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Software Lead (medical device), ARM Cortex-M processor
Location:San Diego, CA
Excellent object-oriented design (OOD), and object-oriented programming (OOP) using C++, and good understandings of UML.
Capable of designing the firmware with OOD, especially the event-driven, state machine based firmware system
Extensive experience in developing device drivers for SPI, I2C, I2S, UART interfaces.
Experience in ARM Cortex-M processor and relevant development environments.
Singapore Withholds Privileges From People With Sinovac Shots
By Kwan Wei Kevin Tan
June 30, 2021, 12:53 AM PDT
Sinovac users have to undergo testing before attending events
Govt does not view Sinovac as an alternative to mRNA jabs
Residents in Singapore who opt for the vaccine made by Chinese company Sinovac Biotech Ltd. won’t get the same benefits as those with government-approved messenger RNA vaccines from Pfizer Inc. and Moderna Inc., reflecting the challenges facing people with less-effective inoculation as countries move to reopen safely.
Doctors are required to tell patients receiving vaccines under the city-state’s special access route -- which Sinovac has qualified for -- “that they may not be regarded in the same manner as those vaccinated under our national programme,” the Ministry of Health said in a statement on Wednesday.
These individuals will still need to undergo pre-event testing, the statement said, referring to precautions that those with the Pfizer or Moderna shots are exempted from.
The move raises the likelihood that those with Sinovac shots will also not be eligible for other easing measures that the Singapore government has signaled are forthcoming, such as being able to travel without serving a 14 day quarantine upon entering the border. With growing evidence that mRNA vaccines are not just more effective at preventing serious illness and death, but can also curb transmission, governments are scrambling to backstop their use of non-mRNA shots like those from the Chinese makers and AstraZeneca Plc.
While those vaccines are able to prevent acute illness or death, they’re less able to stop onward transmission. Rapid spread of new mutations like the delta variant are also fueling concerns that only the super-effective mRNA shots can provide comprehensive protection. Bahrain has started offering a Pfizer vaccine as a booster shot to people fully inoculated with Chinese maker Sinopharm’s vaccine.
In mid-June, Singapore allowed two dozen private clinics to use its existing stock of Sinovac shots, though the vaccine has not been approved by the regulator. Long lines of people came forward for it, reported local media reported, though the government has not released data on how many shots have been administered. The vaccine is made from the traditional method of injecting an inactivated form of the virus to stimulate immune response, and can be given to immuno-compromised people, the World Health Organization said.
From lab to potential jab: China’s Clover’s COVID-19 vaccine story. This could happen to Ino.
https://cepi.net/news_cepi/from-lab-to-potential-jab-clovers-covid-19-vaccine-story/
“We appreciate your questions but we cannot divulge any information other than via routes approved by the SEC. However, I can share that we are speaking to multiple countries and NGOs regarding grants and other measures…
I apologize for not being able to be more specific” 6/30/21
[IMHO, probable countries are Philippines, Indonesia, Malaysia, Paraguay, Argentina, Uruguay, Colombia, Brazil, and Peru. NGOs are CEPI, COVAX, BGMF, BARDA.]
Do your own Due Diligence.
Russia is failing to meet demand from foreign countries for its Sputnik V vaccine
It promised vast numbers of shots, competing with Western producers.
But many never arrived, and now Russia says it needs all available shots for itself.
Russia is falling far short of its aim to provide COVID-19 vaccines for almost a tenth of the world's population by the end of the year.
Many of its orders for shots are behind schedule, prompting countries that trusted Russia to help them beat their coronavirus outbreaks to publicly complain.
Guatemala is one nation that has had enough. So far, it has only received 150,000 doses of the 8 million doses of Sputnik V vaccine Russia promised, for which it paid $80 million, Reuters reported.
Now Guatemala has asked Russia to pay back the it got in advance. Argentina, Mexico, and the Philippines also reported delays in the delivery of doses from Russia.
But Russia has now has its own crushing wave of infections to deal with, and has said that vaccine exports will have to wait.
Promises unmet
Russia's shot came as a lifeline for poorer countries that were struggling to source vaccines. While Western nations were hoarding doses from suppliers like Pfizer and Moderna, Russia appeared to score a victory by filling the void.
67 countries have now approved the use of the Sputnik V. Russia promised 896 million doses of the vaccine to other countries, the Moscow Times reported.
But it has failed to get even one tenth of those to its buyers. As of May, the country had only exported 15 million doses, according to a Reuters tally.
Sputnik V is slightly different from other two-shot vaccines, in that it uses a slightly different component for the first and for the second shot, meaning they are not interchangeable.
Mexico, Argentina, and the Philippines have faced delays in receiving the second dose of the vaccine. [They are all potential customers of 4800].
African countries have also seen an underwhelming return on promises from Russia, Foreign Policy magazine reported on Thursday.
Algeria in January announced plans to deliver 500,000 vaccines free of charge, but only had 50,000 to give as of April 7, Foreign policy reported.
Tunisia, Algeria, and Guinea, three of the biggest markets for Sputnik V, have received just 100,000 doses of the vaccine combined, Foreign Policy reported.
Production of Sputnik V is tricky
Because Sputnik V uses different components in its doses, it is particularly difficult to make.
"The issue with that is you have to have two different factories or at least two separate sections to manufacture the two doses," Vikram Punia, founder of Pharmasyntez, a Russian pharmaceutical company, told The Moscow Times.
As of Tuesday, Russia had produced 36.7 million vaccine doses, Russia's Trade Minister Denis Manturov said.
Up to 37 million doses could be produced in July alone, he said: 30 million in Russia and 5 to 6 million abroad.
That is still far fewer than the hundreds of millions of doses produced by Pfizer and AstraZeneca each month, Reuters noted.
Newly in crisis, Russia's 'absolute priority' is itself
Russia's vaccination campaign had been sluggish for months, with only 11% of its population fully vaccinated as of Tuesday, according to John Hopkins University data.
But a recent spike in cases of COVID-19 driven by the Delta variant, which has prompted Russia to institute a controversial campaign of mandatory vaccination, has led to a rise in demand for the shot domestically.
Russia is now struggling to meet demand at home. Local shortages have been reported in Moscow, St. Petersburg, and elsewhere in the country, the Moscow Times reported on Tuesday.
Kremlin spokesperson Dmitri Peskov said last week: "The absolute priority is domestic consumption, vaccination of Russians. Satisfying the demand abroad is currently not possible; all obligations will be fulfilled later."
Keep Checking ChiCTR for Advaccine P3 4800 trial
http://www.chictr.org.cn/searchprojen.aspx?title=Ino-4800&officialname=&subjectid=&secondaryid=&applier=&studyleader=ðicalcommitteesanction=&sponsor=&studyailment=&studyailmentcode=&studytype=0&studystage=0&studydesign=0&minstudyexecutetime=&maxstudyexecutetime=&recruitmentstatus=0&gender=0&agreetosign=&secsponsor=®no=®status=0&country=&province=&city=&institution=&institutionlevel=&measure=&intercode=&sourceofspends=&createyear=0&isuploadrf=&whetherpublic=&btngo=btn&verifycode=&page=1
FDA partial hold on our CELLECTRA 2000 device, there's no bearing in any other territories. In fact, it's the same device that we had received CE marking from the EU several years ago. So most of the countries outside the U.S. follow the CE marking for medical devices, the EU convention. So we feel very good about the acceptability of our device outside the U.S. And of course, the gating factor for our Phase 3 start is really -- and we've already begun this process is submitting all of our Phase 3 plans, and getting them approved through various countries that we have planned.
So once our first country is set and we're rolling out the trial, and there will be multiple countries at once, we will fully disclose and articulate our strategy and the design more fully.
you asked about the FDA partial hold. We still want to clear that up. As I articulated our strategy long-term submit our BLA. And also we want to make sure that all of the hard work that our team has done is fully realized. So we still plan to do that. But our primary focus right now is executing and opening the countries and the sites for our Phase 3 outside the U.S. using CELLECTRA 2000 delivering INO-4800. And we're on track as we had anticipated earlier this year that we'll be starting this summer and data -- interim data by year end.
in the next few weeks, we will be able to articulate the full strategy and discuss with the public in regards to what we're doing. But what I can share with you now is we're broadly in -- on time and on schedule to start this summer of this case-driven trial. 6/1/21
COVAX Facility portfolio consists of agreements related to 9 vaccines to expand to 10-12 vaccines
Geneva, 30 June 2021 – Gavi, the Vaccine Alliance announced today that it had signed an advance purchase agreement (APA) with Clover Biopharmaceuticals for its SCB-2019 protein-based adjuvanted vaccine candidate against COVID-19. The agreement will make up to 414 million doses available to participants of the COVAX Facility.
Under the APA, Gavi commits to purchase, on behalf of the COVAX Facility, 64 million doses to be made available in 2021 and has the option to purchase up to 350 million doses in 2022. Supply of the vaccine is anticipated to commence in Q4 2021, pending WHO EUL. In order to address the rising threat of variants, the agreement also provides the opportunity to access doses of potential variant-adapted vaccine in the future.
“The pandemic continues to evolve, and in order to be best prepared, COVAX’s actively managed, diverse portfolio will be critical to meeting countries’ needs, and protecting against risks such as regulatory delays, variants, and supply constraints,” said Dr Seth Berkley, CEO of Gavi. “Today’s agreement with Clover Biopharmaceuticals is yet another important step in that direction.”
The COVAX Facility portfolio, administered by Gavi, currently consists of agreements related to 9 vaccines and vaccine candidates – AstraZeneca/Oxford, Clover, Johnson & Johnson, Moderna, Novavax, Pfizer-BioNTech, SII-Covishield, SII-Covovax, and Sanofi/GSK – with the aim to expand to 10-12 vaccines in total, providing participants access to a diverse range of vaccines suitable for use in varied contexts and settings, and to mitigate against the risk of R&D failures, regulatory delays and supply constraints.
Highlighting the end-to-end nature of COVAX, early investments by Gavi partner and COVAX co-lead the Coalition for Epidemic Preparedness Innovations (CEPI), which administers the COVAX R&D portfolio, were critical to funding development and enabling access to these doses. The development and manufacturing of Clover’s vaccine were accelerated by early, significant funding from CEPI and equitable access commitments were directly linked to this funding – ensuring that vaccine output funded by this investment would be made available for procurement and allocation through the COVAX Facility.
