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Please join us on Thursday, January 7, 8:30am EST for an important discussion with Dr. Hatchett, CEO of @CEPIvaccines and Teneo Senior Advisor, @nycoem1, on the #pandemic and the rollout and ongoing development of COVID-19 #vaccines. hubs.li/H0DmlYZ0
Please join us on Thursday, January 7, 8:30am EST for an important discussion with Dr. Hatchett, CEO of @CEPIvaccines and Teneo Senior Advisor, @nycoem1, on the #pandemic and the rollout and ongoing development of COVID-19 #vaccines. https://t.co/UKSwRIuyiA pic.twitter.com/iDj27P44Rg
— Teneo (@Teneo) January 6, 2021
CEPI: We are continuing to invest in #COVID19 vaccine R&D, considering key characteristics like thermostability, manufacturing scalability, and the number of doses needed.
@qz explores the importance of temperature when storing and distributing vaccines
The world needs room-temperature Covid-19 vaccines
https://qz.com/1952256/the-cold-chain-is-a-problem-for-equitable-covid-19-vaccination/
Where the cold chain doesn’t go
In poorer areas, more remote parts of the world and in places where the mean daytime temperature is high and electricity is unavailable or spotty, there are no mechanisms to keep vaccines at low temperatures. There may in fact be no roads—let alone airports—in many of these places either. And even if roads exist, they may be impassable at certain times of the year or inaccessible for political reasons or because of civil unrest.
Both the Moderna and Pfizer vaccines need to be kept frozen and must rely on the cold chain to get anywhere. Only large wealthy countries have the resources to implement a well-developed cold chain, and that means huge parts of the world currently can’t get a Covid-19 vaccine.
This is bad for public health and fails to be equitable and just.
Good thing @InovioPharma has developed #ino4800 which has best in class thermostability, is efficacious, and plasmids can be mass produced easily.
Pretty sure CEPI is well aware of INOs capabilities. After all, they did fund them first in January.
INO-4800 can be stored at room temperature. It doesn’t even require refrigeration for short term.
We are continuing to invest in #COVID19 vaccine R&D, considering key characteristics like thermostability 🌡️, manufacturing scalability🏭and the number of doses needed💉@qz explores the importance of temperature when storing and distributing vaccines⏬https://t.co/XTqAKwGmRo
— CEPI (@CEPIvaccines) January 6, 2021
JK will confirm that 4800 P2 finishes recruiting, first P2 participant on 12/7 already gets second dose.
Also confirmed yesterday 1/5/21 from clinical site in Lexington KY that P2 no longer recruiting but is taking info to start P3 in March/April - sooner than expected.
Ditto Jefferson University and PennU sites in Philly, San Antonio site.
Funding now that 2021 Defense bill was passed, and enacted.
OWS, England Public Health, SCIRO NHP challenges.
SCIRO Paper has been submitted for PR.
COVAX pre-order, CEPI manufacturing scale-up funding updates?
REVEAL 1 VGX-3100, HPV update.
Three GBM 5401, HPV VIN, AIN Rare & Orphan Designations applications.
JK said Ino would file for AIN.
GBM licensing with REGN before or after OS24?
January 11, 2021 06:00 AM ET
H.C. WAINWRIGHT BIOCONNECT 2021 CONFERENCE
Dr. J. Joseph Kim, President & CEO
To update on Ino-4800 progress, partnership, collaboration and licensing agreement, HPV, GBM, oncology pipeline.
On 12/28/20,
H.C. Wainwright analyst Raghuram Selvaraju views the Phase I Covid-19 vaccine results from Inovio Pharmaceuticals last week as "very promising." INO-4800 is stable at room temperature for over a year and at 37 degrees Celsius for over a month, and does not need to be frozen during transportation or storage, which should facilitate global distribution versus mRNA-based COVID-19 vaccines that require cold chain logistics, Selvaraju tells investors in a research note. INO-4800 was immunogenic in 100% of vaccinated subjects with "excellent safety and tolerability," adds the analyst. However, Selvaraju reiterates a Neutral rating on Inovio citing the "nature of the competitive landscape and uncertainty about the future direction of evolution for the pandemic."
Raghuram is a major analyst, fair, friendly to Ino. Expect upgrade from him after 1/11/21 to reflect Advaccine deal, pipeline progress.
1/6/21, VGX-3100 Phase 2 Vulvar Dysplasia Trial Highlights. Based upon these results INOVIO is planning to pursue P3 development.
Trial participants were 24 women between 22 and 70 years of age at entry and other than having HSIL were healthy.
80% (20/25) had VIN3 disease (the more severe form of VIN) and 88% (22/25) had a history of 1 or more recurrences
19 participants had digital photography data, and 12 (63%) had clinically significant lesion reduction as defined by a reduction of lesion area of more than 25%.
20 participants had histology and virology data and 3 (15%) resolved their vulvar HSIL and had no HPV-16/18 virus detectable in the healed area.
Histology was assessed by up to two independent pathologists and non-detectability of HPV-16/18 from lesion tissue using PCR (polymerase chain reaction)-based testing, at six months following the administration of VGX-3100.
Efficacy endpoints were measured six months post-treatment.
Safety will continue to be assessed for 18 months following the last dose.
The most observed adverse event was injection site pain, the majority of which were mild-to-moderate.
No cases of vulvar cancer have been observed in the trial.
Short-seller Citron Capital generated a net return of 155% and a gross return of 202% in 2020 as bets on work-from-home stocks paid off, the fund’s managing partner Andrew Left wrote in a letter to investors.
1/4/21
The firm started an “outsized long position” in Amazon.com Inc. in late March on the theory that the company would prove a big winner regardless of how the pandemic played out, Left wrote.
“The logic was simple,” he said in Citron’s 2020 investor letter dated Jan. 4. “If we continue to stay at home, Amazon is a huge winner. If everything goes back to normal, Amazon will still be a big winner.”
The shift to online shopping and digital sales with stuck-at-home consumers fueled a rally in Amazon’s shares, which jumped 76% last year, extending its winning streak for a sixth year.
The fund also stayed away from “all story stocks” and didn’t short Tesla Inc. or any of the companies with high short interest levels that “became detached from any underlying financial metrics,” he added.
Left shrugged off his one regret -- he didn’t buy Etsy Inc., which was the second-biggest winner on the S&P 500 Index after surging fourfold. “In hindsight, we should have bought Etsy (facemasks) instead - Oh Well,” he wrote.
Citron’s bet against Inovio Pharmaceuticals Inc. was the largest contributor on the short side to the fund’s returns, while GSX Techedu Inc. was one of the biggest losers among its short bets.
For this year, Citron is sticking to a strategy similar to the one it adopted for 2020: “If it is not broken, don’t fix it.”
Proof Ino finished 4800 P2 recruiting
1/5/21:
Unfortunately, at this time we are no longer enrolling in the study. If anything changes or if enrollment opens back up either myself or my coworker, Kaitlyn, will contact you.
Thanks,
Sophie Wambua
Clinical Research Coordinator III
Family and Community Medicine
Thomas Jefferson University
833 Chestnut Street, Suite 301
Philadelphia, PA 19107
215-955-4720
Sophie.Wambua@Jefferson.edu
Jefferson U was the last site to open for P2 on Tues 12/15/20
Last Update Submitted that
Met QC Criteria: December 4 => 16, 2020
Thomas Jefferson University
[ Not yet => Recruiting]
Philadelphia, Pennsylvania, United States, 19107
Contact: Principal Investigator Christopher Chambers Christopher.Chambers@jefferson.edu
China and India are the two most populous countries in the world, with China home to about 1.44 billion people and India to 1.38 billion in 2020. China and India together account for about 36% of total world population and 67% of Asia population. As of 2020, population of China is 59 million more than India.Jun 23, 2020
No one will get 100% market share. That’s why I calculated royalty for 100M, 300M, 500M, 700M, 1B out of 2.45B ppl corresponding to 6.9%, 20.7%, 34.48%, 48.26%, 68.86% market share respectively.
Even with 6.9% market share, 8.5% royalty rate, Ino will earn $264M royalty plus device, needle array (200M units, one per shot) annually.
Ino management is not stupid. They understand China 1.45B and India 1.4B population - huge volume times 2 doses per person.
Advaccine can charge $19.5 per dose as it received no funding from China government.
Pfizer, with its German partner BioNTech, will be given $1.95 billion for 100 million doses, but received no federal funding for the research and development of their vaccine. DoD doc shows it will pay $19/dose of 4800.
Some analysts said SII can manufacture mRNA at $3 per dose including fill, finish, via, packaging. Considering DNA vaccine is much cheaper, easily scaled up, more stable to make, let’s use $3 as cost.
