Vaccine development, historically more of a marathon than a short distance sprint, becomes that and more in the COVID-19 pandemic-charged world. Such a crisis brings out the best in some and the worst in others. With front line health workers exhibiting heroics around the world on one end of the spectrum, some firms practice predatorial practices, capitalizing on the situation for gain, on the other end. Certainly all agree that the faster the world gets out of this situation, the better. A safe and effective vaccine is the best hope declare many world experts. Vaccines are not usually a dinner table topic but given the state of affairs today, that has changed. Unfortunately, some infused jingoism into the process as for some, national pride gets improperly mixed-up with science. In India, for example, a Director General of the renowned national research institute ICMR stated in a leaked communication that an indigenous vaccine would be ready by August 15. There was just one problem: the vaccine’s developer, Bharat Biotech, plans to start clinical trials on July 7. With ICMR establishing 12 clinical trial sites, its just not possible to complete such a major undertaking in a month. But that wasn’t the point. The real reason the milestone date was leaked to the press was to put the Indian bureaucracy, notorious for pay-to-participate stage gates, on notice. But this sort of extreme case highlights, in a sad way, the desperation the world faces with COVID-19. Never before in modern history have economies been turned upside down. That America’s soft underbelly was exposed in this contagion is an understatement, but goes the American economy and goes every other one. None are immune. Hence why the vaccine race, and some healthy and productive competition, is so important. What follows is an update on a selection of some key candidates.
The field of candidates has grown with the urgency worldwide, with over 140 candidates in development. 18 of them have made it to the imperative clinical trials stage where more than likely most, but hopefully not all, will fail. For a comprehensive list of vaccine candidates, see the link to the World Health Organization (WHO) and that organization’s “Draft landscape of COVID-19 candidate vaccines.”
Vaccine Clinical Trials
Clinical trials for vaccine candidates follow a standard general protocol centering on three phases including phase 1 (small tests with focus on safety and immunogenicity), phase 2 and on to phase 3, which are major undertakings involving what can be tens of thousands of volunteer participants in many nations. Ideally, the vaccine can be tested in countries and regions where infections are ongoing so that the investigational product’s true efficacy can be evaluated. That COVID-19 spreads in an uneven manner, possibly impacted by a particular country’s ability (or lack thereof) to organize and direct inhabitants to exhibit particular behavioral patterns is a separate topic. Suffice to say, the world’s largest economy and great remaining superpower has become the epicenter (along with an emerging Brazil) while countries like Thailand and Vietnam see very few cases now despite the fact that they were next to the pathogen’s birthplace in China. On to a selection of candidates.
AZD1222 (AstraZeneca & Oxford University’s Jenner Institute: Now in Phase 3 Clinical Trials in the UK, South Africa and Brazil)
Perhaps this candidate has the greatest momentum? The Oxford University’s Jenner Institute candidate known originally as ChAdOx1 nCoV-19 but since the AstraZeneca partnership now called AZD1222. This candidate, developed from a weakened version of a common cold virus (ChAdOx1) known in chimpanzees, has been genetically modified for humans. The UK-based scientists developed on top of the core vaccine, adding genetic material associated with SARS-CoV-2 proteins known as Spike glycoprotein (S). Found on the surface of the novel coronavirus (SARS-CoV-2), it uses the spike protein to bind to ACE2 receptors on human cells to penetrate human cells and thereby infect the body.
AZD1222 has moved to Phase 3 as recently at a parliamentary hearing reported on by Reuters, one of the vaccine’s developers, Sarah Gilbert, shared that 8,000 volunteers were enrolled in the Phase 3 clinical trial evaluating AZD1222. Ms. Gilbert sent a positive signal, noting, “We’re very happy that we’re seeing the right sort of immune response that will give protection, and not the wrong sort.” The Phase 3 clinical trial, associated with large numbers of volunteers over 18, involves the collection of data to determine the overall safety and efficacy: how well does AZD1222 work to prevent people contracting the virus. The trial now is ongoing in the UK and South Africa as well as now the largest nation in South America.
Oxford University announced on June 27 that a 5,000 Phase 3 trial in Brazil has started and volunteers were already receiving the vaccine treatment. This is Latin America’s first phase 3 COVID-19 clinical trial, which had an official start date of June 20, 2020. Research sites are distributed in Sao Paulo, Rio de Janeiro and a center located in Northeast Brazil.
AZ Deal Making
Part of the U.S. government’s Operation Warp Speed, AstraZeneca received over $1 billion from the U.S. Health and Human Service (HHS) Biomedical Advanced Research and Development Authority (BARDA) to develop what is now called AZD1222. This transaction secured 400 million vaccine doses and the arrangement helped solidify the ability to manufacture 1 billion doses (at risk) with first deliveries by September 2020. By June 4, the Coalition for Epidemic Preparedness (CEPI) announced a $383 million investment in the partnership to produce up to 300 million doses of AZD1222 for the “Global Access Facility.” With an emphasis on equitable access, the UK pharma giant and CEPI’s ACT Accelerator partner GAVI executed a Memorandum of Understanding establishing distribution of the COVID-19 Vaccine Global Access Facility on a non profit basis during the pandemic. Back in April, India’s Serum Institute committed to make up to 60 million doses while on May 25 TrialSite News reported the UK Government inked a deal with Imperial College London and AstraZeneca to produce the AZD1222 investigational candidate, including up to 30 million doses (part of a 100 million dose commitment) for the UK.
