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MRNA - Moderna


DocSnowball
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Just digging into Moderna's phase 1 results. They studied the vaccine in 3 doses 25/100/250 in 18-55 age group. Proof of concept looks solid, based on having antibody titers comparable to those in recovering patients with all doses (including neutralizing antibody titers in 8 of 8 with 25/100 dose that have so far been tested). They had systemic side effects in 250 dose and won't go any further with that. Mouse studies showed prevention by these antibodies.

Phase 2 will look into more efficacy and safety data likely with 25/50/100 or two of these.

Phase 3 likely to be in July or August and study 18-55 age group and older age group, I'd say in a city with an outbreak at the time and/or healthcare workers.

 

Company raised capital and is looking to expand manufacturing capabilities.

Overall as much as I could have hoped for from a first of its kind mRNA vaccine. This is just a little outside my circle of competence, and I'm tempted to expand it and learn more.

 

I guess I still wonder how immunogenic the lower doses will be in the elderly, what about kids, can the vaccine cause a cytokine storm in those who have had true infection before etc. On the whole, the product, the trial design, the team and the company appear impressive. Disconfirming views welcomed  :)

 

More details here:

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine

https://investors.modernatx.com/events-and-presentations

https://www.modernatx.com/modernas-work-potential-vaccine-against-covid-19

 

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Results look fine (for early stages), but many firms are working on a vaccine--who is going to win? Also what does "winning" look like--are people going to allow these firms to profit heavily off the vaccine? From what I understand, Gilead isn't set to make a killing off remdesivir so I don't expect vaccine companies will be "allowed" to make a huge cut off these treatments.

 

Vaccines are also 1x treatments--not recurring revenue/customer.

 

Now that being said, Moderna has someone on the inside of this swampy administration, so maybe they can squeeze out favorable terms (at least in the U.S.)

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Results look fine (for early stages), but many firms are working on a vaccine--who is going to win? Also what does "winning" look like--are people going to allow these firms to profit heavily off the vaccine? From what I understand, Gilead isn't set to make a killing off remdesivir so I don't expect vaccine companies will be "allowed" to make a huge cut off these treatments.

 

Vaccines are also 1x treatments--not recurring revenue/customer.

 

Now that being said, Moderna has someone on the inside of this swampy administration, so maybe they can squeeze out favorable terms (at least in the U.S.)

 

I had put it in the too hard pile too first. But the situation is different, the pandemic is widespread. There are seeds of infection in so many countries, it's not going away by itself IMHO. Phase 1 results have given proof of concept, so I think it's worth taking a look.

 

Key issues from risk side are:

Will the vaccine be effective? Or better asked, what are the ballpark % chances of it being effective - I'd say 50-50 for starters.

Will the FDA approve it, and for what all age groups: 18-55, older, children?

What is the total addressable market? Who all will compete - the greatest question in biotech after derisking. More vaccine doses to more people mean more TAM. Best to think of the North American market as reliable for valuation purposes, all the rest is likely gravy.

How many other competitors will compete once a leader is ahead of the pack? It's not easy to conduct trials once cases decline.

Is there a flywheel that the company has beyond SARS CoV-2?

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Results look fine (for early stages), but many firms are working on a vaccine--who is going to win? Also what does "winning" look like--are people going to allow these firms to profit heavily off the vaccine? From what I understand, Gilead isn't set to make a killing off remdesivir so I don't expect vaccine companies will be "allowed" to make a huge cut off these treatments.

 

Vaccines are also 1x treatments--not recurring revenue/customer.

 

Now that being said, Moderna has someone on the inside of this swampy administration, so maybe they can squeeze out favorable terms (at least in the U.S.)

 

I had put it in the too hard pile too first. But the situation is different, the pandemic is widespread. There are seeds of infection in so many countries, it's not going away by itself IMHO. Phase 1 results have given proof of concept, so I think it's worth taking a look.

 

Key issues from risk side are:

Will the vaccine be effective? Or better asked, what are the ballpark % chances of it being effective - I'd say 50-50 for starters.

Will the FDA approve it, and for what all age groups: 18-55, older, children?

What is the total addressable market? Who all will compete - the greatest question in biotech after derisking. More vaccine doses to more people mean more TAM. Best to think of the North American market as reliable for valuation purposes, all the rest is likely gravy.

How many other competitors will compete once a leader is ahead of the pack? It's not easy to conduct trials once cases decline.

Is there a flywheel that the company has beyond SARS CoV-2?