If you add shipping cost, administration overhead, COGS is $4/dose.
So, net sale is $19.5-4= $15.5/dose
The royalty is tiered based on sale volumes.
9% royalty is $1.395/dose
8.5% royalty is $1.3175/dose
To annually inoculate
100M ppl:200M dose * 1.32 = $264M
300M ppl:600M dose * 1.32 = $792M
500M ppl:1B dose * 1.32= $1.32B
700M ppl:1.4B dose * 1.32= $1.848B
1B ppl:2B dose * 1.32= $2.64B royalty
China 2020 population is 2.45B and rising rapidly to 2.6B in 2021.
Ino is not responsible for the L of P/L.
If you add device, 3-prong needle array disposable after each shot, the revenue would be huge!
Ino will likely announce a manufacturing or a licensing deal with Beijing Apollo in Greater China. The former is more lucrative.
That’s huge annually recurring 100% margin royalty!! What’s not to love?
That’s why Ino did the deal.
Ino does not share the loss part of P/L of commercialization. Ino gets royalty for net sale. 8-K:
“develop, obtain and maintain regulatory approval of INO-4800, as well as the Company’s CELLECTRA device
and arrays for use in connection with the administration of INO-4800, in each region in Greater China.”
Don’t think Advaccine will have a hard time getting approval for Cellectra and 3-prong needle array as Ino has through FDA.
“In the event that the Company has not initiated the planned Phase 3 segment of its ongoing clinical trial of INO-4800 in the US within one year after entering into the Agreement, Advaccine may
elect to conduct a Phase 3 clinical trial outside of Greater China at its own cost and expense for the purposes of obtaining regulatory approval in China, subject to the Company’s right to review and approve the protocols and design of such a trial.”
If FDA blocks Ino in US, Advaccine May go outside Greater China or even in US to conduct P3 depending on where the pandemic hits the hardest.
This guarantees that we will see the 4800, device, needle array commercialization - diversification strategy.
If Advaccine gets EUA first in China (high probability given their government connection), they can quickly apply for EUA in US, then exports to US in small quantities as China needs 1.45B * 2 * 50% population = 1.45B doses annually for its own use.
#FireFauci screwed Inovio on Zika and he’s doing the same to them for Covid. People love him but
he has been bought.
https://seekingalpha.com/instablog/47724076-douglas-mcbride/5088916-inovio-zika-solution-poised-for-commercial-viability-while-nih-zika-solution-flounders
Inovio Zika Solution Poised For Commercial Viability While NIH Zika Solution Flounders
Dec. 20, 2017 11:17 PM ET2 Comments
Summary
As predicted in my previous article in 2016, Inovio’s Zika’s vaccine has proven to be superior to the NIH DNA Zika vaccine solution.
The NIH Zika vaccine solution continues to waste money and was dangerous to thousands of people who took the vaccine before safety of the NIH Zika vaccine could be obtained.
The Inovio Zika vaccine has a good chance at Emergency Use Authorization in 2019 or 2020.
Media has confused the NIH solution with the Inovio solution which is misleading.
In summary: Inovio’s results are safe, effective, fastest Zika trial to humans by any pharma, cheap to produce and validate but underfunded (miniscule amount of funding)
In summary: NIH’s results are safe but with very poor immune responses, expensive to produce, risky to the public (since safety is delayed prior to going to a large population), and overfunded (the NIH is burning billions of tax payer money)
So what is the difference between NIH and Inovio? The difference is experience and technology. Experience comes from the father of DNA vaccines (Dr. David Weiner) who has been working DNA vaccines for almost 30 years. During that career Dr. Weiner experienced failures back in the 1990’s and he learned from them. Dr. Weiner fine tuned the solution, got the sequencing right, got the spacing correct in the promoter region of the plasmid, codon optimized the DNA, and co-founded a synthetic DNA company in the early 2000’s which is now VGXi to optimize the DNA plasmids for maximum efficacy. VGXi became a leader in quality plasmids that evolved in to second generation DNA. The other co-founder (Dr. Joseph Kim) meanwhile joined Inovio to further maximize efficacy by increasing uptake of DNA plasmids by a thousand fold by a process called electroporation. Dr. Weiner has a collaborative research agreement with Inovio by which Inovio can utilize Dr. Weiner’s experience while at the same time providing the electroporation devices required for efficient uptake in to the cells.
Meanwhile the NIH are new to the DNA vaccine space. The NIH has not failed enough to learn from their mistakes. The NIH does minor optimizations but not significant optimizations. And the NIH does not use electroporation which increases DNA plasmid uptake in to the cells by a thousand fold. The story of the NIH with DNA vaccines begins in 2011 with 16 scientists on a West Nile vaccine that had a similar design as the NIH Zika vaccine. Since 2011 only 6 years have passed and NIH has only made minor adjustments to the plasmid but none to the delivery of the vaccine. A different device was used for delivery between the 2011 and 2016 attempts but the functional characteristics of both delivery devices used by the NIH are nearly identical without the use of electroporation that Inovio uses.
In short, the NIH has been wasting tax payer money with inferior solutions while Inovio keeps rocking a great product at much lower cost. And the press should be made well aware of that difference. Inovio is well ahead of the competition in the DNA vaccine space.
1/4/21 Developed by Ino, the DNA-based vaccines, called INO-5401 and INO-9012, are meant to boost anti-tumor immune responses, which can lead to cancer cell death.
Participants started the triple immunotherapy after surgery to remove their tumors. The treatment also could be followed by standard radiotherapy and chemotherapy, if clinically indicated.
The findings, “INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma,” were presented at the virtual 2020 Society for Neuro-Oncology Annual Meeting, recently held online.
“This is a landmark combination trial in which a novel DNA vaccine is combined with a checkpoint inhibitor [Libtayo] and radiation and chemotherapy,” David Reardon, MD, the trial’s coordinating principal investigator, said in a press release.
“We look forward to continuing to review these data, with an eye towards those patients who are most likely to benefit from this innovative approach and to see whether, over time, there is an extension of survival in these very hard-to-treat patients,” said Reardon, also the clinical director of the center for neuro-oncology at the Dana-Farber Cancer Institute, in Boston.
Inovio plans to share additional trial data in the coming months, including potential links between immune responses and tissue data, as well as total treatment exposure and simultaneous medication use.
“Coupling immune response with clinical outcome may prove insightful,” Reardon added.
The INO-5401 vaccine works by promoting immune responses against WT1, hTERT, and PSMA — three proteins found at high levels in several cancer cell types, but minimally present in healthy cells. In turn, INO-9012 promotes the production of the IL-12 protein, which triggers the activation and expansion of immune T-cells, boosting anti-cancer responses.
https://immuno-oncologynews.com/2021/01/04/triple-immunotherapy-combo-including-libtayo-shows-promise-in-hard-to-treat-brain-cancer-early-data-suggest/?fbclid=IwAR2n7XR-lysiXqFv3GUGZX2C7tYAuNe4O2I3o7gUtyLW_gXeK8o-WQla_Dc
INO Doses First Subject in P2 12/7. That person’d comeback for blood draw and second dose today Mon 1/4/21.
The last P2 participant was dosed on 12/23, would come back for second dose on 1/20 Inauguration Day. Then, the P2 trial will have its status changed to Active, Not Recruiting.
It’s a forgone conclusion that 4800, device, needle array will be EUA’ed in China first.
It’s a good bet that China won’t place any hold on P3.
I envy that Greater China ppl will be vaccinated first with the best vaccine, 4800 designed in US, made in China - sound like iPhone 12 Pro Max.
There could be a medical tourism boom in Greater China. How many folks in US would fly to China to get 4800, then come back in 4 weeks for second dose?
SK, Japan, VN, Philippine, Malaysian, Singapore, South East Asian, Indian, Russian might take advantage of this as they are geographically close to China.
China is bordered by 14 countries: Afghanistan, Bhutan, India, Kazakhstan, North Korea, Kyrgyzstan, Laos, Mongolia, Myanmar (Burma), Nepal, Pakistan, Russia, Tajikistan, and Vietnam. Furthermore it shares maritime borders with Brunei, Indonesia, Japan, South Korea, Malaysia, the Philippines, and Taiwan.
Inspirational Women in STEM and Tech: Dr. Kate E. Broderick of ‘INOVIO’ On The 5 Leadership Lessons She Learned From Her Experience
1/2/21
I have been with the company for 14 years and have loved every minute! Our technology is so revolutionary, and I am constantly excited to go to work.
Can you share the most interesting story that happened to you since you began at your company?
Goodness I have so many! This year, it was so inspirational to represent the company in Geneva at the World Health Organization meeting where COVID-19 was first discussed. It was such a critical time early in the pandemic and an important moment for INOVIO.