India Zydus Cadila’s 3-dose DNA Covid vaccine for children above 12 years could be out in August. 6/28
National Technical Advisory Group on Immunisation (NTAGI) chairman Dr Arora also said that the trials are likely to be completed by July-end.
The National Technical Advisory Group on Immunisation (NTAGI) chairman Dr NK Arora on Sunday said that the Covid-19 vaccine developed for children above the age of 12 years by pharmaceutical company Zydus Cadila will be available by August.
Dr Arora also said that the trials are likely to be completed by July-end. “The trials will almost be complete till July-end. We will be able to vaccinate children aged between 12-18 years in August,” Dr Arora said.
Zydus Cadila’s ZyCoV-D will be the first DNA vaccine in the world and will be India’s fourth addition to the vaccine arsenal. DNA-Plasmid based ZyCoV-D will be a three-dose vaccine, according to a report published by news agency PTI. India has granted emergency use approval to the Serum Institute of India’s Covishield, Bharat Biotech’s Covaxin and Russia’s Gamaleya National Center of Epidemiology and Microbiology-Russian Direct Investment Fund (RDIF) developed Sputnik-V. India is also looking forward to Biological E’s Corbevax.
People familiar with the development of the vaccine told news agency PTI that Zydus Cadila is likely to apply to the central drugs regulator seeking emergency use approval for their Covid-19 vaccine later this month. The vaccine is already being tested on children. “When Zydus comes for licensure, hopefully in the next two weeks, maybe we have enough data to take a view on whether the vaccine can be given to children,” NITI Aayog member (Health) VK Paul said earlier.
Manufacturing Electrical Engineer II
Location: San Diego, CA
Experience with FDA GMP Part 820, CE, UL and ISO 13485 preferred.
Manager, Distribution
Location:
San Diego, CA
Department:
Device Manufacturing Operations
provides oversight and day-to-day direction relating to clinical and commercial customer orders and returns of GLP/GMP medical devices for INOVIO and its third-party logistics (3PLs).
Familiarity with CFR Title 21 Part 820 and ISO 13485:2012
Senior Specialist, Regulatory Affairs, Medical Devices
Location:
San Diego, CA
Prepare global regulatory submissions to support the use of the device in clinical studies and ultimate commercialization. Prepare and maintain Technical Files in support of CE marking, device master file in the US to support use as a combination device for delivery of biologics
Principal Mechanical Engineer
Location:
San Diego, CA
Thorough understanding of ISO13485 quality control, ISO 14971, 21 CFR Part 11 compliance and documentation.
6/28 15:06P Inovio call volume above normal and directionally bullish. Bullish option flow detected in Inovio with 20,611 calls trading, 1.4x expected, and implied vol increasing almost 5 points to 91.44%. 7/2 weekly 10 calls and 7/2 weekly 10.5 calls are the most active options, with total volume in those strikes near 3,900 contracts. The Put/Call Ratio is 0.13. Earnings are expected on August 9th.
Inovio has listed 5 new job openings within the last five days. 3 of 5 were posted yesterday. Utkusa2002 tracked their jobs and it’s unusual for them to 1) post on Saturday and 2) post three in one day. 6/27/21
Assembler II (Temporary/Contractor)
Location:
San Diego, CA
Department:
Device Manufacturing Ops
3 Positions available
Assistant, Quality Assurance (Temporary/Contractor)
Location:
San Diego, CA
Department:
Quality Assurance
supporting the daily QA Bioanalytics (laboratory) departmental operations, aiding with equipment program management and oversight of information migration to Blue Mountain Regulatory Asset Manager (RAM). This process is subdivided into two steps: 1) set up of equipment (asset) database asset information upload at the first San Diego facility (until scope of work is complete); and 2) transition to completion of asset information upload at the second San Diego facility.
Associate Director, Regulatory Affairs, Medical Devices -EU
Location:
San Diego, CA
Develop strategies for device regulatory submissions to health authorities worldwide
Manage communications with Notified Body; and European Authorized representative to facilitate device registrations, vigilance reporting etc. Support manufacturing in establishing economic operators in Europe. Thorough knowledge of conformity assessment process for CE Marking. Create and maintain technical documentation.
Define and recommend labelling content for use of devices globally
Manage communications with CROs and provide guidance for completion of global Clinical Trial Applications and regulatory submissions. Knowledge and experience in Latin America, Asia-Pacific, EU and North America desirable
Director, Regulatory Affairs, Medical Devices
Location:
San Diego, CA
Importantly, the data indicated that enhanced respiratory disease (ERD) was not associated with INO-4800 immunization in either the 1 dose or 2 dose regimen.
This data complements an earlier NHP SARS-CoV-2 challenge study which demonstrated reduction in LRT viral loads several months after INO-4800 immunization [14]. However, there are distinct differences between the studies, including different doses and variants used for the challenge stock, and the timing of the challenge. In the study described in this manuscript we challenged the animal four weeks after the last vaccination, at a timepoint when high levels of circulating neutralizing antibodies were present. In the other study, the level of serum SARS-CoV-2 neutralizing antibody was low at the time of challenge, protection appeared to be dependent on the recall of a memory response, with a strong humoral and cellular response against SARS-CoV-2 spike antigen detected in the animals [14]. Here, we did not observe an anamnestic response of a similar magnitude, suggesting protection may have been mediated by the antibodies present in circulation at time of challenge which is supported by the correlation between serum SARS-CoV-2 targeting antibody levels and reductions in viral loads (Supplemental Figure 4). This is in line with reports from other vaccines [27], [29], [30] .
Recently, a number of SARS-CoV-2 variants have demonstrated increased transmissibility, potential for increased pathogenicity and escape of vaccine-induced neutralizing antibody responses [31], [32], [33], [34]. We have tested INO-4800-induced antibody and T cell responses against a panel of SARS-CoV-2 variants of concern. Data generated from samples collected from INO-4800 vaccinees indicated the vaccine-induced T cell responses were impervious to epitope changes in the VOC spike antigens, and neutralizing antibody activity was maintained against B.1.1.7 (Alpha) and P.1 (Gamma), but were reduced against the B.1.351 (Beta) variant [35]. In response to the rising threat of VOCs nucleic acid vaccines are in a strong position to respond rapidly. Vaccines matched to the Beta variant are already in clinical testing [36], and in a proactive approach to the likelihood of many more VOCs arising, vaccines designed to provide pan-SARS-CoV-2 coverage are undergoing testing [37], [38]. For example, we have employed SynCon® technology to create a synthetic DNA vaccine based on a single spike immunogen which induces a host immune response which broadly neutralizes a panel of major VOCs [37]. Phase I/II clinical testing is planned to start imminently.
Importantly, tested as a single dose immunization we observed a positive impact on the lung disease burden and no VED.
https://www.sciencedirect.com/science/article/pii/S0264410X21008070
Karen E.Goocha1Trevor R.F.Smithb1Francisco J.Salgueroa1Susan A.Fotheringhama1Robert J.WatsonaMike J.DennisaAlastairHandleyaHolly E.HumphriesaStephanieLongetaTomTiptonaCharlotteSarfasaLauraSibleyaGillian S.SlackaEmmaRayneraKathryn A.RyanaKatherineSchultheisbStephanie J.RamosbAndrewWhiteaSueCharltonaSally A.SharpeaFergusGleesoncLaurent M.HumeaubYperHallaKate E.BroderickbMiles W.Carrollad
a
Public Health England (PHE), Porton Down, Salisbury, Wiltshire, SP4 0JG, United Kingdom
b
Inovio Pharmaceuticals, Plymouth Meeting, PA, 19462, USA
c
Department of Oncology, Oxford University, Oxford, UK
d
Wellcome Centre for Human Genetics, Nuffield Dept of Medicine, Oxford University, OX3 7BN, UK
Received 16 April 2021, Revised 17 June 2021, Accepted 20 June 2021, Available online 23 June 2021.
In addition to COVID-19, CEPI’s priority diseases include Lassa fever (4500 P1b 220ppl 1/27/21), MERS 4700 P2 542ppl 6/21/21, Nipah, Ebola (4201 P1b 50ppl 9/1/21), Rift Valley fever, Chikungunya and Disease X
https://cepi.net/research_dev/priority-diseases/
https://clinicaltrials.gov/ct2/show/NCT04906629
New INO-4201 P1b as Booster in Healthy VSV-ZEBOV Vaccinees (Boost-EBOV). Sponsor: University of Geneva, Switzerland. Collaborators: DARPA,
Global Urgent and Advanced Research and Development (GuardRX)
Inovio Pharmaceuticals
Ebola virus disease (EVD) is a serious illness with a high fatality rate. Currently only one vaccine is available, VSV-ZEBOV/Ervebo; this vaccine is clinically effective and has been deployed as a preventive measure during recent Ebola outbreaks. The durability of protection afforded by this vaccine is unknown, however, and it is thought that a booster vaccination may be required to maintain immune responses. Recently, a synthetic DNA vaccine, INO-4201, was tested in humans and showed good immunogenicity and an enhanced safety profile.
This study aims to test whether the DNA-based candidate INO-4201 can be used as a booster in healthy volunteers previously vaccinated with VSV-ZEBOV.
Locations
Geneva University Hospitals
Geneva, Switzerland, 1205
50 participants
Estimated Study Start Date :
September 1, 2021
Estimated Primary Completion Date :
April 30, 2022
6/23/21 One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine INO-4800 protects against respiratory tract disease burden in nonhuman primate challenge model
Public Health England (PHE), Porton Down, Salisbury, Wiltshire, SP4 0JG, United Kingdom
Inovio Pharmaceuticals, Plymouth Meeting, PA, 19462, USA
Department of Oncology, Oxford University, Oxford, UK
Wellcome Centre for Human Genetics, Nuffield Dept of Medicine, Oxford University, OX3 7BN, UK
Received 16 April 2021, Revised 17 June 2021, Accepted 20 June 2021, Available online 23 June 2021.