 

I think there will be a couple of vaccines on the market ,  it the first ones has a substantial market potential and it seems like their technology is able to produce a vaccine quicker.

 

Even if it is an imperfect vaccine, in terms of efficacy and side effect provide, it’s going  to find a use case. I first thought that a study for 18-55 year old misses the mark because the main risk groups is >70 years old, but there is a huge market of those who deal with said risk group and also anyone who is immune helps reduce the spread. Think health care workers, first responders, assisted / nursing home living workers, teachers etc.

 

Even a “dirty” vaccine would be better than nothing. In any case, I think vaccines don’t tend to work as well for older folks because it is harder to create the immune response (immune system is weaker) and higher dosing may cause problems for other folks. The doctors here may correct me on that, I don’t claim to be an expert.

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https://en.wikipedia.org/wiki/Moderna

 

Moderna is attempting to insert synthetic mRNA into the living cells of patients to reprogam their cells on how to create their own therapies and vaccines (rather than being created externally, and then injected per the conventential approach);  an advanced technique that was abandoned by large pharmaceutical companies unable to overcome the dangerous side-effects of getting RNA into cells;[6][7][8] As of May 2020, no mRNA vaccine has ever been approved for use in humans.[9][10]

 

The company has a reputation for secrecy and little of its work has ever been published, peer-reviewed, or scientifically validated,[6][7] and its approach has been compared to Theranos by Nature.[12][5]

 

mRNA vaccine work is considered risky, and the main pharmaceutical companies abandoned their mRNA development because of dangerous side effects that can arise in getting the RNA into the living cell.[6][5] As of May 2020, no RNA (or RNA vaccine) has ever been approved for use in humans, and it remains a theoretical concept.[9][10]

 

Let's think about this technology for a second...it has never been done before in a safe way.

 

Traditional vaccines are broken up viral pieces injected into a patient and the patient's immune system sees those particles (for example covid spike proteins) and generates antibodies to those particles through its own intrinsic immune machinery.

 

With Moderna's approach, based on my understanding, an mRNA vaccine utilizes mRNA strands that are inserted into a patient's cells which then start reading the mRNA and producing viral pieces (as if the mRNA were its own genetic material)...now the patient is producing spike proteins...there is potential here for some dangerous 2nd or 3rd order effects developing from messing around with genetic material insertion into a person's cells. Monitoring 8 patients over 2 weeks will not show what those are...

 

For example--suppose your cells start producing spike proteins and you develop an immune response to the spike proteins. Will your immune system now turn its guns on your own cells that are producing these proteins? Could be a helluva autoimmune response.

 

If the first mRNA vaccine ever proves to be effective and safe and solves the covid pandemic, it will be a massive (positive) black swan occurrence. I am not willing to wager $26B in market cap on a co with no current viable products in hope of such a positive black swan occurring.

 

My current probabilistically weighted bets are on a traditional vaccine winning (if anything). I'm not a vaccine expert, so take it for what it's worth.

 

TL;DR: if you assign high probability to a drug that utilizes never-before-approved mechanism of action making it to approval and widespread population level use when you only have partial Phase 1 data, you're gonna have a bad time.

 

The cynic in me makes me think that this administration may have "prodded" Moderna to release these partial results. Corporate greed probably also helped.

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Yeah if you combine all these questions about the technology and data disclosures with how the company was hyped up by the media, the stock price action, the insider selling, the perfectly timed secondary offering, and their connection with the Trump administration, this looks extremely suspicious.

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https://www.cnn.com/2020/05/01/us/coronavirus-moderna-vaccine-invs/index.html

 

The little I’ve read about Moderna is enough to keep me from looking at this any further. The above is just one example.

 

2016:

https://www.statnews.com/2016/09/13/moderna-therapeutics-biotech-mrna/

 

At the center of it all is Stéphane Bancel, a first-time biotech CEO with an unwavering belief that Moderna’s science will work — and that employees who don’t “live the mission” have no place in the company. Confident and intense, Bancel told STAT that Moderna’s science is on track and, when it is finally made public, that it will meet the brash goal he himself has set: The new drugs will change the world.

 

But interviews with more than 20 current and former employees and associates suggest Bancel has hampered progress at Moderna because of his ego, his need to assert control and his impatience with the setbacks that are an inevitable part of science. Moderna is worth more than any other private biotech in the US, and former employees said they felt that Bancel prized the company’s ever-increasing valuation, now approaching $5 billion, over its science.