What do you think makes your company stand out? Can you share a story?
Without a doubt, our technology makes INOVIO stand out. I am confident that INOVIO’s technology will change the world. Our DNA medicines platform has the ability to treat and protect people from infectious diseases, HPV-associated diseases and cancers, as well as provide an innovative strategy for monoclonal antibodies. We have been able to build such an exciting technology platform through the dedication of our brilliant staff. I think the fact that the company truly feels like a family helps us all work together towards our exciting goal of helping to improve the health of people and communities around the world by harnessing the power and potential of DNA medicine.
Are you working on any exciting new projects now? How do you think that will help people?
Absolutely — the COVID-19 vaccine program is probably the most important work of my career. 2020 has been an intense year. The organization has been working non-stop, working diligently but safely to get our DNA vaccine candidate through the clinical development process. Although the effort has been exhausting, every day we are reminded of the critical and pressing need for vaccines to fight the COVID-19 pandemic. We are inspired to push on and have the opportunity to potentially impact people around the world through the use of our DNA vaccine candidate INO-4800.
https://medium.com/authority-magazine/inspirational-women-in-stem-and-tech-dr-kate-e-broderick-of-inovio-on-the-5-leadership-lessons-da8619ec7343
China is 2.8B dose market annually as 2 doses are required 4 week apart. Device and disposable 3-prong needle array would be great recurring annual revenue.
24M Taiwan will get their own from DoD if they buy Ino’s solution.
Warm climate, LMICs would love Ino’s. So do BRIC.
is it possible I can ask your help to request Inovio to sell ino4800 to Taiwan separately? Taiwan is country not part of China.
And by law, Taiwan can not purchase any vaccine or drug from China.
I am a Taiwanese, I am hoping to have ino4800 for my country.
Thanks in advance!
@Yeslin101 Yes, Ino can circumvent Greater China commercial licensing deal by having DoD ships 4800, devices, needle arrays directly to Taiwan government.
DoD and Taiwan vaccine procurement is written in 2021 Defense Bill Which has been passed by Congress. Taiwan ppl are guaranteed to access 4800 by DoD. We are close friends like UK and US.
2B 3-prong needle arrays, device, and 4800 vaccine is recurring revenue as ppl need 2 booster shots annually like flu shot. mRNA vaccines from Moderna and Bntx are not boost-able, have short duration. They require at least 4 booster shots per year, which are not feasible since they are not boost-able.
China loves 4800 due to unparalleled no cold store requirement, long duration, working well on mutants due to great B/T cell responses, full length S spike encoding, best safety, using as booster for other vaccines.
4800, device, 3-prong needle array will be run-away Blockbuster annually in Greater China and worldwide including US eventually.
I was pounding the table on the importance of Advaccine, Apollo partnerships while no one here had an inkling of what’s coming.
China regulatory would fast track Ino’s pipeline products unlike FDA and US BP mischievously held them back for Faucci’s babies.
That’s said device/disposable needle array deals in China, SK, India, P3 hold lifted will be immediate term catalysts.
House and Senate overrides DT’s veto of Defense bill.
This could enable DoD to announce $330M funding.
CEPI grant to continue supporting in manufacturing scale-up and COVAX pre-order for LMICs could be announced upon P3 hold lifted.
Analysts now start to realize Ino’s Blockbuster potential and start upgrading Ino.
It’s too risky to short now.
The vaccine is good, but the Cellectra/device will be the honeypot.
The vaccines can be used on Infectious disease/Cancer..... whatever the vaccine used, there will always be the required electroporation device needed for every vaccine given!!
The quiet before the storm was about 8 months of quiet.
This could be one hell of a storm!
Ino may announce granting Beijing Apollo Saturn Biological Technology Ltd., a license to use the device in SK as part of an agreement allegedly valued at more than $30M per GeneOne court docket.
The deal with Advaccine is for vaccine only.
Ino May strike another deal in China to manufacture CELLECTRA® 2000 and CELLECTRA® 3PSP which uses 3-prong needle array which is disposed after each injection.
If 1B out of 1.45B of GreaterChina population receive 4800, 2B needle arrays are annually needed for 2 doses like flu vaccine booster. The net sale royalty for devices and needle arrays is going to be 12-15% as Ino owns all aspects of the design; whereas, in the vaccine licensing Ino does not own the DNA plasmid manufacturing process and needs Advaccine collaboration to exchange trial data.
Medical devices always get higher GM than vaccines. I like the lucrative razor-blade or ink cartridges-printer business model which commands high price for ink cartridges.
Advaccine has great connections with China BP and government regulatory. Thus, 4800 won’t be slow walked as it was in the US. Ino+Advaccine chance of success is high in greater China.
The 2021 Defense bill shows close vaccines procurement and R&D collaboration between DoD and Taiwan (24B population). This would grease the skid for Taiwan buying what DoD procures.
1/4/21 Inovio, Advaccine enter collaboration, license agreement for INO-4800 Inovio and Advaccine Biopharmaceuticals announced that they have entered into a collaboration and license agreement for COVID-19 DNA vaccine candidate INO-4800. Under the collaboration and license agreement, Advaccine will have the exclusive right to develop, manufacture and commercialize INO-4800 within Greater China, inclusive of Mainland China, Hong Kong, Macao, and Taiwan. Advaccine will license its plasmid manufacturing process for use with INO-4800 and other INOVIO pipeline product candidates to INOVIO with the right to sublicense to INOVIO's manufacturing partners. Additionally, Advaccine will provide its clinical data to INOVIO in support of INOVIO's global INO-4800 regulatory filings and INOVIO will provide its INO-4800 clinical data for Advaccine to incorporate into its marketing applications in Greater China. Advaccine will make to INOVIO an upfront payment of $3M as well as pay an aggregate of $108M upon the achievement of specified development and sales-based milestones for INO-4800 in Greater China. INOVIO will be entitled to receive a royalty equal to a high single-digit percentage of annual net sales in each region within Greater China.
An interesting article, explains why the focus on neutralizing antibodies and not on T-Cells could be misguided.
The article underlines the advantage of the INO-4800 (which generates a balanced immune response that includes both antibodies and T-Cells) over the other vaccines which generate very high antibody levels but weak to non-existent cellular (T-Cell) responses.
Here is a short excerpt:
"...
Most vaccine developers are shooting for a robust antibody response to neutralize the virus and are focusing on a single protein, called the spike protein, as the immunizing antigen.
Yet, compelling evidence shows that both of these approaches are problematic, said Hellerstein, a UC Berkeley professor of nutritional sciences and toxicology.
A better strategy is to take a lesson from one of the world's best vaccines, the 82-year-old yellow fever vaccine, which stimulates a long-lasting, protective T-cell response. T-cells are immune cells that surveil the body continuously for decades, ready to react quickly if the yellow fever virus is detected again..."
Full text here:
https://www.news-medical.net/news/20200911/New-review-explores-the-role-of-antibodies-and-T-cells-towards-an-effective-COVID-vaccine.aspx
By R.Daneel
New review explores the role of antibodies and T-cells towards an effective COVID vaccine
9/11/2020
More than 100 companies have rushed into vaccine development against COVID-19 as the U.S. government pushes for a vaccine rollout at "warp speed" -- possibly by the end of the year -- but the bar set for an effective, long-lasting vaccine is far too low and may prove dangerous, according to Marc Hellerstein of the University of California, Berkeley.
Most vaccine developers are shooting for a robust antibody response to neutralize the virus and are focusing on a single protein, called the spike protein, as the immunizing antigen.
Yet, compelling evidence shows that both of these approaches are problematic, said Hellerstein, a UC Berkeley professor of nutritional sciences and toxicology.
A better strategy is to take a lesson from one of the world's best vaccines, the 82-year-old yellow fever vaccine, which stimulates a long-lasting, protective T-cell response. T-cells are immune cells that surveil the body continuously for decades, ready to react quickly if the yellow fever virus is detected again.
We know what really good vaccines look like for viral infections. While we are doing phase 2 trials, we need to look at the detailed response of T-cells, not just antibodies, and correlate these responses with who does well or not over the next several months. Then, I think, we will have a good sense of the laboratory features of vaccines that work. If we do that, we should be able to pick good ones."
Marc Hellerstein, University of California
Using a technique Hellerstein's laboratory developed and perfected over the past 20 years that assesses the lifespan of T-cells, it is now possible to tell within three or four months whether a specific vaccine will provide long-lasting cells and durable T-cell-mediated protection.
Hellerstein laid out his arguments in a review article published today in the journal Vaccine.
"There isn't a lot of room for major error here," Hellerstein said.