We have tested INO-4800-induced antibody and T cell responses against a panel of SARS-CoV-2 variants of concern. Data generated from samples collected from INO-4800 vaccinees indicated the vaccine-induced T cell responses were impervious to epitope changes in the VOC spike antigens, and neutralizing antibody activity was maintained against B.1.1.7 (Alpha) and P.1 (Gamma), but were reduced against the B.1.351 (Beta) variant [35]. In response to the rising threat of VOCs nucleic acid vaccines are in a strong position to respond rapidly. Vaccines matched to the Beta variant are already in clinical testing [36], and in a proactive approach to the likelihood of many more VOCs arising, vaccines designed to provide pan-SARS-CoV-2 coverage are undergoing testing [37], [38]. For example, we have employed SynCon® technology to create a synthetic DNA vaccine based on a single spike immunogen which induces a host immune response which broadly neutralizes a panel of major VOCs [37]. Phase I/II clinical testing is planned to start imminently.
https://www.sciencedirect.com/science/article/pii/S0264410X21008070
GENEOS and INOVIO both submitted GBM clinical studies at 24 month. Compassionate Use PATIENT X ACTUAL SURVIVAL IS OVER 36 MONTHS SINCE SURGERY.
PATIENT X ....FIRST PERSON TO RECEIVE PERSONALIZED DNA MEDICINE !
Geneos is also presenting data from its ongoing collaboration with Dr. Tanner Johanns and colleagues at Washington University School of Medicine to treat a patient with newly diagnosed anaplastic astrocytoma/GBM under a single patient compassionate use IND. The patient is undergoing monotherapy treatment with their personalized cancer vaccine (GNOS-PV) and pIL12 in an adjuvant setting following resection of their tumor. As of the ASCO 2021 conference date the patient remains recurrence free 36 months since primary surgery and 23 months since initiation of the GNOS-PV + pIL12 treatment. The interim data demonstrated that the treatment was generally well tolerated with no treatment related serious adverse events. The patient received a vaccine comprising of 30 tumor antigens including 27 cancer neoantigens and 3 shared antigens. On-treatment immune analysis showed the induction and persistence of neoantigen directed T cells in the patient's blood to 28 of 30 (93%) encoded antigens following GNOS-PV + pIL12 treatment.
GBM patients can get Ino-5401 through 'right-to-try' or “Compassionate Use”. ERC cancer vaccine is first drug to be given to a 'right-to-try' patient 1/10/19.
A cancer vaccine being developed by Epitopoietic Research Corp. has become the first drug to be given to a U.S. patient under new "right-to-try" legislation that gives terminally ill patients access to experimental drugs.
ERC has said (PDF) it informed the FDA last June that it intended to make the vaccine—called Gliovac (ERC-1671)—available to a California patient who hadn’t met the eligibility criteria for enrollment in the company’s ongoing phase 2 U.S. study in brain cancer.
The agency acknowledged the request last July, and in November the unidentified patient, who had been diagnosed with recurrent glioblastoma, was treated with the vaccine at the University of California, Irvine, School of Medicine.
The right-to-try law dictates that any compound used in this way must have successfully completed phase 1 safety testing and be under the FDA’s ongoing approval process. The patient only needs a physician and the drugmaker to sign off on the request, although the FDA has to be informed.
Critics say the law will have little impact on medicines access, could expose patients to exploitation by unscrupulous parties and is unnecessary given that the FDA already approves (PDF) 99% of requests to access unapproved treatments under compassionate-use policies.
UC Irvine neuro-oncologist Daniela Bota, M.D., Ph.D., insists however that the right-to-try laws “may be the only alternative for many patients who may not qualify for clinical trials based on a variety of factors, including progression of disease, comorbidities, existing medications, physical limitations and others.”
ERC, meanwhile, has made extensive use of compassionate-use programs outside the U.S., with more than 28 patients with recurrent, terminal gliobastoma treated with ERC-1671 in Belgium, Germany, Colombia, South Africa and Australia by the end of 2018.
The vaccine is based on freshly extracted tumor cells and lysates that, according to ERC, “stimulates the patient’s immune system to recognize and reject cancer cells.”
The Goldwater Institute, which is an advocate for right-to-try, says the law is important because it allows patients to “seek … treatment from the manufacturer without having to first navigate bureaucratic and time-consuming federal red tape.” It notes that in addition to the federal law, 41 states have implemented their own right-to-try laws.
Last year, Israeli biotech BrainStorm backed away from providing an experimental treatment to a patient with neurodegenerative disease amyotrophic lateral sclerosis under right-to-try. In that case, the decision stemmed not from ethical, legal or practical consideration but because the company decided it wouldn’t be possible to fund treatment for all patients who wanted to try it.
https://www.fiercebiotech.com/biotech/erc-cancer-vaccine-first-drug-to-be-given-to-a-right-to-try-patient
6/26/21 UK records 18,270 new coronavirus cases, highest since Feb. 5. 83.7% of adults had had a first dose. 61.2% had had two.
LONDON, June 26 (Reuters) - The United Kingdom recorded 18,270 new coronavirus infections on Saturday, the highest daily rise since Feb. 5, and 23 deaths, official data showed.
Daily positive cases have been rising in Britain for a month but a rapid vaccination programme appears to have largely broken the link between infections and deaths, with daily fatalities remaining around 20 or lower.
On Friday, 15,810 new cases were reported.
The data also showed that 83.7% of adults had had a first dose of the vaccine and 61.2% had had two.
https://www.reuters.com/world/uk/uk-records-18270-new-coronavirus-cases-highest-since-feb-5-2021-06-26/
Health and Human Services Secretary Alex Azar’s phone rang with an urgent request: Could he help someone at the White House obtain an experimental coronavirus treatment, known as a monoclonal antibody?
[Ino-5401 GBM could get “compassionate use” by FDA.]
If Azar could get the drug, what would the White House need to do to make that happen? Azar thought for a moment. It was Oct. 1, 2020, and the drug was still in clinical trials. The Food and Drug Administration would have to make a “compassionate use” exception for its use since it was not yet available to the public. Only about 10 people so far had used it outside of those trials. Azar said of course he would help.
Azar wasn’t told who the drug was for but would later connect the dots. The patient was one of President Donald Trump’s closest advisers: Hope Hicks.
A short time later, FDA Commissioner Stephen Hahn received a request from a top White House official for a separate case, this time with even greater urgency: Could he get the FDA to sign off on a compassionate-use authorization for a monoclonal antibody right away? There is a standard process that doctors use to apply to the FDA for unapproved drugs on behalf of patients dealing with life-threatening illnesses who have exhausted all other options, and agency scientists review it. The difference was that most people don’t call the commissioner directly.
The White House wanted Hahn to say yes within hours. Hahn, who still did not know who the application was for, consulted career officials. The FDA needs to go by the book, the officials insisted. Hahn relayed the message back to the White House. They kept pressing him to effectively cut corners. No, we can’t do that, Hahn told them several times. We’re talking about someone’s life. We have to actually examine the application to make sure we’re doing it safely.
When Hahn later learned the effort was on behalf of the president, he was stunned. For God’s sake, he thought, it’s the president who’s sick, and you want us to bend the rules? Trump was in the highest-risk category for severe disease from covid-19 — at 74, he rarely exercised and was considered medically obese. He was the type of patient with whom you would want to take every possible precaution. As it did with all compassionate-use applications, the FDA made a decision within 24 hours. Agency officials scrambled to figure out which company’s monoclonal antibody would be most appropriate given the clinical information they had, and selected the one from Regeneron, known simply as Regen-Cov.
A five-day stretch in October 2020 — from the moment White House officials began an extraordinary effort to get Trump lifesaving drugs to the day the president returned to the White House from the hospital — marked a dramatic turning point in the nation’s flailing coronavirus response. Trump’s brush with severe illness and the prospect of death caught the White House so unprepared that they had not even briefed Vice President Mike Pence’s team on a plan to swear him in if Trump became incapacitated.
Ino to announce First Dose of P2 4700 MERS. Lassa fever 4500 First dose 2/23/21. Fully funded by CEPI’s $56M grant. EUA as a stockpile product post-Phase 2 testing.
1Q21: Initiated Phase 1B field study for Lassa with INO-4500 funded by CEPI. 220 participants in Ghana. Started 1/27/21. First dose 2/23/21. Updated 6/21/21.
2Q21: Initiated Phase 2 MERS study with INO-4700 funded by CEPI. 542 participants in Lebanon, Jordan. Started 6/21/21. Updated 6/24/21.
INOVIO previously received a $56 million grant from CEPI in 2018, under which the company is developing vaccine candidates for Lassa fever and Middle East Respiratory Syndrome (MERS). INOVIO and CEPI are committed to making a vaccine available as soon as possible for emergency use as a stockpile product post-Phase 2 testing.
https://clinicaltrials.gov/ct2/history/NCT04588428?A=9&B=10&C=merged#StudyPageTop
https://clinicaltrials.gov/ct2/history/NCT04093076?A=16&B=17&C=merged#StudyPageTop
6/3 GBM 5401 FDA Update: to measure OS30. Ino cannot yet assess the median survival rate until the Methylated group B patients go to 50% survival. We're now sitting at 25 months, which is good news.
Primary Completion: June => December 30, 2021 [Anticipated]
Study Completion: June => December 30, 2021 [Anticipated]
These patients are living longer than standard of care. So Ino needs to push out the timeline to get to where they can measure the longer survival rate.
70% of patients in group B were alive after 18 months (1.5 years).
Since more than half of group B patients were still alive, their median overall survival could not be assessed. Of note, the median overall survival for people with glioblastoma given standard of care treatment is about 23.2-25 months.
Overall survival at 18 months (OS18) presented at SNO 2020 Annual Meeting:
• Promoter Methylated OS18 of 70% (14/20)
• MGMT Promoter Unmethylated OS18 of 50% (16/32)
• Median overall survival in the unmethylated GBM patients was 17.9 months, which compares favorably to historical controls
• Median OS for methylated patients has not yet been reached and the study is ongoing
• This study shows that INO-5401+INO-9012 with cemiplimab and radiation/TMZ have an acceptable tolerability profile, are immunogenic, and may improve survival in newly diagnosed GBM
• 24-month OS data expected later this year, including correlative immunology and tissue data, as well as total study drug exposure and concomitant medication use
WEDNESDAY, April 21, 2021 (HealthDay News) -- Chemotherapy for glioblastoma (GBM) may work better in the morning, according to a study recently published online in Neuro-Oncology Advances.