 

Has all the makings of Theranos II (except for the successful $1.3B capital raise in public markets)

 

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Yeah if you combine all these questions about the technology and data disclosures with how the company was hyped up by the media, the stock price action, the insider selling, the perfectly timed secondary offering, and their connection with the Trump administration, this looks extremely suspicious.

 

This Vaccine / Moderna seems like a Hail Mary approach or sorts. I kind of think we get a vaccine that may not work. The incentives are strong to get out something... anything.

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https://www.cnn.com/2020/05/01/us/coronavirus-moderna-vaccine-invs/index.html

 

The little I’ve read about Moderna is enough to keep me from looking at this any further. The above is just one example.

 

2016:

https://www.statnews.com/2016/09/13/moderna-therapeutics-biotech-mrna/

 

At the center of it all is Stéphane Bancel, a first-time biotech CEO with an unwavering belief that Moderna’s science will work — and that employees who don’t “live the mission” have no place in the company. Confident and intense, Bancel told STAT that Moderna’s science is on track and, when it is finally made public, that it will meet the brash goal he himself has set: The new drugs will change the world.

 

But interviews with more than 20 current and former employees and associates suggest Bancel has hampered progress at Moderna because of his ego, his need to assert control and his impatience with the setbacks that are an inevitable part of science. Moderna is worth more than any other private biotech in the US, and former employees said they felt that Bancel prized the company’s ever-increasing valuation, now approaching $5 billion, over its science.

 

Has all the makings of Theranos II (except for the successful $1.3B capital raise in public markets)

 

+1.

 

Also this "Moderna Inc (MRNA) CFO Kim Lorence Sold 241,000 Shares worth $19,791,361 on May 18 at avg price of $82.12/share".

 

https://www.sec.gov/Archives/edgar/data/1643746/000112760220017220/xslF345X03/form4.xml

 

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I hope Bill Gates and his people monitor Moderna's progress and will apply necessary pressure/controls for them not to release worthless or dangerous vaccine. It could be quite a hit to the reputation of Bill Gates and his foundation if Moderna screws up while being supported by them.

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I love the skepticism all round, it's healthy and I share some of it. What I understood is that 8 out of 8 individuals who had detailed analysis produced neutralizing antibodies in response to the vaccine, certainly a proof of concept for a novel mRNA vaccine against Coronavirus. Before this data, I wasn't sure if it will work at all. The final vaccine dose that will go forward to Ph3 trial is not clear yet, and will become clearer with the detailed phase 1 and phase 2 trials.

 

The data is limited, but the trial was conducted by NIH rather than Moderna itself, which makes it unlikely to be a scam or misrepresented data on the lines of Theranos. A high failure rate does deserve to be thrown in given the novel mechanism, somewhere between 20 and 50% making it a binary investment. I do think the leadership, business model and valuation are the more interesting aspects to study. Finally, the fact is that this is proceeding to Phase 2 (to decide optimal dose) and likely Phase 3.

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I love the skepticism all round, it's healthy and I share some of it. What I understood is that 8 out of 8 individuals who had detailed analysis produced neutralizing antibodies in response to the vaccine, certainly a proof of concept for a novel mRNA vaccine against Coronavirus. Before this data, I wasn't sure if it will work at all. The final vaccine dose that will go forward to Ph3 trial is not clear yet, and will become clearer with the detailed phase 1 and phase 2 trials.

 

The data is limited, but the trial was conducted by NIH rather than Moderna itself, which makes it unlikely to be a scam or misrepresented data on the lines of Theranos. A high failure rate does deserve to be thrown in given the novel mechanism, somewhere between 20 and 50% making it a binary investment. I do think the leadership, business model and valuation are the more interesting aspects to study. Finally, the fact is that this is proceeding to Phase 2 (to decide optimal dose) and likely Phase 3.

 

The fact that a CEO goes on CNBC to read out the results of a phase 1 study to pump his stock, subsequently issues a secondary offering at an inflated share price, while insiders are dumping says enough about the company.

 

I'm glad to see that even Dalal spotted this.

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I love the skepticism all round, it's healthy and I share some of it. What I understood is that 8 out of 8 individuals who had detailed analysis produced neutralizing antibodies in response to the vaccine, certainly a proof of concept for a novel mRNA vaccine against Coronavirus. Before this data, I wasn't sure if it will work at all. The final vaccine dose that will go forward to Ph3 trial is not clear yet, and will become clearer with the detailed phase 1 and phase 2 trials.