"We can't just go headfirst down a less than optimal or even dangerous avenue. The last thing we want is for immunized people to get sick in a few months or a year, or get sicker than they would have. Whoever is paying for or approving the vaccine trials has the obligation to make sure that we look at the quality and durability of the T-cell response. And this would not delay the licensing process."
Misplaced focus on antibodies
Hellerstein points out that antibodies are not the primary protective response to infection by coronaviruses, the family of viruses that includes SARS-CoV-2. Indeed, high antibody levels to these viruses are associated with worse disease symptoms, and antibodies to coronaviruses, including SARS-CoV-2, don't appear to last very long.
This was noted in people infected by the first SARS virus, SARS-CoV-1, in 2003. SARS patients who subsequently died had higher antibody levels during acute infection and worse clinical lung injury compared to SARS patients who went on to recover.
In MERS, which is also a coronavirus infection, survivors with higher antibody levels experienced longer intensive care unit stays and required more ventilator support, compared to subjects with no detectable antibodies.
In contrast, strong T-cell levels in SARS and MERS patients correlated with better outcomes. The same has also played out, so far, in COVID-19 patients.
"A strong antibody response correlates with more severe clinical disease in COVID-19, while a strong T-cell response is correlated with less severe disease. And antibodies have been short-lived, compared to virus-reactive T-cells in recovered SARS patients," Hellerstein said.
The most worrisome part, he said, is that antibodies also can make subsequent infections worse, creating so-called antibody-dependent enhancement. Two vaccines -- one against a coronavirus in cats and another against dengue, a flavivirus that affects humans -- had to be withdrawn because the antibodies they induced caused potentially fatal reactions. If an antibody binds weakly against these viruses or falls to low levels, it can fail to "neutralize" the virus, but instead help it get into cells.
Antibody-dependent enhancement is well known in diseases such as dengue and Zika. A recent UC Berkeley study in Nicaragua showed that antibodies produced after infection with Zika can cause severe disease, including deadly hemorrhagic fever, in those later infected by dengue, a related viral disease.
This dangerous cross-reaction may also occur with antibodies produced by a vaccine. Hellerstein noted that a robust T-cell response is key to maintaining high levels of antibodies and may prevent or counteract antibody-dependent enhancement.
T-cells are a long-lasting defense
Hellerstein primarily studies the dynamics of metabolic systems, tagging the body's proteins and cells with a non-radioactive isotope of hydrogen, deuterium and tracking them through the living body. He began to study the birth and death rates of T-cells in HIV/AIDS patients over 20 years ago, using sophisticated mass spectrometric techniques designed by his laboratory.
Then, three years ago, he teamed up with immunologist Rafi Ahmed and his colleagues at Emory University to determine how long T-cells induced by the yellow fever vaccine stick around in the blood.
Surprisingly, he said, the same T-cells that were created to attack the yellow fever virus during the first few weeks after a live virus vaccination were still in the blood and reactive to the virus years later, revealing a remarkably long lifespan.
He and the team estimated that the anti-yellow fever T-cells lasted at least 10 years and probably much longer, providing lasting protection from just one shot. Their long lifespan allows these cells to develop into a unique type of protective immune cell.
"They (the T-cells) are a kind of adult stem cell, sitting silently in very small numbers for years or decades, but when they see viral antigen they go wild -- divide like crazy, put out cytokines and do other things that help to neutralize the virus," he said.
"They are like seasoned old soldiers resting quietly in the field, ready to explode into action at the first sign of trouble."
The same deuterium-labeling technique could be employed to measure the durability of a COVID-19 vaccine's T-cell response, helping to pinpoint the best vaccine candidates while trials are ongoing, he said.
"We can, in my view, tell you the quality and durability or longevity of your T-cell response within a few months," he said. "These tests can be used to judge vaccines: Is a candidate vaccine reproducing the benchmarks that we see in highly effective vaccines, like the ones against smallpox and yellow fever?"
Hellerstein said that he was motivated to write a review on the role of antibodies versus T-cells in protective immunity against SARS-Cov-2 when he heard from experts in vaccine development that companies would likely not be interested in testing anything beyond the antibody response. The reason given was that it would slow down the approval process or could even turn up problems with a vaccine.
"That is why I wrote this review, honestly, because I was so upset by this response," he said. "At this moment in history, how can we not want to know anything that might help us? We need to get beyond the narrow focus on antibodies and look at the breadth and durability of T-cells."
Worrisome focus on spike protein
Hellerstein was also alarmed that most vaccines under development are focusing exclusively on inducing an antibody response against only one protein, or antigen, in the COVID-19 virus: the spike protein, which sits on the surface of the virus and unlocks the door into cells. But important new studies have shown that natural infection by SARS-CoV-2 stimulates a broad T-cell response against several viral proteins, not just against the spike protein.
T-cells produced after natural infection in SARS patients are also very long-lived, he said. A recent study showed that patients who recovered from SARS-CoV-1 infection in 2003 produced CD4 and CD8 T-cells that are still present 17 years later.
These T-cells also react to proteins in today's SARS-CoV-2, which the patients were never exposed to, indicating that T-cells are cross-reactive against different coronaviruses -- including coronaviruses that cause common colds.
These findings all call into question whether limiting a vaccine to one protein, rather than the complement of viral proteins that the body is exposed to in natural infection, will induce the same broad and long-lasting T-cell protection that is seen after natural infection.
In contrast, vaccines like the yellow fever vaccine that employ attenuated viruses -- viruses that divide, but are crippled and can't cause damage to the body -- tend to generate a robust, long-lasting and broad immune response.
"If you are going to approve a vaccine based on a laboratory marker, the key issue is, 'What is its relationship to protective immunity?' My view is that T-cells have correlated much better than antibodies with protective immunity against coronaviruses, including this coronavirus. And T- cells haven't shown a parallel in COVID-19 to antibody-dependent enhancement that could make things worse, not better," he said.
The effectiveness and durability of the first COVID-19 vaccines could impact, for years, the public's already questioning attitude toward vaccines, he warned.
"It would be a public health and 'trust-in-medicine' nightmare, with potential repercussions for years -- including a boost to anti-vaccine forces -- if immune protection wears off or antibody-dependent enhancement develops and we face recurrent threats from COVID-19 among the immunized," he wrote in his review article.
Source:
University of California, Berkeley
Journal reference:
Hellerstein, M., (2020) What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV2?. Vaccine:X. doi.org/10.1016/j.jvacx.2020.100076
https://www.sciencedirect.com/science/article/pii/S2590136220300231?via%3Dihub
JK’s Ace in the hole is China, SK, balanced efficacy. 10 is P3 hold lifted this Jan, COVAX, DoD device, vaccine order, CEPI, $330M DoD P2/3 funding announcement. Q is BRIC, LMICs, SK, Taiwan orders.
Will there be a Straight or Royal?
Boost ability can augment other vaccines annually in US. Huge worldwide market like flu vaccine.
Safest. Elderly pre-conditioned, co-morbidity, Anaphylactic folks MUST prefer this in US. Large worldwide market.
No cold store required lends itself to Cheap, existing infrastructure In LMICS including BRIC countries, 80% of 8B world population.
Advaccine started P1 late Sept, completed P2 640 ppl enrollment; whereas, Ino started P1 Apr, finished recruiting in Dec. Advaccine moved fast. China ppl don’t trust their own vaccines.
Ino-4800’s Clear advantages:
Excellent B and T cell responses. Balanced Immunogenicity lends itself to excellent efficacy.
Length of Immunity
Boost ability can augment other vaccines annually. Huge market like flu vaccine.
Safest. Elderly pre-conditioned, co-morbidity, Anaphylactic folks MUST prefer this. Large worldwide market
No cold store required lends itself to Cheap, existing infrastructure In LMICS including BRIC countries, 80% of 8B world population.
I talked to CVS, Walgreens, Safeway, ... They have to spend tens of Billions dollars to refurbish for cold chain for mRNA vaccines let alone LMICS (Low, Mid Income Countries)
No disease enhancement
Cheap to manufacture. GM would be high.
Will be best seller in China due to Advaccine’s effort. Should do well in LMICs, BRIC, Warm Climate countries.
SII partnership is more likely. That was revealed in court docket in June, which also divulged Ino talked to China manufacturers.
4800 will likely obtain EUA in China before US. China normally moves much faster than US. Advaccine’s Bin Wang is very influential and well-connected in China Pharma industry.
See how fast Chinese built Tesla plant in Shanghai.
Considering 4800 P1 started in China late Sept, it already finished enrolling all 640 ppl in P2 while 4800 started P1 in US April 3rd
and completed P2 Recruiting at the same time as China.
China ppl don’t trust their own vaccine especially the huge middle class and upper.