Anna R. Damato, from the Washington University School of Medicine in St. Louis, and colleagues assessed whether timing of maintenance temozolomide (TMZ) administration affects GBM patient outcome. The analysis included 166 patients with newly diagnosed GBM from 2010 through 2018, who had surgery, had chemoradiation, and were prescribed TMZ for either the morning or evening. Patients were followed for a median of 5.07 years.
The researchers found that patients taking TMZ in the morning showed longer overall survival (OS) compared with those taking TMZ in the evening (median OS, 1.43 versus 1.13 years) with a significant year 1 restricted mean survival time difference (RMST; -0.09). In an analysis of O6-methylguanine-DNA-methyltransferase-methylated patients, median OS was six months longer for patients taking TMZ in the morning, with significant RMST differences at years 1 to 2.5. Among all patients, superiority of morning TMZ at years 1, 2, and 5 was supported by RMST difference regression in an adjusted analysis.
"Many oncologists give it in the evening because patients tend to report fewer side effects then," a coauthor said in a statement. "We saw that in our study as well. But it could be that the increased side effects -- which we can manage with other therapies -- are a sign that the drug is working more effectively."
https://clinicaltrials.gov/ct2/history/NCT03491683?A=26&B=27&C=merged#StudyPageTop
https://s23.q4cdn.com/479936946/files/doc_presentations/INOVIO-Investor-Deck-Presentation_June2021-(website).pdf
https://www.google.com/amp/s/consumer.healthday.com/amp/timing-of-chemotherapy-for-glioblastoma-may-matter-2652082666
The emergence of SARS-CoV-2 variants underscores the urgent need to double down our efforts to bring COVID-19 under control through the deployment of safe and effective vaccines globally. 6/25/21
https://cepi.net/news_cepi/the-vaccines-and-the-variants-cepis-work-to-tackle-an-evolving-threat/
Making ‘variant-proof’ vaccines of the future
In March 2021, we announced that we would provide up to $33m in funding to VBI Vaccines to develop their enveloped virus like particle (eVLP) vaccine candidate through Phase I clinical development against SARS-CoV-2 variants, including the B.1.351 variant. In addition, CEPI is also investing up to $14.2m in SK Bioscience’s recombinant protein vaccine candidate to support its adaptation against variants of concern. Further funding is advancing SK Bioscience’s manufacturing methods to enable the potential production of hundreds of millions of doses of its candidate vaccine.
If both vaccines are successful, VBI and SK bioscience have agreed that the vaccines supported by CEPI will be made available to COVAX for allocation to vulnerable populations worldwide. The shots could be used to increase initial supplies of vaccines and/or as potential booster doses.
Considering the threat of additional variants and potential future outbreaks caused by other coronaviruses, CEPI has also announced that it will provide up to $200m to vaccine developers to advance work to move away from the traditional “one bug, one drug” approach and create an all-encompassing coronavirus shot. Open worldwide to organisations with expertise in vaccine development, CEPI plans to invest in promising multi-coronavirus vaccine candidates up to clinical proof-of-concept.
While an incredibly challenging area of work, a broadly protective coronavirus vaccine could provide significant benefits, through potentially helping to avert another COVID-19-like pandemic, minimising the need to continually update vaccine components, and ultimately reducing virus circulation.
The work forms part of CEPI’s long-term $3.5bn investment strategy, announced in March, 2021, to tackle the imminent threat of COVID-19, while also advancing the innovative tools and networks to reduce or even mitigate future pandemics and epidemics.
6/24 Update: INO-4700 P2 MERS Study Start: June 21, 2021
American University of Beirut Medical Center
[ Not yet => Recruiting]
Beirut, Lebanon
https://clinicaltrials.gov/ct2/history/NCT04588428?A=9&B=10&C=merged#StudyPageTop
6/22/21 Inovio Has 4 Sources Of Potential Value
* DNA plasmid technology has many applications.
* Inovio’s Covid-19 vaccine may still have a global market.
* Inovio potential HPV related therapies look headed for success.
* Glioblastoma therapy success is contingent but would be highly valuable.
In 2020, for a few weeks, Inovio (INO) stock shot up to over $20 per share, up over $30 one day, from a base of about $2.50 per share, based on hopes it might be a victor in the race for a Covid-19 vaccine. At its pre-Covid price I argued it was undervalued. When it shot up, I stressed value was contingent not just on development of its own vaccine but on how other potential vaccines worked out. I also stressed there is underlying value in its HPV and glioblastoma (brain cancer) therapies. In this article I will update the Inovio scenario against a background of a share price that lately has trended between $8.00 and $9.00 per share, giving the company a market capitalization of about $1.8 billion.
DNA plasmid platform
Inovio is a leader in DNA plasmid technology. A plasmid is a DNA structure found in cell cytoplasm, outside the nucleus or chromosomes. As with DNA found in chromosomes, the plasmid DNA can be transcribed to mRNA (messenger RNA) and then into protein production. While the concept is simple, the technology for making it work in humans has been subject to over a decade of development. Because the plasmids must enter human cells, an electroporation device, currently Cellectra, is used for administration.
In theory, if you need to make a protein inside the human body for therapeutic purposes, you can make the corresponding DNA and insert it using plasmids and electroporation. This can be used to make vaccines, in which the body reacts to the protein to form antibodies. It can also be used to generate large proteins, including antibodies, more directly. Currently the Inovio pipeline includes 11 potential therapies in clinical trials, but that is a tiny subset of what is possible.
DNA plasmid technology has advantages. The DNA does not need to be incorporated into the chromosomes, making it safer and easier to administer. It can produce dose dependent results, also a safety feature. And it can produce long-term protein production, rather than requiring ongoing dosing, as is the case with current antibody therapies.
Covid-19 vaccine: lost in America, but still some global potential
Despite getting off to a quick start, Inovio’s Covid vaccine candidate, INO-4800, did not get chosen as a premier candidate by the Trump administration Warp Speed program. There were also delays in trial approvals at the FDA, some involving questions about using Cellectra for dosing, rather than the more familiar needle-based injection approach for mRNA and other vaccine candidates. At this point in time, we are approaching a nearly fully vaccinated public in the United States, while INO-4800 has only completed its Phase 2 trial. As a result Inovio has partnered with Advaccine to conduct a global Phase 3 trial. Trial subjects will be primarily in Latin America and Asia. Given the positive Phase 2 results, I expect Phase 3 results will also be positive. However, no specific timeline has been announced. The trial will need to be completed, the data analyzed, and applications made to global health agencies. That means, even if all goes well, no sales until well into 2022. However, given the number of people globally who have not been vaccinated, there could still be substantial income from sales. INO-4800 can be stored at room temperature, so it could be particularly attractive to nations with poor infrastructure. Since the situation is evolving, I do not want to place any particular value on INO-4800 at this time. If it does eventually produce revenue, that would be an upside. It could even be a very large upside if there is still sufficient demand for it.
For me, most of the current value of Inovio is in the HPV-targeting therapies VGX-3100, INO-3107, and MEDI0457. Of these VGX-3100 is the most advanced. It is in clinical trials for treatment of three varieties of precancerous cervical dysplasia caused by HPV infections: cervical, vulvar, and anal. In China VGX-3100 is partnered with ApolloBio, but Inovio retains global rights. In March 2021 Inovio announced the first VGX-3100 Phase 3 trial for cervical dysplasia had positive results. This made it the first DNA medicine to achieve efficacy endpoints in a Phase 3 clinical trial. Full results will be presented at a science meeting later this year. Topline results were that 23.7% of patients achieved histological regression with viral clearance, versus 11.3% in the placebo group. Positive secondary results included HPV clearance.
A second Phase 3 trial of VGX-3100 is ongoing, with enrollment completion expected in 2021. That means FDA approval is possible in 2022. Revenue could be substantial. Pricing of the therapy, which is currently unknown, makes it difficult to predict future revenue. Precancerous cervical dysplasia caused by HPV run at about 195,000 cases annually in the U.S. If the therapy were priced at $10,000 (cheap for cancer, expensive for a vaccine) and 100,000 cases were treated per year, revenue would run at $1 billion per year. However, that is just a guess within a possible broad range of outcomes.
Hopefully, the results of VGX-3100 trials for vulvar and anal precancers will also be a success and the label will be enlarged. The same for INO-3107 for recurrent respiratory papillomatosis. In addition, Inovio is partnered with AstraZeneca (AZN) for MEDI0457 for HPV caused head and neck cancer, as well as cervical, anal, penile, and vulvar cancers, currently all in Phase 2 trials.
Glioblastoma therapy: good data so far, but risky
Inovio is conducting a Phase 1/2 novel combination trial of INO-5401 and INO-9012 and Regeneron’s (NASDAQ:REGN) PD-1 inhibitor Libtayo (cemiplimab) for newly diagnosed GBM (glioblastoma multiforme), the most aggressive form of brain cancer. In late 2020, INOVIO shared encouraging interim OS18 (overall survival at 18 months) data, which also demonstrated immunogenicity and tolerability in a majority of patients. The company anticipates sharing two-year (24 months) overall survival data later in 2021.
While this is encouraging data, new glioblastoma therapies have a long record of failure, including when Phase 3 trials followed positive Phase 2 trials. Presuming a Phase 3 trial is started, that makes Inovio even harder to value. Success would propel Inovio into the upper ranks of companies generating novel therapies. One might add $5 billion to $10 billion in market capitalization with that outcome. I do not like to assign any significant value to glioblastoma therapies, but I might be willing to change my view if the full Phase 2 results seem particularly strong. I would prefer to see data from a much larger number of patients.
Cash position
At the end of Q1 2021 Inovio had $519 million in cash and equivalents, which should allow it to reach multiple data points. In January 2021 it had increased its share count with an offering of over 20 million shares at $8.50 per share, generating $162 million in new cash. Operating expenses are running at about $50 million per quarter. Whether more cash will need to be raised (further diluting current shareholders) depends on upcoming data and FDA interactions. While it is at least conceivable that VGX-3100 could begin producing substantial revenue before Inovio runs through its cash, I would expect a cash raise again if strong data leads to a rise in the stock price. Milestones from current partnerships or new deals could also extend the cash runway.
