should have been published in 4Q, aren't expected until 1921. (11/1920) sane msn by BP BU ath anes PESTBloomberg Intelligence 3. Modema Final Etficacy Similar to Pizer, Both Better Than Astra [At 94.19 efficacy, Modera's vaccine, in its final readout at 196 Covid-19 cases, has matched Pfizer-BioNTech’s significant efficacy of 95% based on 170 cases, Pfizer didn’t do quite as well as Moderna on reducing the number of severe cases, with the latter reporting no severe cases on vaccine out of 30-vs. one out 11 fer Pfizer. This may just be a chance finding, but the fact that Moderna's tral had 3x the number of severe cases, may highlight demographic differences. Phzer has also noted that its vaccine showed an efficacy of more than 94% in subjects older than 65 years, which is a solid result given the immune system weakens with age, Modema had 15 of ts 95 cases in older people at its interim analysis, while the CEO, Stephan Bancel, has suggested similar efficacy in this population to that in the overall tril. (1/3020) 1 ble inl Ana rst Release How. 18 4. Modems Hits 94% Efficacy Despite Potentially Riskier Subjects PfizerBioNTech's had four additional cases of Covid-19 in the vaccinated group on its latest analysis, with 72 of the new cases since the interim report (on 94 cases) in the placebo group. I's possible that the eight vaccinated individuals who developed mild Covid-19 were either in the early Cohort of participants, or were exposed to the virus soon after their second shot. If this isthe case then the PiizerBioNTech vaccine could eventually prove to have efficacy even higher than 95%. Moderna’s vaccine, hit a 94.1% efficacy on its latest analysis, ona higher case count suggesting riskier subjects, “The other important point is that vaccines at these levels of efficacy have @ goad shot at being sterlzing, le, preventing infection, not just disease. But unfortunately we won't have proof of this for some time yet. (1/3020) Modema and Phizer-BioNTech Vaccine Data to Date sy sin Pha ate etsoratae sn etBloomberg Intelligence While is still early days, Pizer-BioNTech tolerability data looks better than the safety data for Moderna’s vaccine. Though manageable, Moderna's appears to have worse levels of severe side effects than It di in its earlier Phase It trials, Grade 3 adverse events ~ classified as severe events in more than 2% of patients - weren't seen in Moderna’s early trials, while they were observed at relatively meaningful rates in the Phase ill trial. Pfizer's data back its decision to go. with BNT162b2, whicn was much mare tolerable in Phase Ill than 162b1, while looking as effective, \We don't think tolerability is an issue for the broader use of the vaccines, but it may point to ‘another differentiating factor for Pizer-BioNTech vs. Moderna, beyond their cold-chain, requirements. 12901720 Modema Vaccine Safety Data 6, Astra Tal Design, Potentially Spike Sequence, Created Issues Given Moderna and Pfizer's vaccine data, we believe others have a good chance of hitting thelr ‘main goals, but its Astrazeneca that's the concer, Astra's vaccine induced robust neutralizing antibody responses in Phase I rials, but wasn't as high as seen with others, though that’s based fon crose-trial comparisons, Astra’s Arazil and U.K. trals have had design changes, having started {asa single dose and later converted to a two-dose trial, a well as a dosing errors, muddying the true efficacy, There's also the issue of the spike-protein sequence used by Astra, which in independent experiments, has shown a lower ability to induce an immune response, (1130720) Phase Il Vaceine-Tal Details 7. Explaining the Divergent Data on Astra’s Vaccine Astra's vaccine data suggests that a low dose followed by a high dose as a booster 28 days later may be more effective than using two high doses, There has been much speculation as to why, The data are, in our view, only hypothesis-generating, given they were from a subgroup analysis of patients injected with an erroneous starting dose. The most popular explanation is that it may be because a low frst dose avoids generating a neutralizing immune reaction to the adenovirus. delivery mechanism of the vaccine, But that's negated by several data points from the Oxford Covise19 Vaccine Trial Group that conducted the tral, in thelr paper published in the Lancet, Based on current data, the most reasonable explanation Is that the 90% efficacy Is either because of differences in patient characteristics or simply due to chance. ( ancl netomat by BR si ortharatiners nen ene ee nang neeBloomberg Intelligence High and Low-Dose Group Antibody Data Are the Same oe spenig0n todo) se eoyeevomep omen) “RG toes a High-dose group ened Low-dose group 8, Astra Phase Il Interim Data Breakdown by Groups Astra's vaccine had 62% efficacy in one dose cohort vs. 80% in another in patients exclusively from the UK. our analysis suggests, That's based on comments in the press release stating that only in the U.K trial half the dose was used on some first injections. We find it tough to believe that the difference in efficacy is due ta the dosing regime, rather than the likely fewer cases on half dose or 2 diferent patient population, We think that assessing the vaccine's efficacy by combining the two data sets ~ which gets to 70% ~ doesn’t have statistical rigor, ‘The good thing is that the vaccine prevented severe Covid-19 disease or hospitalizations. On the other hand, we have ne details on the vaccine’s tolerability yet. 1129720) Simaraten iar ors yond ayo San Se paces Bh a ‘tnanc neonate by BP orth aiBloomberg Intelligence Bl