They consider 4800 as their China safest, most potent, longest duration, boost-able, easily room temperature stored, transported, distributed vaccine.
China and IVI SK May be JK’s Aces in the hole despite many blunders and BP political swamp.
I know at least 10 people that can't take either Pfizer or Moderna vaccine due to this:
"Severe allergy-like reactions in at least eight people who received the COVID-19 vaccine produced by Pfizer and BioNTech over the past 2 weeks may be due to a compound in the packaging of the messenger RNA (mRNA) that forms the vaccine’s main ingredient, scientists say. A similar mRNA vaccine developed by Moderna, which was authorized for emergency use in the United States on Friday, also contains the compound, polyethylene glycol (PEG).
PEG has never been used before in an approved vaccine, but it is found in many drugs that have occasionally triggered anaphylaxis—a potentially life-threatening reaction that can cause rashes, a plummeting blood pressure, shortness of breath, and a fast heartbeat. Some allergists and immunologists believe a small number of people previously exposed to PEG may have high levels of antibodies against PEG, putting them at risk of an anaphylactic reaction to the vaccine. "
By Doover.
CD8+ killer T cells also hunt and kill virus in infected cells, hence called cellular response. This makes 4800 highly potent.
4800 uses a team sport balanced strategy inducing both B humoral and T cell cellular responses in addition to nAb.
Imagining a single-dimensional defense that has a robust front-4 defensive line (NAb) but weak linebackers, cornerbacks, safety (CD4+ helper T cell), weak or non-existing defensive end rushing QB (CD8+ killer T cell).
That defense would be roasted by a good passing offense.
Another analogy to T cell long term memory aka durability, length of Immunity brought up by CEPI scientists is imagining the coach lost the playbook. He can’t send the play to the QB.
Or the players don’t remember well the plays practiced long before the game.
I’ve tried to dumb down as much as I can for layman’s.
JK can use the same analogy in Ino’s Analyst Day to educate analysts.
Investors can do the same to educate one another, shorts, or potential shorts.
Hope some of them understand American Football.
Analysts are so idiotic. JK needs to issue additional PR and holds Analyst day to educate them and clarify 4800 differentiating advantages. It’s reasonable if You fault JK for not doing just that.
MRNA Stock Is Down 36% Since Hitting 52-Week High
12/31/2020 2:57pm EST
By Will Ashworth, InvestorPlace Contributor
Moderna’s stock hit a 52-week and all-time high of $178.50 on Dec.1. It’s lost 36% of its value since then through Dec. 29. Since hitting the record high, it has fought valiantly to remain at or near those levels.
Unfortunately, for anyone who bought at the beginning of December, the final month of the year has turned out to be a major dud.
So, what’s driving the selloff? An article from Trefis and Forbes gives us some insight into the matter.
“While Moderna trades at a reasonable valuation (about 6x consensus 2021 Revenue) for a biotech poised to post big growth next year, the impact of the Covid-19 vaccine is likely to be fleeting for the company (likely only 2021 and 2022) and investors are possibly looking beyond the pandemic,” the Dec. 29 article stated.
“While Moderna has validated its mRNA technology with its Covid-19 shot, investors will likely be waiting for more data and developments relating to the company’s other products before the stock can see further gains.”
This was always a sticking point with investors when it came to Moderna because this is the company’s first commercial drug, albeit a critical one.
To make it in the big bad world of biotechnology, you’ve got to bring another drug to market, and another, and so on. It’s very much what have you done for me lately.
Other Possible Concerns?
I think the elephant in the room for Moderna investors is the fear that something happens with the vaccine that puts one or more people in the hospital with adverse reactions.
On the other hand, the public relations nightmare that would befall Moderna, while possibly overcome with a deft hand, would surely give investors second thoughts about the rest of its potential pipeline of vaccines and therapeutics, including products for cytomegalovirus, influenza, and respiratory syncytial virus.
Further characterization of volunteers’ T cell responses revealed that the proportions of anti-spike CD8+ T cells were balanced between effector, effector memory and central memory cells.
[CD8+ killer T cells also hunt and kill virus in infected cells, hence called cellular response. This makes 4800 highly potent.
4800 uses a team sport balanced strategy inducing both B humoral and T cell cellular responses in addition to nAb.
Imaging a single-dimensional defense that has a robust front-4 defensive line (NAb) but weak linebackers, cornerbacks, safety (CD4+ helper T cell), weak or non-existing defensive end rushing QB (CD8+ killer T cell).
That defense would be roasted by a good passing offense.
Analysts are so idiotic. JK needs to issue additional PR and holds Analyst day to educate them and clarify 4800 differentiating advantages. It’s reasonable if You fault JK for not doing just that.]
Viral targets for vaccines against COVID-19
Lianpan Dai & George F. Gao
Nature Reviews Immunology (2020)
Accepted
19 November 2020
Published
18 December 2020
DOI
https://doi.org/10.1038/s41577-020-00480-0
emerging data have demonstrated the importance of both humoral and cellular immunity in protection. A strong correlation has been found between vaccine-induced neutralizing antibodies (nAbs) and a reduction of viral loads in non-human primates (NHPs) after SARS-CoV-2 infection3,4,5,6. In humans, passive administration of convalescent plasma7,8,9,10, purified IgG11,12 or monoclonal antibodies13 have been reported to show benefit for the treatment and prevention of infection by SARS-CoV-2. In particular, a nAb recently received authorization by the US Food and Drug Administration for emergency use as a treatment for COVID-19 (ref.14). Moreover, analysis of a COVID-19 outbreak aboard a fishery vessel with high infection rates supported the correlation of nAbs with protection15. In addition to nAbs, T cell responses also play critical protective roles in CoV infections. The depletion of T cells in mice has been shown to impair virus clearance in SARS-CoV, MERS-CoV and SARS-CoV-2 infections16,17,18,19. In patients, virus-specific CD4+ and CD8+ T cell responses are associated with milder disease, suggesting an involvement in protective immunity against COVID-19 (refs20,21,22). Therefore, an ideal vaccine is expected to evoke both the humoral and cellular arms of the immune system.
Concluding remarks
An ideal COVID-19 vaccine target would be expected to induce high titres of nAbs, reduce non-nAb production to minimize ADE potential, elicit robust TH1 cell-biased responses but low TH2 cell-biased responses to lower the ERD potential, maintain long-lasting immunological memory, and provide cross-protection between CoVs. No combination of different targets has yet been tested as a multiple-target vaccine but it might be worthwhile in the future to look at this possibility.
Strategy Construct Developer B cell and T cell responses
DNA. Full-length S Inovio with IVI in SK. Induction of S-specific, S1-specific and RBD-specific IgG and nAbs in mice, S-specific IgG and nAbs in guinea pigs; induction of IFN?-associated T cell responses Phase II
mRNA. Full-length S with two proline substitutions (K986P and V987P) Moderna. Induction of S-specific IgG and nAbs in mice, NHPs and humans, with nAb titres higher than convalescent plasma; induction of high TH1 cell responses but low TH2 cell responses in mice, NHPs and humans Phase III
Bntx. Induction of S1-specific IgG and nAbs in humans, with nAb titres higher than convalescent plasma
Protein sub-unit (CHO). Full-length S with two proline substitutions (K986P and V987P) and three mutations at furin cleavage site (R682Q, R683Q and R685Q). Nvax. Induction of S-specific IgG and nAbs in mice, NHPs and humans, with nAb titres in humans higher than convalescent plasma; induction of high TH1 cell responses but low TH2 cell responses in mice, NHPs and humans
NAb wanes after a few months. Ino-4800 triggers a balanced response which is optimal. There are several protecting components akin to NFL team sport.
Only T cell has long term memory and protection. CEPI scientists said a vaccine having short duration which needs boosting while not boost-able is worthless. I couldn’t agree more.
f you compare 1mg to 2mg; you can see that 1mg has higher nab but less T cell response and the 2mg is opposite. What this tells us is, once your body obtain sufficient CD8+ and memory cd4+ cd8+ and B cells, high nab is not needed. nab were higher in 1mg because T cells is lacking a little, they both balance themselves out
Some back of the envelope math for the SP implications of an approved INO- 4800 vaccine.
Moderna sold 100M vaccines to the DoD for $1.9B - in the near future Inovio will do the same either here or abroad.
Let’s assume that revenue results in earnings of 15% or $285M. Dividing by outstanding shares of 169M we get $1.69 EPS. Multiply that by a very conservative P/E of 15 and you get a SP of a little over $25. Biotech P/Es are all over the map, but I’ve seen 45 as a rule of thumb. That produces a SP of $76. That’s for every 100M vaccines sold - a range of $25-76 SP. A billion doses sold equates to ten times that for a whopping SP in the range of $250-$760.