Conclusion
If I am right at guessing U.S. revenue at $1 billion or more (with label and geographic expansion or a higher list price) per year for VGX-3100, then even without a successful Covid-19 approval and launch, Inovio could see its market capitalization and stock price more than double by, say, 2023. Some discounting for the risk of Phase 3 trial failures, or resistance of insurers to pricing, is always in order.
If, like me, you believe in the potential of the DNA plasmid platform, then accumulating shares at $8 to $9 per share makes sense. If you believe that my estimate of $10,000 per therapy for VGX-3100 is too high, that the Covid vaccine will arrive too late to result in significant revenue, and that any glioblastoma therapy success is unlikely, then of course $8 seems too high. When there are so many contingencies, the future is anyone’s guess. My best guess is that VGX-3100 is highly likely to achieve commercial status and then label expansion. At current price, I believe upside potential outweighs downside risks. My take is Inovio is a good Buy for investors with diverse portfolios who can stand the risk.
6/21/21 Nature: In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains
Rapidly-emerging variants jeopardize antibody-based countermeasures against SARS-CoV-2. While cell culture experiments have demonstrated loss of potency of several anti-spike neutralizing antibodies against SARS-CoV-2 variant strains1–3, the in vivo significance of these results remains uncertain. Using a panel of monoclonal antibodies (mAbs) corresponding to many in advanced clinical development by Vir Biotechnology, AbbVie, AstraZeneca, Regeneron, and Lilly, we report the impact on protection in animals against authentic SARS-CoV-2 variants including viruses with B.1.1.7, B.1.351, or B.1.1.28 spike genes. Although some individual mAbs showed reduced or abrogated neutralizing activity in cell culture against B.1.351, B.1.1.28, B.1.617.1, and B.1.526 viruses with E484 spike protein mutations, low prophylactic doses of mAb combinations protected against infection by many variants in K18-hACE2 transgenic mice, 129S2 immunocompetent mice, and hamsters without emergence of resistance. Exceptions were mAb LY-CoV555 and LY-CoV555/LY-CoV016 mono- and combination therapy, which lost all protective activity, and AbbVie 2B04/47D11, which showed partial loss of activity. When administered after infection as therapy, higher doses of several mAb cocktails protected in vivo against viruses with a B.1.351 spike gene. Thus, many, but not all, of the antibody products with Emergency Use Authorization (EUA) should retain substantial efficacy against the prevailing SARS-CoV-2 variant strains.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vari- ant strains have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.28 [also called P.1]) and elsewhere containing substitutions in the N-terminal domain (NTD) and the receptor binding motif (RBM) of the RBD. Cell-based assays suggest that neutralization by many antibodies may be diminished against variants expressing spike mutations, especially at position E4841–5. However, the in vivo significance of this loss of mAb neutralizing activity remains uncertain, particularly for combination mAb therapies.
To evaluate the effects of SARS-CoV-2 strain variation on mAb protection, we assembled a panel of infectious SARS-CoV-2 strains with sequence substitutions in the spike gene (Fig 1a-b) including a B.1.1.7 isolate from the United Kingdom, a B.1.429 isolate from California, a B.1.617.1 isolate (India clade), and two B.1.526 isolates from New York. We also used a Washington SARS-CoV-2 strain with a D614G substitution (WA1/2020 D614G), a SARS-CoV-2 strain with N501Y and D614G substi- tutions (WA1/2020 N501Y/D614G), and chimeric SARS-CoV-2 strains with B.1.351 (Wash-B.1.351) or B.1.1.28 (Wash-B.1.1.28) spike genes in the Washington strain background1,6. All viruses were propagated in Vero cells expressing transmembrane protease serine 2 (TMPRSS2) to pre- vent the emergence of mutations at or near the furin cleavage site in the spike protein that impact virulence7. All viruses were deep-sequenced to confirm the presence of expected mutations prior to use (Supple- mentary Table S1).
We first assessed the impact of SARS-CoV-2 spike variation on anti- body neutralization (Fig 1c-d). We tested individual and cocktails of mAbs in clinical development that target the RBD including 2B04/47D11 (AbbVie), S309/S2E12 (Vir Biotechnology), COV2-2130/COV2-2196 (Vanderbilt University Medical Center with derivatives being evalu- ated by AstraZeneca), REGN10933/REGN10987 (synthesized based on casirivimab and imdevimab sequences from Regeneron), and LY-CoV555 (synthesized based on bamlanivimab sequences from Lilly). All individual mAbs tested efficiently neutralized the WA1/2020 D614G, WA1/2020 N501Y/D614G, and B.1.1.7 strains, and several mAbs (COV2-2130, COV2-2196, S309, S2E12, and 47D11) showed little change in potency against the Wash-B.1.351, Wash-B.1.1.28, B.1.429, and B.1.526 strains (Fig 1c-d). In comparison, REGN10987 or LY-CoV555 respectively showed a ~10-fold or complete loss in inhibitory activity against the B.1.429 and B.1.617.1 strains, which is consistent with studies identi- fying L452 and adjacent residues as interaction sites for these mAbs (Supplementary Table S2). Moreover, REGN10933, LY-CoV555, and 2B04 exhibited a substantial or complete loss of neutralizing activ- ity against Wash-B.1.351, Wash-B.1.1.28, B.1.617.1, and B.1.526 (E484K) viruses that contain mutations at residue E484 (Fig 1c-d and Extended Data Fig 1), which corresponds with structural and mapping studies (Supplementary Table S2). Analysis of mAb cocktails showed that COV2- 2130/COV2-2196, S309/S2E12, and REGN10933/REGN10987 neutralized all virus strains tested, with the latter combination retaining potency corresponding to the mAb with inhibitory activity in the cocktail for a given virus. While the 2B04/47D11 mAb combination efficiently neu- tralized WA1/2020 D614G, WA1/2020 N501Y/D614G, B.1.1.7, and B.1.429 strains, its activity against Wash-B.1.351, Wash-B.1.1.28, B.1.617.1, and B.1.526 (E484K) reflected the less potent 47D11 mAb component (EC50 of 384-2,187 ng/mL) (Fig 1c-d). Additional mutations in B.1.617.1 decreased the potency of the 2B04/47D11 combination further. In contrast, virtu- ally all mAbs retained neutralizing potency against B.1.526 (S477N).
Monoclonal antibody purification
The mAbs studied in this paper (COV2-2196, COV2-2130, S309, S2E12, 2B04, 47D11, REGN10933, REGN10987, LY-CoV555, and LY-CoV016) have been described previously31,36–42. COV2-2196 and COV2-2130 mAbs were produced after transient transfection using the Gibco ExpiCHO Expres- sion System (ThermoFisher Scientific) following the manufacturer’s protocol. Culture supernatants were purified using HiTrap MabSelect SuRe columns (Cytiva, formerly GE Healthcare Life Sciences) on an AKTA Pure chromatographer (GE Healthcare Life Sciences). Purified mAbs were buffer-exchanged into PBS, concentrated using Amicon Ultra-4 50-kDa centrifugal filter units (Millipore Sigma) and stored at ~80 °C until use. Purified mAbs were tested for endotoxin levels (found to be less than 30 EU per mg IgG). Endotoxin testing was performed using the PTS201F cartridge (Charles River), with a sensitivity range from 10 to 0.1 EU per mL, and an Endosafe Nexgen-MCS instrument (Charles River). S309, S2E12, REGN10933, REGN10987, LY-CoV016, and LY-CoV555 mAb proteins were produced in CHOEXPI cells and affinity purified using HiTrap Protein A columns (GE Healthcare, HiTrap mAb select Xtra #28-4082-61). Purified mAbs were suspended into 20 mM histidine, 8% sucrose, pH 6.0. The final products were sterilized by filtration through 0.22µm filters and stored at 4 °C.
https://www.nature.com/articles/s41586-021-03720-y_reference.pdf
12/15/20 $37.6 million grant from DARPA will leverage AstraZeneca's monoclonal antibody and INOVIO's DNA-encoded monoclonal antibody (dMAb®) technologies in the fight against COVID-19
- COVID-19 dMAbs offer a cost-effective treatment option, are fast to administer to subjects, and can be quickly manufactured and scaled up compared to traditional recombinant monoclonal antibody-based therapies
- dMAbs do not require cold chain transport/storage, and the overall approach can be applied beyond COVID-19 for any pathogen or disease that can be treated by recombinant monoclonal antibody-based therapies
Bombshell analysis traces new Ebola outbreak to survivor of West Africa crisis
A survivor of the massive 2014-2016 West African Ebola outbreak almost certainly triggered an outbreak currently underway in Guinea, according to a new genetic analysis, news that has landed like a bombshell in the community of researchers who study the dangerous virus.
The analysis suggests that a survivor of the historic Ebola outbreak continued harboring the virus at least five years after being infected, eventually transmitting it to someone. Previously, the longest an Ebola survivor was believed to have shed the virus was about 500 days.
“I was completely shocked,” Angela Rasmussen, a virologist affiliated with the Georgetown Center for Global Health Science and Security, told STAT.
The discovery was revealed in a genetic analysis of viruses from the current outbreak that was conducted by scientists from Guinea, the Institut Pasteur in Senegal, the University of Nebraska Medical Center, and the University of Edinburgh. It was posted online Friday.
The scientists compared several genetic sequences from the current outbreak — in which 18 people have been infected to date — with sequences from viruses collected during the West African outbreak. Given the long interval between the two events, the assumption had been that this new outbreak was triggered by a new spillover of Ebola viruses from nature. That wasn’t what researchers found.
“The new genomes are most closely related to five identical Ebola virus Makona variant genomes sampled in August 2014 from the same region,” the scientists reported. Makona is the name of the Ebola Zaire strain that caused the 2014-2016 outbreak.
The new viruses had a small number of mutations — roughly a dozen. That’s far fewer than what one would have expected if there had been ongoing but undetected transmission of the virus in the region.
On Twitter, Rasmussen noted that given the rate at which the Makona variant evolved during the 2014 to 2016 period, the current viruses would have been expected to have amassed hundreds of mutations.
“The results are quite remarkable,” said Mike Ryan, who heads the World Health Organization’s Health Emergencies Program. Ryan said that the rate at which the virus had changed was far slower than the rate at which the Makona strain evolved during the 2014-2016 outbreak.