The AstraZeneca/Oxford partnership shows real potential with heavy amounts of capital, scientific talent, manufacturing infrastructure and positive momentum.
mRNA-1273 (Moderna, in a slight delay to Phase 3; some drama but a powerful underlying technology)
mRNA-1273 is built on Moderna’s (Nasdaq: MRNA) mRNA platform offering advances in efficiency, expediency which could offer advantages in clinical development and manufacturing. The platform allows for the development and sequencing of the virus without the need for actually involving the virus. As described by its maker, mRNA-1273 is an mRNA vaccine COVID-19 encoding for a prefusion stabilized form of the Spike (S) protein, selected by Moderna in collaboration with investigators from Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Disease (NIAID), part of the NIH. The first batch of the investigational product was funded by the Coalition for Economic Preparedness Innovations (CEPI) and completed February 7, 2020. The first participant doses in the NIAID-led Phase 1 study of mRNA-1273 was dosed on March 16 in an incredibly expedited 63 days form sequence selection to Phase 1 study dosing.
By May 10, TrialSite News communicated the start of the Phase 2 clinical trial, which actually commenced May 29, 2020 according to Clinicaltrials.gov. The ongoing Phase 2 study includes only American sites, including Meridian Clinical Research, Heartland Research Associates, Trial Management Associates, Benchmark Research and Velocity Clinical Research.
By May 18, 2020, the company released press sharing positive interim clinical data from the Phase I study sponsored by NIAID. Then on June 11, the Cambridge, MA-based venture reported after U.S. FDA feedback, it completed its Phase 3 vaccine clinical trial protocol; the clinical trial targeted launch date was sometime in July and would include 30,000 participants. Moreover, that same day researchers published a non-peer reviewed preclinical research study on mice revealing positive data: mRNA-1273 vaccination triggered neutralizing antibody and CD8 T cell responses and offered security against SARS-CoV-2 infection mice lungs and noses.
Deal Making & Drama
By April, TrialSite News reported that Moderna had secured up to $483 million from the U.S. government via BARDA to accelerate the development of mRNA1-273. The company also was showcased as part of Operation Warp Speed announced by President Donald Trump. On June 17, Moderna and Israel entered into a deal, securing vaccine product for that nation.
In the meantime, some key people in Moderna have been collecting big payouts. With the stock popping 30% in mid-May and up nearly 250% for the year, certain executives benefited from the company’s 10b5-1 trading plan leading to a $30 million windfall. Such plans exist to protect executives and key employees from any insider trading allegations. However, with methodical press releases and associated positive “chatter” to the market, some industry observers became suspicious. After all, in the middle of a deadly pandemic, shouldn’t the incentivization scheme direct all insiders to a higher-order imperative such as a vaccine to market?
But apparently a sell pattern formed just when all else calls for a buy. With Operation Warp Speed’s embrace (and associated tax payer dollars) comes a nationwide expectation for a collective investment (meaning a hold). Is a pattern of stock selling in a pandemic contagion healthy or indicative of a bright future for mRNA-1273?
Now with a delay in the Phase 3 trial, a pause can be a moment for reflection. Damian Garde with STAT reported that participating investigators shared anonymously that the protocol was again under modification. A relatively common event, data sources from University of Illinois at Chicago and NIH Director Francis Collins all indicated as best they could tell the company was still on track to a start date of the Phase 3 trial in July. But the company’s target of producing key data by November could be at risk. The political stakes are gargantuan: The Operation Warp Speed imperative: that a safe and effective vaccine would be ready by January 2021 presupposes everything moves expeditiously. Moderna is definitely motivated to keep on track and demonstrate the ultimate evidence of success.
Ad5-nCoV (CanSino Biologics has technically led the race and now the Chinese Military ‘Volunteer’ for Phase 3)
The basis for this candidate was formed over a decade ago in Toronto when a group of Chinese scientists discussed over a barbeque how the safety and quality of developing world vaccines (including China at the time) was behind the West. Four of those scientists eventually left prestigious “big pharma” positions to form CanSino Biologics (CASBF) in Tianjin, China. As the Japan Times recently reported, the company now has global attention on both sides the Pacific as one of the frontrunners in the race to develop a COVID-19 vaccine.
Developed by China’s CanSino Biologics in partnership with China’s Institute of Biotechnology, Academy of Military Medical Sciences, Ad5-nCoV represents the first SARS-CoV-2 vaccine to enter clinical trials in the world’s most populous nation and second largest economy. Developed with CanSino Biologics’ adenovirus-based viral vector technology platform, the investigational candidate has been genetically engineered with replication-defective adenovirus type 5 as the vector to express the COVID-19 spike protein.