Do that same exercise for INO’s MERS, Lassa fever, Zika, Ebola and well, you understand why Kim thinks INO will be the Tesla of Biotechs. Hope he keeps building that global consortium of manufacturers!
We can talk about the rest of the pipeline some other time, but for now, think about dmAbs which are a $120B opportunity that grows each year.
First line of Defense: NAb,
akin to front-4 NFL Defensive Line
Second Line of Defense: akin to Linebacker, Cornerback, Safety.
CD4+ helper T cell helps B cell produces Ab for humoral (body fluid) response outside of cells.
CD8+ killer T cells hunt and
Kill virus in infected cells are
Responsible for long memory duration - akin to Defensive End rushing QB.
mRNA vaccines are not efficacious due to short duration and boost-able.
4800 induces a balanced response that is its key differentiator.
Cellular (T cell) response were observed to multiple regions of the spike protein including the RBD region. 74% had measurable cellular responses at the 1.0 mg dose group and 100% of the subjects in the 2.0 mg dose group demonstrated cellular responses.
4800 would work on mutants.
Finally, some COVID vaccine progress
Zhiyuan Sun (TMFZhiyuanSun)
Dec 30, 2020 at 7:02AM
This coronavirus vaccine drugmaker has already made many of its early investors rich, but its valuation is still dirt cheap.
Inovio's most promising candidate is INO-4800, a DNA vaccine for protection against SARS-CoV-2. Yet ever since the company began developing it, it appeared that almost anything that could go wrong did go wrong.
The company (and the public) endured an excruciating wait for independent verification of INO-4800's phase 1 clinical trial results. Inovio sued the contract manufacturing organization it had partnered with, alleging it lacked the capacity to produce INO-4800, but was "holding hostage" the technology and data required to allow other manufacturers to do so. The FDA put a pause on the candidate's phase 2/3 clinical trial due to concerns about the specialized device required for inoculating patients with it. (The halt on the phase 2 section of that study has since been lifted.) And notable short-seller Citron Research alleged Inovio was a "dangerous stock promotion."
But now, it appears that Inovio's luck is about to change. At long last, on Dec. 24, INO-4800's phase 1 clinical results passed the peer-review process, and are now publicly available on The Lancet's website. According to the study, approximately 78% to 84% of healthy volunteers who received the experimental vaccine developed neutralizing antibodies against the coronavirus. In addition, 100% of participants developed measurable immune responses, and INO-4800 was well-tolerated with no incidences of serious adverse events.
Compared to Pfizer's or Moderna's coronavirus vaccines, which showed 100% neutralizing antibody response in phase 1, INO-4800 doesn't look that impressive in terms of efficacy. However, it has significant logistical advantages compared to those vaccines.
Vaccines developed using Inovio's DNA platform should be shelf-stable at room temperature for more than a year, and at 37 degrees Celsius (normal human body temperature) for more than one month. At standard refrigeration temperatures, INO-4800 could have a shelf life of more than five years.
Considering that half of the world's manufactured vaccines go to waste due to improper temperature control or issues during transport, that high level of stability could well give INO-4800 an edge over its competitors in the marketplace. The two coronavirus vaccines currently approved for emergency use by the FDA -- BNT162b2 and mRNA-1273 -- both require below-freezing temperatures for long term storage.
Right now, INO-4800 is in phase 2 clinical testing. The Department of Defense is fully funding the later stages of the investigation. To date, the company has not issued any press releases regarding pre-orders of INO-4800, but that may change soon given the news from the phase 1 study.
What's the verdict?
So far, coronavirus vaccines' ability to demonstrate efficacy (in terms of inducing the immune system to produce neutralizing antibodies) in early-stage clinical trials has correlated well with their success in later-stage trials. Now that researchers have independently verified INO-4800's results, we can expect that the candidate has a good chance of making it past phase 3. If this vaccine ever reaches approval, Inovio stock would arguably skyrocket.
Right now, the company only has a market cap of $1.7 billion despite having multiple candidates in its pipeline aside from INO-4800. That is incredibly low. Consider its competitor CureVac, whose market cap soared from $2.8 billion at its August IPO to $18.1 billion as of Dec. 24 due to vaccine hype. The company convinced the EU to sign a contract for 225 million doses of its candidate off just phase 1 data (though that deal is, of course, contingent on the vaccine earning regulatory approval).
Overall, I do not expect that smallish positions in Inovio stock will make their holders wealthy. First of all, the company's progress toward a COVID-19 vaccine has been a bit slow compared to the field of competitors. However, Inovio shares definitely possess the potential to deliver triple-digit percentage returns if INO-4800 receives regulatory clearance. If you are a biotech investor looking for growth stock opportunities, or if you want to get into coronavirus vaccine stocks but missed their spectacular rally, it's not too late to buy shares of Inovio Pharmaceuticals.
4Q20 10-K and 1Q21 10-Q will record massive revenue from:
1. $16.6M C-2K from DoD
2. Part of $54.5M 3PSP development from DoD
3. Part of $56M CEPI grant for MERS P2 and Lassa fever P1
4. More than $30 M from
Among GeneOne's specific claims are that Inovio has breached the license agreement by using the Cellectra device for its clinical trials in Korea, and Inovio has breached the license agreement by granting a Chinese company, Beijing Apollo Saturn Biological Technology Ltd., a license to use the device in Korea starting next year as part of an agreement allegedly valued at more than $30 million.
2Q20 10-Q, pg 31-32:
In April 2018, the Company entered into agreements with CEPI, pursuant to which the Company intends to develop vaccine candidates against Lassa fever and MERS. The goal of the collaboration between the Company and CEPI is to conduct research and development so that investigational stockpiles will be ready for clinical efficacy trial testing during potential disease outbreaks. The agreements with CEPI contemplate preclinical studies, as well as Phase 1 and Phase 2 clinical trials, occurring over multiple years.
As part of the arrangement between the parties, CEPI has agreed to fund up to an aggregate of $56 million of costs over a five-year period for preclinical studies, as well as planned Phase 1 and Phase 2 clinical trials, to be conducted by the Company and collaborators, with funding from CEPI based on the achievement of identified milestones.
During the three and six months ended June 30, 2020, the Company received funding of $1.8 million and $2.9 million, respectively, related to the CEPI Lassa fever and MERS grants and recorded such amounts as contra-research and development expense. During the three and six months ended June 30, 2019, the Company received funding of $1.5 million and $3.2 million, respectively, related to these grants and recorded such amounts as contra-research and development expense. As of June 30, 2020, the Company had $5.3 million recorded as deferred grant funding on the condensed consolidated balance sheet related to these CEPI grants.
In January 2020, CEPI awarded the Company a grant of up to $9.0 million to develop a vaccine against COVID-19. This initial CEPI funding is intended to support preclinical and clinical development through Phase 1 human testing in the United States of INO-4800, the Company's COVID-19 vaccine candidate against COVID-19. In April 2020, CEPI awarded the Company a grant of $6.9 million to work with the International Vaccine Institute ("IVI") and the Korea National Institute of Health ("KNIH") to conduct clinical trials of INO-4800 in South Korea, a grant of $5.0 million to accelerate development of the Company's next- generation intradermal electroporation device, known as CELLECTRA® 3PSP, for the intradermal delivery of INO-4800, and a grant of $1.3 million to support large-scale manufacturing of INO-4800.
During the three and six months ended June 30, 2020, the Company received funding of $5.8 million and $8.1 million, respectively, from CEPI related to these grants for INO-4800 and recorded such amounts as contra-research and development expense. As of June 30, 2020, the Company had an accounts receivable balance of $2.9 million and $101,000 recorded deferred grant funding on the condensed consolidated balance sheet related to the CEPI grants related to INO-4800.
Bill & Melinda Gates Foundation
In October 2018, the Bill & Melinda Gates Foundation (“Gates”) awarded and funded the Company a grant of $2.2 million to advance the development of DNA-encoded monoclonal antibody technology (“dMAb”) to address issues in infectious disease prevention and therapy. This technology has high relevance for the control of influenza and HIV. This next-generation approach to the delivery of monoclonal antibodies would make the technology accessible to low and middle-income countries. In August 2019, Gates funded an additional $1.1 million for the project.
During the three and six months ended June 30, 2020, the Company recorded $36,000 and $170,000, respectively, and during the three and six months ended June 30, 2019 recorded $698,000 and $1.8 million, respectively, as contra-research and development expense related to the Gates dMAb grant. As of June 30, 2020, the Company had $858,000 recorded as deferred grant funding on the condensed consolidated balance sheet related to the grant.