He warned the news could lead to further stigmatization of Ebola survivors, if they are seen within their communities as possible long-term sources of the virus. “Survivors deserve our support,” Ryan said. “They’ve been to hell and back.”
He suggested the finding underscores the need for programs that support survivors and that include follow-ups on their health. It also highlights the need to learn more about the phenomenon known as “viral persistence.”
Jason Kindrachuk, an assistant professor of emerging diseases from Canada’s University of Manitoba, recently received a research grant to do just that; he will be working with survivors of the West African outbreak in Sierra Leone.
He, too, was dumbfounded by the finding. “There’s that lump-in-your-throat moment,” Kindrachuk admitted.
It’s been known for years that some survivors of Ebola harbor virus in their bodies for periods of time after their infection.
The virus hides in places where the immune system can’t ferret it out — the testicles of some infected men, occasionally in the eyeball, or in spinal fluid. In some rare cases, survivors suffer a relapse when the virus reactivates. A Scottish nurse who worked in Sierra Leone during the West Africa outbreak, Pauline Cafferkey, suffered three bouts of disease over a couple of years.
These wells of hidden Ebola in survivors can also on rare occasions infect other people. Transmission events typically involve a male survivor who infects a female sexual partner.
The working hypothesis is that this is what happened in the most recent case. But currently there aren’t enough details known about how this outbreak started to be able to trace back the event to a survivor of the earlier outbreak.
The first known case in the current Guinea outbreak was a nurse who became sick in mid-January and died on Jan. 28. A number of the subsequent cases were people who attended her funeral on Feb. 1. But there have been reports the nurse had cared for her mother, who had been sick before her.
Daniel Bausch, a veteran of multiple Ebola outbreaks, said that in most known cases where a survivor has infected another person, it’s been a man who passed the virus to a sexual partner in his semen. Finding a male who might have transmitted the virus to the nurse or her mother — or someone else before them — might not be doable at this point.
“Can we get that far back? I don’t know. The trail gets cold pretty readily when everybody’s dying,” said Bausch, director of the U.K. Public Health Rapid Support Team, a partnership between Public Health England and the London School of Hygiene and Tropical Medicine. “We may never know.”
Bausch noted that until the West African crisis — which was the first time Ebola transmitted in African cities — outbreaks were small, often only a few dozen cases. The West African outbreak involved more than 28,000 cases and over than 11,000 deaths.
Prior to that, the largest was in Gulu, Uganda, in 2000 and involved 425 people, which at the time was thought to be a hellishly large event.
But more recently, the northeastern corner of the Democratic Republic of the Congo endured a two-year battle with Ebola in an outbreak that recorded 3,470 cases and 2,287 deaths. Bausch said this new experience with large outbreaks — which leave large numbers of survivors — may be giving the world a chance to see something that it could never spot in outbreaks of 50 or 60 people that left only 20 or so survivors.
“Is this just that now we have a sample size that is big enough so that rare events, we’re catching [them]?” he wondered.
https://www.statnews.com/2021/03/12/bombshell-analysis-traces-new-ebola-outbreak-to-survivor-of-west-africa-crisis/
https://clinicaltrials.gov/ct2/show/NCT04906629?term=Inovio&draw=6&rank=49
New INO-4201 P1b as Booster in Healthy VSV-ZEBOV Vaccinees (Boost-EBOV). Sponsor: University of Geneva, Switzerland. Collaborators: DARPA,
Global Urgent and Advanced Research and Development (GuardRX)
Inovio Pharmaceuticals
Ebola virus disease (EVD) is a serious illness with a high fatality rate. Currently only one vaccine is available, VSV-ZEBOV/Ervebo; this vaccine is clinically effective and has been deployed as a preventive measure during recent Ebola outbreaks. The durability of protection afforded by this vaccine is unknown, however, and it is thought that a booster vaccination may be required to maintain immune responses. Recently, a synthetic DNA vaccine, INO-4201, was tested in humans and showed good immunogenicity and an enhanced safety profile.
This study aims to test whether the DNA-based candidate INO-4201 can be used as a booster in healthy volunteers previously vaccinated with VSV-ZEBOV.
Federal funding would reduce capitalized r& d costs vs hitting the income statement. “In June 2020, the Company entered into an Other Transaction Authority for Prototype Agreement (the “OTA Agreement”) with 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. The Company has determined that the OTA Agreement should be considered under Subtopic 958-605, Not-for-Profit Entities- Revenue Recognition, which is outside the scope of Topic 606, as the government agency granting the Company funds is not
receiving reciprocal value for their contributions. The Company will record contra-research development expense on the condensed consolidated statement of operations in the same period that the underlying expenses are incurred.
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. The Company has determined that the Procurement Contract does not currently fall under the scope of ASC 606 as contingencies remain regarding INO-4800 which does not give the Company the ability to satisfy its obligations under the arrangement.
During the three months ended March 31, 2021, the Company recorded $7.8 million as contra-research and development expense related to these agreements with the DoD. As of March 31, 2021 and December 31, 2020, the Company had an accounts receivable balance of $9.6 million and $11.4 million, respectively, on the condensed consolidated balance sheet from the DoD.
1Q21 10-K
“Inovio said it answered the FDA’s questions using data from the P2 study, but it would not disclose the specifics of the agency’s queries. “It was nothing about the safety or the use of the device in the clinic,” Broderick says. “It’s more logistical areas for us to clarify.”
In addition to Inovio, at least three other companies— Genexine, Takis, and OncoSec—are conducting human studies of an electroporated DNA vaccine against COVID-19. Other companies, such as Ichor Medical Systems and IGEA Clinical Biophysics, have developed electroporation devices that they license to pharma companies for DNA vaccine delivery against other diseases.”
G. What happens if I think my response is complete, but the FDA disagrees?
If FDA finds that your response is not complete, FDA will notify you as soon as possible by phone or other means of rapid communication, but no later than 30 days after receipt of your response. The Agency will tell you what information is needed to make it a complete response. The 30-day clock will not start until the FDA receives what it believes to be a complete response to the clinical hold letter.
H. How will the FDA handle an amendment providing additional information to the complete response that is submitted after the 30-day review clock has started? Will FDA extend the 30-day review clock?
No. Such an amendment received during the 30-day review process will not extend the clock. The division may choose to review the amendment in the time remaining, or stop the 30-day clock and start a new 30-day clock based on the receipt date of the amendment.
Amendments to the IND on nonclinical hold issues will be handled in the usual way.
I. What happens once the Agency receives the complete response?
The FDA will review your complete response within 30 calendar days after the receipt of a complete response, indicating whether the hold is lifted and, if not, specifying the reasons why not. After an IND has been placed on clinical hold, the study may not be initiated until the Agency has contacted you (via phone, fax, letter, or e-mail) telling you that the study may proceed (21 CFR 312.42(e)). (Communications by phone, fax, or e-mail will be followed by a letter.)
J. What happens if the Agency does not meet the 30-day response deadline?
As soon as possible after the review team determines that it will not meet the 30-day deadline, the Agency will telephone you and discuss the review progress to date and what is being done to facilitate completion of the review.
https://www.fda.gov/media/72548/download
REVEAL2 6/1 Update: Study Officials: Prakash Bhuyan, MD, PhD => Jeffrey Skolnik, MD. JK at Jeffries 6/1/21: “ VGX-3100 is our lead immunotherapy candidate, currently being studied in two sets of Phase 3 pivotal trials, REVEAL 1 and REVEAL 2. Both trials are ongoing right now, each enrolling about 200 patients. It's a randomized double-blinded placebo-controlled study, where in the first quarter we reported the top line efficacy data from REVEAL 1 trial, where we were able to meet all of the -- not just the primary efficacy endpoints, but all of the secondary efficacy endpoints in all evaluable subjects. And we were excited to hit those endpoints, the primary being not just a regression of the disease in the cervix, but also it's a composite endpoint where we want to see the clearance of the virus, HPV Type 16 and 18, which cause the disease in the first place.
So what we're doing now is we're in the safety follow-up period, which should hit in the second half of this year. So before the end of the year, we will have the full readout reported from REVEAL 1 efficacy trial. Concurrently, we have the second study, the confirmatory Phase 3 trial going, REVEAL 2. So we're also executing that and we should have full enrollment this year and data readout in '22.
What's different about REVEAL 1 and REVEAL 2 is they're identical across the design, except for the safety follow-up. So REVEAL 1 has a one year safety follow-up from the 36 week initial primary time point. REVEAL 2 has a one month follow-up. So it's much closer to finish from the primary endpoint. So we're very looking forward to having both REVEAL 1 full data set this year and REVEAL 2 in 2022. So that program is moving well, and we're very active and very excited around these programs.”
https://clinicaltrials.gov/ct2/history/NCT03721978?A=29&B=30&C=merged#StudyPageTop
Ino-3107 RRP 5/26 Update. University of Cincinnati Medical Center [Not yet => Recruiting] Cincinnati, Ohio, United States, 45267
Contact:Contact: Aaron Friedman, MD
https://clinicaltrials.gov/ct2/history/NCT04398433?A=14&B=15&C=merged#StudyPageTop
6/3 Update: P2a INO-5401 + INO-9012 in Combination With Atezolizumab in Locally Advanced Unresectable or Metastatic/Recurrent Urothelial Carcinoma
Primary Completion: July => December 30, 2021 [Anticipated]
Study Completion: December 30, 2021 [Anticipated]
Primary Purpose:
Treatment
35 participants
This is a Phase I/IIA, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of INO-5401 + INO-9012 delivered by intramuscular (IM) injection followed by electroporation (EP), in combination with atezolizumab in participants with locally advanced unresectable or metastatic/recurrent Urothelial Carcinoma (UCa). The trial population is divided into two cohorts: Cohort A: Participants with locally advanced unresectable or metastatic/recurrent UCa, who have confirmed disease progression during or following treatment with anti-Programmed Death receptor-1/Programmed Death receptor Ligand-1 (anti-PD-1/PD-L1) therapy; Cohort B: Participants with locally advanced unresectable or metastatic/recurrent UCa, who are treatment naïve and ineligible for cisplatin-based chemotherapy. A safety run-in will be performed with up to six participants (safety analysis participants) from cohort A.
https://clinicaltrials.gov/ct2/history/NCT03502785?A=22&B=23&C=merged#StudyPageTop
“ An announcement of further advances of INO-4800 PHIII human trials in China with their China partner Advaccine, announcements of further funding from CEPI, orders from COVAX or another international partner who may want to stockpile their MERS vaccine or even stockpile INO-4800 could change the outlook for Inovio's price action and an erosion of the bear thesis.