 

The data is limited, but the trial was conducted by NIH rather than Moderna itself, which makes it unlikely to be a scam or misrepresented data on the lines of Theranos. A high failure rate does deserve to be thrown in given the novel mechanism, somewhere between 20 and 50% making it a binary investment. I do think the leadership, business model and valuation are the more interesting aspects to study. Finally, the fact is that this is proceeding to Phase 2 (to decide optimal dose) and likely Phase 3.

 

The fact that a CEO goes on CNBC to read out the results of a phase 1 study to pump his stock, subsequently issues a secondary offering at an inflated share price, while insiders are dumping says enough about the company.

 

I'm glad to see that even Dalal spotted this.

 

The last part of that truly makes it a pump and dump. Oh well  :)

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I love the skepticism all round, it's healthy and I share some of it. What I understood is that 8 out of 8 individuals who had detailed analysis produced neutralizing antibodies in response to the vaccine, certainly a proof of concept for a novel mRNA vaccine against Coronavirus. Before this data, I wasn't sure if it will work at all. The final vaccine dose that will go forward to Ph3 trial is not clear yet, and will become clearer with the detailed phase 1 and phase 2 trials.

 

The data is limited, but the trial was conducted by NIH rather than Moderna itself, which makes it unlikely to be a scam or misrepresented data on the lines of Theranos. A high failure rate does deserve to be thrown in given the novel mechanism, somewhere between 20 and 50% making it a binary investment. I do think the leadership, business model and valuation are the more interesting aspects to study. Finally, the fact is that this is proceeding to Phase 2 (to decide optimal dose) and likely Phase 3.

 

The fact that a CEO goes on CNBC to read out the results of a phase 1 study to pump his stock, subsequently issues a secondary offering at an inflated share price, while insiders are dumping says enough about the company.

 

I'm glad to see that even Dalal spotted this.

 

What else would you expect him to do?  We are in the midst of pandemic and his company needs additional funding to ensure that people can be immune from this deadly virus.  While safety and efficacy are of key importance here, so is speed.  I'd be more upset if he didn't take advantage of this initial readout to NOT get funding.  I don't really understand all the negativity that I've seen surrounding the capital raise.  Not like we haven't seen this before.  And today we are in absolutely unchartered territory.  Makes sense to me.  And I see a lot of nonsense surrounding stock sales.  The stock is up over 300% this year!  And most of the sales are 10B5-1 Sales---is anyone really surprised by this?

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I hope Bill Gates and his people monitor Moderna's progress and will apply necessary pressure/controls for them not to release worthless or dangerous vaccine. It could be quite a hit to the reputation of Bill Gates and his foundation if Moderna screws up while being supported by them.

 

The probability of making questionable decisions and falsifying data is high when the character of management is shady, pressure to succeed is intense, you have the ear not just the scientific community but the white house itself and of other rich and powerful investors. And the worst part is that if things go south once they expand this to larger group (say bad adverse events in a lot of treated subjects), anti-vaxxers will be up in arms saying "I told you so".

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This probably should also be in J&J thread. This is genuinely good news on vaccine -

 

https://science.sciencemag.org/content/early/2020/05/19/science.abc6284

 

They infected monkeys with the virus after the treatment and saw robust response.

 

Abstract:

"The global COVID-19 pandemic caused by the SARS-CoV-2 virus has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. Following vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates."

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This probably should also be in J&J thread. This is genuinely good news on vaccine -

 

https://science.sciencemag.org/content/early/2020/05/19/science.abc6284

 

They infected monkeys with the virus after the treatment and saw robust response.

 

Abstract:

"The global COVID-19 pandemic caused by the SARS-CoV-2 virus has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 Spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. Following vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates."

 

DNA vaccines--even riskier than mRNA vaccines. You are altering the DNA of a person's cells...unlike mRNA, this can lead to irreversible change to genetic material in those cells and can cause all sorts of problems down the road (can anyone say cancer?).

 

https://en.wikipedia.org/wiki/DNA_vaccination

 

Several DNA vaccines are available for veterinary use. Currently no DNA vaccines have been approved for human use.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896608/

 

Among the risks that WHO,10 FDA,11 and EMA12 lists for the use of DNA vaccines is the hazard of integration into recipient's chromosomal DNA with the resulting risk of insertional mutagenesis or spreading of antibiotics resistance genes.
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DNA vaccines--even riskier than mRNA vaccines. You are altering the DNA of a person's cells...unlike mRNA, this can lead to irreversible change to genetic material in those cells and can cause all sorts of problems down the road (can anyone say cancer?).