In March 2020, Gates awarded and funded the Company a grant of $5.0 million to accelerate the development of the CELLECTRA® 3PSP device for the intradermal delivery of INO-4800. During the three and six months ended June 30, 2020, the Company recorded $850,000 and $913,000, respectively, as contra- research and development expense and had $4.1 million recorded as deferred grant funding on the condensed consolidated balance sheet related to this Gates grant.
DoD has option to extend $71M contract by $16,570,397 *3
usaspendingDOTgov shows CELLECTRA-2000-ARRAY Total-Funding-Obligated $66,281,588.00
$16,570,397 times 4 equals $66,281,588
Total Funding Obligated
1/4 each procures CELLECTRA® 2000 device, 5-prong needle array, smart device CELLECTRA® 3PSP, 3-prong needle array which is disposable per shot.
This is the lucrative razor-blade, or ink cartridges-printer biz model.
DoD will order vaccine for devices.
8-K, Item 1.01: On June 22, 2020, Inovio Pharmaceuticals, Inc. (the “Company”) entered into an Other Transaction Authority for Prototype Agreement (the “OTA Agreement”) with the U.S. Department of Defense (the “DoD”) to fund the Company’s efforts in developing its next-generation intradermal electroportation device, known as CELLECTRA® 3PSP, and associated arrays to be used for delivery of the Company’s vaccine candidate, INO-4800, as protection against COVID-19. Under the OTA Agreement, the Company intends to develop the CELLECTRA 3PSP device and arrays for use in the U.S. military population and the U.S. population as a whole, subject to approval of the device by the U.S. Food and Drug Administration (the “FDA”). The OTA Agreement is also expected to support large-scale manufacturing of the CELLECTRA 3PSP device, as well as large-scale DNA plasmid production for manufacture and supply of a specified number of doses of INO-4800 in support of FDA approval of the device. The total amount of funding being made available to the Company under the OTA Agreement is approximately $54.5 million.
Under the OTA Agreement, the Company has agreed that, for a period of six years, it will not offer, sell or otherwise provide the production model of the CELLECTRA 3PSP prototype to any entity at a price lower than that offered to the DoD. In addition, if the Company develops a commercialized version or derivative of the production model of the prototype with similar capability and intended application, but at a lower unit price, the Company will be obligated to make the DoD aware of the similar product and the technical and price differences between the products, and no entity will be entitled to receive a lower price than the DoD for similar purchase quantities of such product.
Additionally, on June 19, 2020, the Company was awarded a fixed-price contract (the “Procurement Contract”) from the DoD for the purchase of the Company’s intradermal CELLECTRA® 2000 device and accessories. The CELLECTRA 2000 devices will be used to inject INO-4800 in the Company’s planned later-stage clinical trials. The total purchase price under the Procurement Contract is approximately $16.6 million.
The foregoing description of the material terms of the OTA Agreement and the Procurement Contract does not purport to be complete and is qualified in its entirety by reference to such agreements, which will be filed with the Securities and Exchange Commission as exhibits to the Company’s Quarterly Report on Form 10-Q for the quarter ending June 30, 2020.
https://www.sec.gov/Archives/edgar/data/1055726/000119312520179128/d924073d8k.htm
2Q20 10-Q, pg 32: Department of Defense (DoD)
In June 2020, the Company entered into an Other Transaction Authority for Prototype Agreement (the “OTA Agreement”) with the U.S. Department of Defense (the "DoD"), to fund the Company’s efforts in developing the CELLECTRA® 3PSP device and associated arrays to be used for delivery of INO-4800 against COVID-19. Under the OTA Agreement, the Company intends to develop the CELLECTRA® 3PSP device and arrays for use in the U.S. military population and the U.S. population as a whole, subject to approval of the device by the U.S. Food and Drug Administration (the “FDA”). The OTA Agreement is also expected to support large-scale manufacturing of the CELLECTRA® 3PSP device, as well as large-scale DNA plasmid production for manufacture and supply of a specified number of doses of INO-4800 in support of FDA approval of the device. The total amount of funding being made available to the Company under the OTA Agreement is approximately $54.5 million.
Additionally, in June 2020, the Company was awarded a fixed-price contract (the “Procurement Contract”) from the DoD for the purchase of the Company’s intradermal CELLECTRA® 2000 device and accessories. The CELLECTRA® 2000 devices will be used to inject INO-4800 in the Company’s planned later-stage clinical trials. The total purchase price under the Procurement Contract is approximately $16.6 million.
During the three and six months ended June 30, 2020, there was no contra-research and development expense nor deferred grant funding recorded related to these agreements with the DoD.
http://d18rn0p25nwr6d.cloudfront.net/CIK-0001055726/952770fd-3b6b-47c0-b357-0bed3f628b83.pdf
WHO chief scientist not confident vaccines prevent transmission
Even people who have received the vaccine could infect others, Dr. Soumya Swaminathan warns
Officials at the World Health Organization warned that the COVID-19 pandemic that has ravaged every corner of the world “is not necessarily the big one” — and that the novel coronavirus may never truly go away.
What’s more, chief scientist Dr. Soumya Swaminathan said the WHO hasn’t yet determined whether the approved vaccines being administered in Canada, the U.S. and Europe are effective at preventing transmission, the Guardian reported.
“I don’t believe we have the evidence on any of the vaccines to be confident that it’s going to prevent people from actually getting the infection and therefore being able to pass it on,” Swaminathan said.
The top three vaccines — Moderna, Pfizer-BioNTech and AstraZeneca — have been found in large trials to prevent recipients from becoming sick or seriously ill, but researchers are still trying to determine whether the vaccines prevent the virus from spreading from the recipient to others.
Even if people have received the vaccine, countries still need to assume that they should adhere to public health measures such as social distancing. If a vaccine recipient wants to travel, he should still be required to quarantine.
Moderna’s chief medical officer said last month he believes his company’s vaccine would prevent transmission of the virus but there is not yet “sufficient evidence” of that yet.
“When we start the deployment of this vaccine we will not have sufficient concrete data to prove that this vaccine reduces transmission,” Tal Zaks told Axios.
The first goal of the vaccine was meant to prevent symptomatic disease, severe disease and deaths, Swaminathan said.
Dr. Mark Ryan, the head of the WHO emergencies program, said after that first goal has been tackled, “we will deal with the moonshot of potentially being able to eliminate or eradicate the virus.”
Ryan said, “The existence of a vaccine, even at high efficacy, is no guarantee of eliminating or eradicating an infectious disease. That is a very high bar for us to be able to get over.”
Instead, the “destiny” of the virus is to become endemic, said David Heymann, the chair of the WHO’s strategic and technical advisory group for infectious hazards.
You asked “Secondly - Ben Matone has refused to comment on who is funding Korea/China- he is very polite when discussing cepi - easy to deal with but reinforces dod is priority after which gavi/covax can take place
Would it be common sense to safely assume cepi funding for 2/3 in Korea has also been received?
I have heard that glioblastoma eua is very very likely and this was from Ben Matone as he cross referenced Pfizer treatment for lung ca. He was very confident/ change in voice when discussing the likelihood of this...rumours on the message board today suggested last week January/ week 2 feb we will receive great news outside of Covid pipeline . Do you agree ? “
Answer: CEPI funded 4800 trial in SK run by IVI.
Advaccine funds P2 in China. They recently finished raising funds from Private Equity funds in China.
After GBM 5401, 9012 OS24, Ino will start P3. Ino will likely apply for Rare, Orphan Designation before OS24, and EUA upon great OS 24 readout which may also grease the skid for REGN licensing partnership.
If the Congress can override DT’s veto on $740.5B Defense bill, there is no reason for DoD not to release purse string on $330M funding.
The just passed Stimulus bill
Allocated $20B to vaccine funding to OWS which May start doling out manufacturing scale-up grant to second wave vaccine.
GAVI flushed with $4B from US gov can start device and vaccine preorder for second wave vaccines and fund manufacturing scale-up.
$16,570,397 times 4 equals $66,281,588
Total Funding Obligated
1/4 each procures CELLECTRA® 2000 device, 5-prong needle array, smart device CELLECTRA® 3PSP, 3-prong needle array which is disposable per shot.
This is the lucrative razor-blade, or ink cartridges-printer biz model.
DoD will order vaccine for devices.
usaspendingDOTgov shows CELLECTRA-2000-ARRAY Total-Funding-Obligated $66,281,588.00
Click list symbol on top right corner. Select Award Search, Keyword Search.
Enter Inovio. The site displays a long list of DoD contracts.
The most recent contract is
W911QY20C0084
COVID-19 Obligated Amount
$33,140,794.00
Obligated Amount
$16,570,397.00
Current Amount
$16,570,397.00
Potential Amount
$16,570,397.00
Total Funding Obligated
$66,281,588.00
DoD is obligated to post the contract within 30 days of the grant date unless they ask for 30 to 60 day extension.