Additionally, Inovio is going to report in the coming quarters the 24 month overall survival for patients enrolled in clinical trials for the treatment of the deadly brain disease Glioblastoma while using INO-5401 in combination with INO-9012 and a PD-1 checkpoint inhibitor from Regeneron (NASDAQ:REGN). For that reason, I remain optimistic on the price being a buy at these levels. Your due diligence is necessary in the volatile biotech investing arena. Some sage advice: Only invest what you can afford to lose. Time, not timing, creates wealth. Margin calls create liquidity in the market.”
A silent decimation: South America’s losing battle against Covid. 6/18/21
Strained and underfunded health systems, economics and misinformation have all led to a surge in deaths
The cold, tired and desperate relatives camped outside the Barrio Obrero general hospital in Asunción don’t need charts or datasets to confirm what they can see with their own eyes.
As Paraguay records the world’s highest daily proportion of Covid deaths, the huddled families wait for news of their loved ones – and for the sudden requests for medicine and supplies that the country’s chronically underfunded health system cannot provide.
“There’s really so little support from the government – it’s a disaster,” said Jessica Ortigosa, whose father was languishing in a chair instead of a bed. “They should have prepared for all this from the start of the pandemic.”
As she spoke, two women collapsed on a sofa in the hospital’s entrance, their uncontrollable tears announcing the death of Paraguay’s most recent coronavirus victim.
Natalia Bernal, who stood nearby, was relieved to be able to drop the brave face she had just put on for her mother, who lay intubated in hospital a day after losing her husband to Covid.
“I couldn’t let my mom see me in the state I was in,” said Bernal. Still, she added, at least her mother had got a bed.
“We needed intensive care yesterday for my dad and there wasn’t any. There just isn’t any.”
On Wednesday this week, Paraguay registered 18.09 deaths per million, compared with 2.71 in India, 2.2 in South Africa, 1.01 in the US, and 0.14 in the UK.
And as the US and Europe begin to emerge from the pandemic, discard their masks and ponder how best to spend the recovery funds, the crisis most evident in Paraguay is playing out across much of South America.
India may have commanded much of the world’s attention over recent weeks, but Paraguay, Suriname, Argentina, Uruguay, Colombia, Brazil and Peru are suffering – in that order – a silent decimation by Covid unlike that anywhere else in the world. Even in seventh-placed Peru, the number of deaths per million stands at 9.12 – more than three times the figure in India.
In the early months of the pandemic, Paraguay and nearby Uruguay were praised as Latin America’s standout success stories in Covid management.
But since March the two countries have seen an explosion of the disease, largely attributed to the aggressive Brazilian variant that has torn through much of South America, and to decreased compliance with social distancing measures.
n Uruguay, not even one of Latin America’s quickest vaccination programmes has been able to contain the spread. Paraguay, meanwhile, has faced the continuing emergency under the strain of entrenched poverty, a historically underfunded health system, and with many questions over government corruption. Anger and frustration prompted widespread street protests earlier this year and a manslaughter case against the government has been opened by the public prosecutor’s office.
Argentina was also seen as a model, with low case numbers at the start of the pandemic when the government introduced strong restrictions that were respected by the public.
‘People die in less than a week’: Covid wave catches Argentina off-guard
Read more
But that scenario has changed drastically. Covid has become Argentina’s main killer, far outstripping heart disease and cancer and claiming an average of 528 deaths a day over the past two weeks.
Vanina Edul, an ICU doctor in Buenos Aires, says the lack of the kind of scenes witnessed in some countries during the first wave of the pandemic is misleading: “What generates the notion of sanitary collapse is when people die in their homes or on the street, but in Argentina people are dying behind closed doors in Covid wards so Covid deaths remain invisible and almost unreal.”
Claudio Belocoppitt, the head of the Argentinian Health Union, (UAS), which represents private health insurance firms, argues that the country’s chronic social and economic problems play a part in the high Covid death rate.
“Our poverty markers have grown hugely in the last decade, our inflation rate is one of the highest in the world, so why should we be expected to suddenly become geniuses at managing a calamity like this?” he asks.
ensions between the ruling progressive Peronists, who have stood by the science but allowed their traditional populist reflexes to influence decisions, and the pro business Together for Change opposition, with its denialist tendencies, have not helped.
Earlier this week, the government announced an overhaul of the country’s health system to integrate public and private care providers – a decision Belocoppitt likens to “reorganising your army in the middle of a war”.
And yet Argentinians remain optimistic – and largely unaware of the high death rate – as the news is drowned out by the country’s complex political wrangling.
Argentina’s vaccination programme is in full swing and the vaccination menu has diversified with Sputnik, Sinopharm and AstraZeneca, the main vaccines administered. Almost 40% of the population has got at least one jab and nearly 8% two jabs so far.
Latin America’s lack of a united front on Covid has had disastrous consequences
Andre Pagliarini
Read more
While underinvestment, economics, new variants and slow vaccination programmes bear responsibility for much of the region’s current crisis, so do many of its politicians. And no leader on the continent faces a charge sheet quite as damning as that of Jair Bolsonaro.
Brazil, about to reach the awful landmark of 500,000 deaths, has been led by a president who dismissed the coronavirus as a “little flu”, who resisted containment strategies, and who was fined last weekend for failing to wear a mask at a biker rally in São Paulo. He is now being investigated by a congressional inquiry over his calamitous response to the public health emergency.
Those involved in the Covid response – including representatives of pharmaceutical companies – have told the inquiry that the Bolsonaro administration dismissed offers to acquire the vaccine last year. The country has so far managed to immunise just 11.4% of its 212 million citizens.
Worse still, acceptance of the vaccine has also been stymied by Bolsonaro’s vehemently anti-science posturing.
“The biggest issue in Brazil – and one that’s having a terrible effect on vaccine take-up – is the denialism in politics,” said Chrystina Barros, a member of the group fighting Covid-19 at the Federal University of Rio de Janeiro.
“We have a denialist president whose speech and behaviour run contrary to medical advice – and which are influencing people against getting the vaccine. It’s a perfect storm.”
'The heart of darkness': neighbors shun Brazil over Covid response
Read more
With average daily deaths of 2,000, Brazil is becoming increasingly isolated worldwide. Several nations – including its neighbour Argentina – are restricting entry to Brazilian passengers, and the country has been the subject of international opprobrium.
“If Brazil doesn’t take the pandemic seriously, it will continue to affect the entire neighbourhood there and beyond,” Tedros Adhanom Ghebreyesus, director-general at the World Health Organization, said at the end of March. “It’s not just about Brazil.”
Political upheaval – not to mention decades of underinvestment in public healthcare – has also taken its toll in neighbouring Peru.
Héctor Araújo, a 51-year-old nutritionist who worked in a clinic for the elderly in central Lima, died a fortnight after being diagnosed with Covid. He left behind three children aged 18, 16 and 10.
“He died because of the health system’s inefficiency,” said his younger sister, Patty. “Then the disease consumed him.”
Despite making his social security payments, Héctor Araujo spent 10 days in intensive care in a hospital that lacked the staff needed to deal with complicated cases.
“My brother needed 24-hour attention with specialists and ICU equipment that they couldn’t give him,” said Patty Araujo.
She, like tens of thousands of bereaved Peruvians, is furious at the successive governments that have invested a paltry portion of GDP in the healthcare system - less than half what neighbouring countries put into public health – despite two decades of strong economic growth.
Days before a deeply divisive second round ballot between two candidates at opposite ends of the political spectrum, a government review confirmed what Peruvians had long suspected: the true number of Covid-19 deaths in the country was 180,764 – almost triple the official death toll of 69,342. The belated revision made Peru the country with the highest death rate per capita in the world.
Peru may have imposed one of the earliest and strictest lockdowns in Latin America back in March 2020, but high labour informality, overcrowded households and even shopping habits meant the measures failed to curtail infections.
The vaccine rollout has been slow and the second wave of the virus was worse than the first, forcing Peru into another severe lockdown after a surge in infections that pushed hospitals to the edge of the collapse. Progress has also been scuppered by the political turmoil which saw three presidents in a week last year, and the situation wasn’t helped by the revelation in February that former leader Martín Vizcarra and nearly 500 others had been vaccinated in secret
A caretaker government steered the vaccination drive back on track and about 2m Peruvians – 7% of the population – have now been fully vaccinated.
The death rate, which peaked in April, has slowly decreased but the grief and anger remain.
“The strange thing about this pandemic is that all the death has not sunk in,” said Patty Araújo. “Sometimes, I think we believe it’s all a bad dream.”
Jessica Ortigosa sees little prospect of a swift end to the nightmare as she waits for word on her father and wonders whether he’ll be able to swap his chair for a bed.
“This is how it is,” she said amid the cold and the tears and the embraces outside the Barrio Obrero general hospital. “It’s like this here every day. Every day.”
INVENTOR OF THE MRNA VACCINE EXPOSES THE DANGERS AND THAT FDA KNEW! mRNA vaccine states "FDA was notified of the spike protein cytotoxic effects"
https://twitter.com/inoviolt/status/1405228672865509376?s=21
CureVac blames variants as a closely-watched Covid vaccine goes down in flames, failing pivotal study with woeful data
CureVac was widely expected to come in with a late but likely late-stage winner in the race to develop new vaccines for the Covid-19 pandemic. Instead, late Wednesday, the German biotech said their mRNA candidate CVnCoV flat failed a pivotal trial — quashing any hopes for a quick entry in the blockbuster field and gutting their share price.
CVnCoV demonstrated an interim vaccine efficacy of 47% against COVID-19 disease of any severity and did not meet prespecified statistical success criteria. Initial analyses suggest age and strain dependent efficacy.
That’s a woeful result, presenting the world with some challenging questions.