Analysis of AstraZeneca's Data 8, Astra's Lancet Data Also Raise Flag for J&'s Vaccine ‘Astra's Phase Il Covid-19 vaccine data published in the Lancet showed that, while a high or low dose ofits vaccine made no difference to its ability to Induce an antibody response, a single shat of the vaccine wasn't as effective vs. two doses, and saw declining antibody levels. This raises our concerns on the current 60,000-subject Johnson & Johnsan vaccine tial, which only uses a single dose, with a similar number of viral particles to that inthe high-dose group of the Astra tral, though it's impossible to know the exact effective dose of each vaccine 18] s also testing a two-dose regime in its 30,000-patient rial that's now also recruiting in the U.S. ‘key diference between J6j's vaccine and Astra’ is that it uses a different adenoviral vector and spike-protein sequence, which may help it do better. (3/25/20) «fe Vaccine Wale Use $2205 Vial Patiles, The 3,000 Su 10. After a Great Start, Long Vaccine Road Ahead ‘Though Prizer-BioNTech's vaccine isthe first to read out with effectiveness beyond the level that we had expected, there are many other questions that need to be answered before the true potential ofthis vaccine, is known, Foremost is safety, with two months of data on half of the vaccinated individuals expected next week, By the time the vaccine is ready for broad use, much more safety data will be available, hopefully with no sigh of vaccine-mediated disease fennancement, ‘There is also the question of durability By continuing the trial and not switching placebo patients to vaccine, Pizer will be able to build a good picture of durability over the next 12 months. t's also Important to know ifthe vaccine induces a broad antibody and T-cell response and how the virus responds in those vaccinated. (1108720) sy sin Pha ate etsoratae sn etBloomberg Intelligence 11. All Vaccine Makers Have Shipping Edge Over Pizer-BioNTech fectiveness and safety aside, vaccines' need for cold storage could significantly affect their utlty, with Pfizer BioNTech’s vaccine needing to be kept at minus 70 degrees Celsius during shipping and storage at the site of use posing a major issue. Maderna’s requirements are a less fonerous, with minus 20 Celsius for shipping and storage in a normal refrigerator for up to thirty days. Prizer's can only be stored at that temperature for a maximum of 5 days. Also, Pfizer's vaccine, which is produced with five doses per vial, needs to be used with six hours past-llution, a problem for clinies with lower throughput Astra, J6) and Novavax win on the shipping and storage front, needing only normal refrigerator temperatures all the way, I's not clear how long a vial of vaccine can be stored after it has been opened. 1116120) 12. Risk of Virus Mutations Lurks in The Background White the current dominant form of the virus, the D614G variant, may be more susceptible to neutralization by the antibodies, other new mutants may nat be as easy to deal with. While we don't know much about the virus mutations in the Danish mink farms, @ paper published by Emma ‘Thompson etal. has found another mutation in the SARS CoV.2 spike pratein called N439K, This mutant has been observed twice, and as of October, it has been found in 12 countries. ‘The authors have shown two key things. Fist, that antibodies in human convalescent plasma bind less well to this variant. Second, several of the monoclonal antibodies in development are affected by the mutation. This raises the possibilty that vaccinated individuals will eventually succumb to a newer version of the virus, (2216/20 13, Mature Ant-Spike Antibodies Correlate With Recovery Research by Tomer Zohar, etal, shows patients who recavered from Covid-19 had antibodies that mostly targeted the spike-protein of the virus .., exactly the target used in most current vaccine ‘candidates. Those wha died had more antibodies to other parts of the virus, and these were unable 1 immune system needed to clear the virus. to recruit the help of other crucial elements oft Patients with moderate cases of the virus had delayed development of these mature antibodies, but eventually got there. Also, comorbidities for severe disease ~ older age, diabetes and obesity ~ have a detrimental effect on the maturation of antibodies. The authors developed a model that could classify survivors vs. non-survivors with 72% accuracy, based on their antibody response in the first week of symptom onset. (11/05/20 14. T-Cell Immunity May be Needed For Longer Term Erficacy ‘trance ners by BF Brotha atte.Bloomberg Intelligence Most vaccines work by inducing neutralizing antibodies (Nabs). So far all Covid-19 vaccines are ‘much the same on this regard, but only some induce CD8 T:cells which may be required for full or long term efficacy. The results of an in-depth study of the immune response to SARS-CoV-2 infection showed that a coordinated immune response comprising antibodies, CD4 and COB T-cells was detected in mild cases of the disease, whereas this coordination was disrupted in patients over 65 years old and those who got a worse aisease. Separately, Nabs generated against various forms of the SARS-CoV-2 spike protein were found to have differing effects on a vaccine's ability to confer protection in preclinical tests, with the best effect trom a modified spike sequence which resembles those used by J&) and Novavax. (23/1924 ‘ang Carlated With Clea Response - «Florian Kramer ager on toed: J) and Novavax May Wave ions and Removal a olyoase Cleavage ste Som Fave ot mfozet@bloomberg.net sy sin UP ha ate etsoratae sn et