 

https://en.wikipedia.org/wiki/DNA_vaccination

 

Several DNA vaccines are available for veterinary use. Currently no DNA vaccines have been approved for human use.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896608/

 

Among the risks that WHO,10 FDA,11 and EMA12 lists for the use of DNA vaccines is the hazard of integration into recipient's chromosomal DNA with the resulting risk of insertional mutagenesis or spreading of antibiotics resistance genes.

 

Just to be clear, I was also trying to point out the lack of disclosures of substantial data from Moderna (they did do press release with PR mumbo-jumbo) as opposed to J&J's vaccine effort published in the journal science. As for DNA vaccine's risk of integration into human genome, that is a (theoretical) risk no doubt. However, numerous recent human data points to the risk being much lower (although not obviously zero). On the other hand, experts see more immediate immunogenic reaction risk from mRNA vaccine. See more recent review -

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631684/

 

"When DNA vaccines initially entered into human clinical trials, concern was raised about the theoretical possibility of them causing autoimmunity or that the DNA would integrate into the genome. The rationale for concerns about autoimmunity was that anti-DNA antibodies are a hallmark of various autoimmune diseases. To date, both pre-clinical testing and careful clinical monitoring have shown DNA vaccines to not induce or to worsen auto-immunity, and in fact, human clinical trials employing DNA vaccines for therapy of two autoimmune diseases (diabetes mellitus and multiple sclerosis) gave encouraging results in human clinical trials for a therapeutic benefit of the DNA vaccines."

 

In the above publication see table 3, most of the Moderna's vaccine candidates at that time (June 2019) for rabies, flu, zika had no substantial data published, but definitely had press releases.

 

P.S: DNA vaccines insert viral/bacterial DNA into human cells with the hope of invoking human cellular machinery to generate viral protein from these DNA sequences and triggering human immune reaction. So not sure what you meant by changing a person's DNA. The insertion of viral DNA into human sequence could happen in theory as a side effect though.

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I love the skepticism all round, it's healthy and I share some of it. What I understood is that 8 out of 8 individuals who had detailed analysis produced neutralizing antibodies in response to the vaccine, certainly a proof of concept for a novel mRNA vaccine against Coronavirus. Before this data, I wasn't sure if it will work at all. The final vaccine dose that will go forward to Ph3 trial is not clear yet, and will become clearer with the detailed phase 1 and phase 2 trials.

 

The data is limited, but the trial was conducted by NIH rather than Moderna itself, which makes it unlikely to be a scam or misrepresented data on the lines of Theranos. A high failure rate does deserve to be thrown in given the novel mechanism, somewhere between 20 and 50% making it a binary investment. I do think the leadership, business model and valuation are the more interesting aspects to study. Finally, the fact is that this is proceeding to Phase 2 (to decide optimal dose) and likely Phase 3.

 

The fact that a CEO goes on CNBC to read out the results of a phase 1 study to pump his stock, subsequently issues a secondary offering at an inflated share price, while insiders are dumping says enough about the company.

 

I'm glad to see that even Dalal spotted this.

 

What else would you expect him to do?  We are in the midst of pandemic and his company needs additional funding to ensure that people can be immune from this deadly virus.  While safety and efficacy are of key importance here, so is speed.  I'd be more upset if he didn't take advantage of this initial readout to NOT get funding.  I don't really understand all the negativity that I've seen surrounding the capital raise.  Not like we haven't seen this before.  And today we are in absolutely unchartered territory.  Makes sense to me.  And I see a lot of nonsense surrounding stock sales.  The stock is up over 300% this year!  And most of the sales are 10B5-1 Sales---is anyone really surprised by this?

 

You can't blame him for using questionable tactics for raising funds if investors are willing to bite. The day the announcement was made, the number of robinhood holders of the stock peaked, so it's the retail investor holding the bag (as usual) while insiders can sell at an all-time high.

 

But we're on a value investing board here and from my point of view, I would not want to be invested in a company that uses this kind of tactics to raise money. Makes me wonder if they would not try to bend the numbers to make things look better than they actually are. The Trump administration connection in the stock is an additional red flag for me. 

 

Overall, I also wonder whether the company that will end up with a useful covid vaccine will be that successful financially as there will be a lot of pressure to sell those vaccines at cost or with a small profit.

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