The data were not what investors were waiting to hear. After rewarding CureVac with a massive spike in its share price earlier, its stock cratered on the news, falling 46% after the bell and wiping out more than $8 billion of market cap.
The 2 leading vaccines — from Pfizer/BioNTech and Moderna — both utilize the same basic mRNA tech in challenging the immune system with copies of the spike protein on cell surfaces. They each come with high efficacy rates and clear safety.
CureVac, though, says its late entry was forced to contend with an “unprecedented” situation where 13 variants are circulating now.
In total, 134 Covid-19 cases were assessed in this interim analysis. Out of these cases, 124 were sequenced to identify the variant causing the infection. The outcome confirms that only one single case was attributable to the original SARS-CoV-2 virus. More than half of the cases (57%) were caused byVariants of Concern. Most of the remaining cases were caused by other less characterised variants such as Lambda or C.37, first identified in Peru (21%) and B.1.621, first identified in Colombia (7%). In this context, the interim results suggest efficacy in younger participants but did not allow to conclude on efficacy in the age group above 60.
“While we were hoping for a stronger interim outcome, we recognize that demonstrating high efficacy in this unprecedented broad diversity of variants is challenging. As we are continuing toward the final analysis with a minimum of 80 additional cases, the overall vaccine efficacy may change,” said CureVac CEO Franz-Werner Haas in a prepared statement. “In addition, the variant-rich environment underlines the importance of developing next-generation vaccines as new virus variants continue to emerge.”
If CureVac is right, and variants vanquished what would otherwise have been an effective vaccine, the implication is that the others are being similarly impacted. We have no evidence of that, but that’s a major question facing health authorities around the globe.
There’s another side to this argument as well. CureVac made a bet — attractive to the Gates Foundation — on unmodified mRNA that would overcome a variety of obstacles, like the cold chain supply line that hobbled the leaders. If that’s a bust, then the company has a painful period of realignment ahead.
Another consideration: Novavax just 2 days ago posted a solid 90.3% efficacy rate across nearly 30,000 patients in the US and Mexico, raising further questions about CureVac’s case.
That could all be bitter news to GSK CEO Emma Walmsley, who anted up €150m earlier this year to collaborate more extensively with the mRNA runner up. To be left at the starting gate with another R&D loser would leave a mark.
The latest news comes at a critical time in the war against Covid. Vaccine resistance has now slashed vaccination rates in the US while the most affluent nations in the world stand first in line for the best vaccines. Meanwhile poorer nations are being forced to stand at the back of the line, waiting indefinitely for the vaccines to arrive.
Two other vaccines, from J&J and AstraZeneca, have entered the fray in many countries, but safety issues have marred their rollout, raising questions on how soon the globe can stop the pandemic before one of the variants breaks loose.
New INO-4201 P1b as Booster in Healthy VSV-ZEBOV Vaccinees (Boost-EBOV). Sponsor: University of Geneva, Switzerland. Collaborators: DARPA,
Global Urgent and Advanced Research and Development (GuardRX)
Inovio Pharmaceuticals
Information provided by (Responsible Party):
Angela HUTTNER, University of Geneva, Switzerland
Ebola virus disease (EVD) is a serious illness with a high fatality rate. Currently only one vaccine is available, VSV-ZEBOV/Ervebo; this vaccine is clinically effective and has been deployed as a preventive measure during recent Ebola outbreaks. The durability of protection afforded by this vaccine is unknown, however, and it is thought that a booster vaccination may be required to maintain immune responses. Recently, a synthetic DNA vaccine, INO-4201, was tested in humans and showed good immunogenicity and an enhanced safety profile.
This study aims to test whether the DNA-based candidate INO-4201 can be used as a booster in healthy volunteers previously vaccinated with VSV-ZEBOV.
Detailed Description:
This randomized placebo-controlled phase 1b trial will evaluate the safety, tolerability and immunogenicity of the DNA-based vaccine candidate INO-4201 in healthy adult volunteers who previously received a single injection of VSV-ZEBOV. These participants will be randomized to either INO-4201 or placebo, injected once intradermally (ID) followed by electroporation (EP) with the CELLECTRA2000 device. Volunteers will be observed for 1 hour after vaccination and will attend follow-up visits at the Clinical Trials Unit in the 24 weeks after injection (8 visits in all).
Primary outcome parameters are (i) the incidence of adverse events in relationship with INO-4201 from day 0 to 14, and (ii) geometric mean titers (GMT) of EBOV-GP-binding IgG antibodies at 4 weeks post-injection.
https://clinicaltrials.gov/ct2/show/NCT04906629?term=Inovio&draw=6&rank=49
4700 MERS P2 Started 5/18 in Lebanon, Jordan Update 6/2
Locations: Jordan
Clinical Research Center, Irbid Specialty Hospital (CRC/ISH)
[Not yet recruiting]
Irbid, Jordan, 21110
Jordan
Pharmaceutical Research Center / Jordan University of Science and Technology
[Not yet recruiting]
Irbid, Jordan, 22110
Lebanon
American University of Beirut Medical Center
[Not yet recruiting]
Beirut, Lebanon
Hammoud Hospital University Medical Center
[Recruiting]
Saida, Lebanon
https://clinicaltrials.gov/ct2/history/NCT04588428?A=8&B=9&C=merged#StudyPageTop
CureVac says its vaccine showed only 47% efficacy against #covid19 in 40K-person trial, citing "unprecedented context of at least 13 variants circulating within the study population."
Pivotal study conducted in 10 countries in fast changing environment of at least 29 COVID-19 variant strains; original strain almost completely absent.
At second interim analysis, statistical success criteria not met. Favorable safety profile confirmed
Initial analyses show trend for age and variant dependent efficacy.
Results communicated to EMA, study progressing to final analysis within the next few weeks.
In total, 134 Covid-19 cases were assessed in this interim analysis. Out of these cases, 124 were sequenced to identify the variant causing the infection. The outcome confirms that only one single case was attributable to the original SARS-CoV-2 virus. More than half of the cases (57%) were caused by Variants of Concern. Most of the remaining cases were caused by other less characterised variants such as Lambda or C.37, first identified in Peru (21%) and B.1.621, first identified in Colombia (7%). In this context, the interim results suggest efficacy in younger participants but did not allow to conclude on efficacy in the age group above 60.
“While we were hoping for a stronger interim outcome, we recognize that demonstrating high efficacy in this unprecedented broad diversity of variants is challenging. As we are continuing toward the final analysis with a minimum of 80 additional cases, the overall vaccine efficacy may change,” said Dr. Franz-Werner Haas, Chief Executive Officer of CureVac. “In addition, the variant-rich environment underlines the importance of developing next-generation vaccines as new virus variants continue to emerge.”
The HERALD study, conducted by Curevac in conjunction with Bayer, enrolled approximately 40,000 participants in ten countries in Latin America and Europe. The second interim analysis included 134 cases, occurring at least two weeks after administration of the second dose. To identify strains causing COVID-19 infections within the trial, sequencing of virus variants has so far been performed on 424 COVID-19 cases, of which 124 fulfilled adjudication criteria and were included in the present efficacy analysis.
https://www.curevac.com/en/2021/06/16/curevac-provides-update-on-phase-2b-3-trial-of-first-generation-covid-19-vaccine-candidate-cvncov/
That’s pretty interesting…. Having a study goes beyond the targeted date as it appears that patients must be responding well to the treatment. Skolnik explained that patients are split by a biomarker called MGMT promoter methylation status. Patients whose tumors are not methylated tend to have a worse prognosis. Inovio’s treatment could potentially be used for both types of patients, but the clinical trial may provide some clues about who might benefit the most.
“Ultimately, the question is, why are some patients doing better than others? Who are the patients that could benefit the best from this? Will it be everybody at the end of the story?” Skolnik said.
At the one year data cut off in the trial, 85% of patients were still alive, which Skolnik called very encouraging. At 18 months, 70% of methylated and 55% of non-methylated patients were alive. Inovio will release two-year data later this summer after the June cut off. The trial is now yielding different data beyond the survival rates that can help in future trials, according to Skolnik.
Ino wants to find out OS30 and median (50%) remaining life span for methylated, i.e., at what month 50% of methylated patients still survives, tissue data, correlation of protection.
Inovio, which has fully sponsored the glioblastoma study, is currently having conversations about the next clinical step for the INO-5401 and INO-9012 combination. While the company has not formally partnered with Regeneron, Skolnik said the two companies have collaborated well on the trial, with Regeneron offering up Libtayo. He hopes that will continue as the combination moves into later development.
As for when the combo might be put to regulators, Skolnik said the FDA wants to see randomized data for trials like this, which Inovio has not done yet. The company’s next step is likely to try to compare the combo with standard of care.
https://www.fiercebiotech.com/biotech/inovio-going-after-impossible-tumor-left-dust-new-cancer-meds
Under the Original Agreement, Advaccine made an upfront payment to the Company of $3.0 million and a payment of $2.0 million upon the dosing of the first subject in a Phase 2 clinical trial of INO-4800 in China. Under the Restated Agreement, the Company is entitled to receive up to an aggregate of $206.0 million upon the achievement of additional specified milestones related to the development, regulatory approval and commercialization of INO-4800, including the achievement of specified net sales thresholds for INO-4800 in the expanded territory, if approved. The Company will also be entitled to receive a royalty equal to a high single-digit percentage of annual net sales in each region within the licensed territory, subject to reduction in the event of competition from biosimilar products in a particular region and in other specified circumstances. Advaccine’s obligation to pay royalties will continue, on a licensed product-by-licensed product basis and region-by-region basis, for ten (10) years after the first commercial sale in a particular region in the licensed territory or, if later, until the expiration of the last-to-expire patent covering a given licensed product in a given region. Beginning in the first calendar year following the first commercial sale of INO-4800 in the licensed territory outside of Greater China, Advaccine will pay the Company an annual maintenance fee of $1.5 million for a period of five years, which fee will be creditable against any royalties payable by Advaccine with respect to sales outside of Greater China.
https://d18rn0p25nwr6d.cloudfront.net/CIK-0001055726/d5635a56-9b51-4c13-aa63-013e071207e2.rtf
6/2 VGX-3100 Vulvar HSIL Update
https://clinicaltrials.gov/ct2/history/NCT03180684?A=34&B=35&C=merged#StudyPageTop