$330M P2/3 funding will show up in the above Website eventually. Ino-4800 is not a top secret project. There is no reason to postpone the posting.
11/16/20 Ino announced:
“ The DoD has agreed to provide funding for both the Phase 2 and Phase 3 segments of the INNOVATE clinical trial, in addition to the $71 million of funding previously announced in June for the large-scale manufacture of the company's proprietary smart device CELLECTRA® 3PSP and the procurement of CELLECTRA® 2000 devices.”
defenseDoTgov/Newsroom/Contracts/
Contracts valued at $7.5 million or more are announced each business day at 5 p.m.
This had been announced on 12/11. It’s not a new contract which is ordered by US gov using DoD money.
U.S. Government Exercises 1st Option for Additional 100 Million Doses of Moderna’s COVID-19 Vaccine Candidate
December 11, 2020 at 4:30 PM EST
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Dec. 11, 2020-- Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, today announced that the U.S. government has exercised its option to purchase an additional 100 million doses of mRNA-1273, Moderna’s COVID-19 vaccine candidate, bringing its confirmed order commitment to 200 million doses.
Of the first 100 million doses purchased by the U.S. government, approximately 20 million doses will be delivered by the end of December 2020 and the balance will be delivered in the first quarter of 2021. Today’s new order of 100 million doses will be delivered in the second quarter of 2021. These deliveries are subject, in each case, to receipt of an Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) for the vaccine.
Definitive Contract
PIID
W911QY20C0084
COVID-19 Spending
In Progress
(2 days remain)
COVID-19 Obligated Amount
$33,140,794.00
Obligated Amount
$16,570,397.00
Current Amount
$16,570,397.00
Potential Amount
$16,570,397.00
[This could be for 900 3PSP units procurement]
Total Funding Obligated
$66,281,588.00
https://www.usaspending.gov/award/CONT_AWD_W911QY20C0084_9700_-NONE-_-NONE-
Inovio Pharmaceuticals Inc.,* Plymouth Meeting, Pennsylvania, was awarded a $16,570,397 firm-fixed-price contract for 900 CELLECTRA 2000 DNA vaccine injection devices. Bids were solicited via the internet with one received. Work will be performed in Plymouth Meeting, Pennsylvania, with an estimated completion date of Dec. 31, 2020. Fiscal 2020 defense emergency response funds in the amount of $16,570,397 were obligated at the time of the award. U.S. Army Contracting Command, Aberdeen Proving Ground, Maryland, is the contracting activity (W911QY-20-C-0084). (Awarded June 19, 2020)
https://www.defense.gov/Newsroom/Contracts/Contract/Article/2228273/
Inovio COVID vaccine leans toward T cell responses: Data Byte
BY SANDI WONG, ASSISTANT EDITOR
DEC 28, 2020 | 6:22 PM PST
Phase I data for Inovio’s COVID-19 vaccine suggest INO-4800 may stimulate T cell responses more potently than neutralizing responses. The preliminary readout also provided evidence the DNA vaccine induces both CD4+ and CD8+ memory T cell responses.
The company, which announced the data Thursday, ticked up $0.19 to $10.07 Thursday before giving back the gains on Monday, when its shares fell $0.66 to $9.60.
The tepid market reception suggests that, as in June when shares of Inovio Pharmaceuticals Inc. (NASDAQ:INO) lost 15% with the announcement of “overall immune responses” in 94% of trial participants at week six that investors see neutralization titers as the key benchmark of COVID-19 immunity.
The data, published on Dec. 24 in EClinicalMedicine, show prime-boost administration of 2 µg INO-4800 led to strong T cell responses against the SARS-CoV-2 spike protein at week eight vs. baseline in all 19 evaluable subjects, and induced neutralizing antibodies in 16 (84%) of them.
The study also evaluated prime-boost administration of 1 µg INO-4800. The lower dose led to lower humoral and cellular response rates but higher neutralization titers than the 2 µg dose.
With a single exception, all trial participants produced either detectable neutralizing antibodies, detectable T cell responses or both. The one individual who generated neither response was in the low dose group.
Further characterization of volunteers’ T cell responses revealed that the proportions of anti-spike CD8+ T cells were balanced between effector, effector memory and central memory cells. Anti-spike CD4+ T cells predominantly had a central memory phenotype.
The assumption that humoral immunity will be key to protection from SARS-CoV-2 gained more traction via a Dec. 22 bioRxiv paper from Yale University’s Akiko Iwasaki and colleagues linking early generation of neutralizing responses with better patient outcomes.
Patients who produced neutralizing antibodies within 14 days of symptom onset were more like to clinically improve and survive than those who produced antibodies after that time window.
Although the role of T cells in protecting against COVID-19 has been studied far less, at least one non-human primate study has shown that robust antiviral CD8+ T cell responses can compensate for weak humoral immunity, indicating the T cell responses induced by Inovio’s vaccine may protect individuals who failed to mount a strong antibody response.
INO-4800 does have an advantage over COVID-19 vaccines that require storage at very cold temperatures: the intradermal vaccine is stable at 37° C for over a month and at room temperature for over a year. It has an expected 5-year shelf-life at normal refrigeration temperatures of 2-8° C, according to the company.
Another candidate that is stable at 2-8° C is NVX-CoV2373 from Novavax Inc. (NASDAQ:NVAX). The biotech announced Monday the start of the U.S. and Mexican Phase III PREVENT-19 trial testing intramuscular prime-boost administration of NVX-CoV2373 in up to 30,000 subjects. The primary endpoint of the placebo-controlled study is prevention of symptomatic COVID-19.
According to the complete protocol, the pivotal trial’s final analysis is expected to occur at 144 events; interim analyses are planned to occur when 50% and 75% of 144 events have accrued. A representative for Novavax told BioCentury the company cannot predict when it will have the data needed to apply for emergency use authorization; timing will depend on factors including enrollment speed and epidemiology.
Novavax, whose vaccine’s timeline is behind that of several others, lost $12.49 (10%) to $116.85 Monday.
https://www.biocentury.com/article/633044/inovio-covid-vaccine-leans-toward-t-cell-responses-data-byte
Summary of COVAX Agreement with Inovio
Scope of agreement
? Vaccine Development
Scale-up of manufacturing
Supply of vaccine
[The last 2 items will be check-marked by COVAX]
Inovio is a public company with its headquarters in Pennsylvania, USA. Inovio and CEPI had an existing agreement to develop non-COVID-19 vaccines. An initial investment of $9m was made under a new agreement to fund the phase 1 clinical trial of the COVID-19 vaccine. The nucleic acid vaccine requires a device for delivery and funding of $5m was provided to develop the device. A further $8m was provided in support of manufacturing work. CEPI’s funding ends upon completion of the phase 1 trial.
Where will the vaccine be made? USA
How much vaccine will be supplied to the COVAX Facility? Inovio agreed to develop an appropriate Equitable Access Plan with CEPI which may include offering doses to the COVAX Facility both during the pandemic and after the pandemic.
[Keywords are during and after, i.e., recurring order]
How will be the Price be determined? The agreement defines Equitable Access as meaning that appropriate products are first available to populations when and where they are needed and at prices that are affordable to the populations at risk, especially Low-income and Middle-income Countries, or to public sector entities that procure on their behalf. Thus, Inovio has agreed contractually with CEPI’s equitable access principles.
How will results support the research community? Inovio has agreed to abide by the guidance on access to data and open publications provided by WHO and Wellcome, and additional CEPI obligations in the agreement.
https://cepi.net/wp-content/uploads/2020/12/Enabling-equitable-access-to-COVID19-vaccines-v1-17Dec2020.pdf
Pg 13 of 18 proves that CEPI may provide manufacturing scale-up and COVAX will place orders for device and Ino-4800.
The legislation sets aside nearly $70 billion for a range of public health measures, including $20 billion for the purchase of vaccines, $8 billion for vaccine distribution and an additional $20 billion to help states continue their test-and-trace programs.
A Look at What’s in the Stimulus Package Trump Signed
The $900 billion package provides more relief beyond the $600 checks that have become the focus in Washington.
4800 length of immunity, CD4+ helper, CD8+ killer T cell titters should shine in OWS NHP challenge resulting in second wave OWS funding to Ino for manufacturing scale-up OWS granted $975M in two tranches to Moderna plus $2B vaccine order.
Moderna got vaccine preorder very early on when they are in P2.
Ino could get device and vaccine pre-order during P2 as well.
All eyes are now on OWS NHP challenge result, England Public Health, and CSIRO which has submitted ferret paper for peer review per JK in 3Q20 ER.