Considered a frontrunner in the vaccine race, the company was the first sponsor worldwide to initiate a clinical trial of a SARS-CoV-2 focused experimental vaccine. And just 2.5 months later, the they achieved the next first in the COVID-19 vaccine race, publishing peer reviewed data assessing the safety and immunogenicity of Ad5-nCoV based on its Phase 1 clinical trial. In this preliminary safety study, 108 volunteers received one of three doses of the candidate product. The company reported a majority of those participants developed levels of antibodies and T cells specifically targeting the spike protein associated with SARS-CoV-2 that equate to what could be classified as an immune response.
The data, however, revealed some critical questions. The company disclosed that only 75% of the volunteers that received a high dose of the experimental vaccine and 50% of those receiving a medium to low dose actually developed levels of neutralizing antibodies considered high by researchers.
Dennis Burton, an immunologist with Scripps Research, reminded all that SARS-CoV-2 is novel never before studied by scientists. So no one really knows what levels of neutralizing antibodies are actually required to protect a human being from the novel coronavirus infection. But the San Diego-based researcher did comment that the CanSino Biologics’ vaccine results at this stage “are not overwhelming by any means at all.”
In April, the company launched a Phase 2 clinical trial in China working in collaboration with Jiangsu Province Centers for Disease Control and Prevention, Hubei Provincial Center for Disease Control and Prevention and Zhongnan Hospital.
By May 13, the company and the nation of Canada announced intentions to work together on the vaccine and shortly thereafter Health Canada authorized the Phase 2 COVID-19 vaccine clinical trial with Dalhousie University in Nova Scotia and the Canadian Center for Vaccinology. With the National Research Council of Canada now involved the country was moving forward to secure a nationwide order of the investigational product. Associated with vaccine purchases, on June 2, Canada ordered 37 million syringes associated with forthcoming vaccine activities.
In the meantime, in China by May 22 the company issued a press release showcasing the positive results demonstrating that a single dose of the experimental product” produces virus-specific antibodies and T cells in 14 days, making it a potential for further investigation,” reported Beijing Institute of Biotechnology Professor Wei Chen, one of the key players behind the sciences in the collaboration with CanSino Biologics.
In another first for CanSino Biologics, the Chinese military received the approval to utilize the SARS-CoV-2 vaccine candidate co-developed by its research unit and the Company. On June 25, the Central Military Commission of China approved the use of the vaccine by members of the military for a one year duration, effectively converting this into a Phase 3 clinical trial on military personnel over the next year.
A company investor, Gary Rieschel, also a founding partner of Qiming Ventures Partners, notes the clinical trial on Chinese troops is a “huge step forward” and that the vaccine race isn’t about nationalism but rather health. As a successful investor, Mr. Rieschel undoubtedly is concerned about dollars and could care less about jingoism, however TrialSite News reported that China did the opposite in a state sponsored press release positioned that it is in a race with the U.S. to find a vaccine and that it had “systems advantages,” such as the ability to accelerate the examination and approval procedure.
Of course back in March, TrialSite News interpreted that statement as the advantage of a more authoritarian-leaning command and control government over a more democratically elected one. Interesting to note that state-sponsored press release that TrialSite News linked to was yanked sometime later as the jingoism emanating out of China in February and March got tempered down in the Spring.
CanSino Biologics has essentially created a Phase 3 clinical trial evaluating Ad5-nCoV on at least some volunteers within the Chinese military. Additionally, the company has formed an alliance with Canada to distribute the vaccine should it eventually get approved. Arguably, CanSino Biologics has a leadership position in the vaccine race.
BNT162 (BioNTech & Pfizer Project ‘Lightspeed’ could be a winner)
Germany-based BioNTech, backed by a German billionaire pharma entrepreneur, was founded in 2008 and is traded on the Nasdaq under the symbol BNTX. The company’s mRNA-based candidate to halt SARS-CoV-2 disease infection is known as BNT162b1. Actually four candidates under a product umbrella, the COVID-19 program is known as project “Lightspeed” and each candidate (of the four) represents various mRNA formats and target antigens.
As reported in Precision Vaccinations, two of the vaccine candidates incorporates the larger spike sequence while the other two candidates include optimized RBD from the spike protein.
Two of the four vaccine candidates include a nucleoside modified mRNA (modRNA), one includes a uridine containing mRNA (uRNA), and the last candidate uses self-amplifying mRNA (saRNA). Each mRNA format is combined with a lipid nanoparticle (LNP) formulation. While the RBD-based candidates include what the company deems the most important part of the spike for triggering antibodies to inactivate SARS-CoV-2.
On April 9, 2020 Pfizer announced more details on its alliance with the vaccine maker. Pfizer made an upfront payment of $185 million including an equity investment of approximately $113 million and as part of the consideration, the German biotech venture would be eligible for milestone payments of up to $563 million for a total potential upside of $748 million. Now both Pfizer and BioNTech would jointly develop the COVID-19 vaccine in the U.S. and Europe and scale up manufacturing capacity to support global supply. Their goal: be in a position to be able to supply millions of vaccine doses by the end of 2020 subject to technical milestones and of course regulatory approval. Thereafter, they plan on a further rapid scale up of capacity to be able to produce hundreds of millions of doses by 2021. In this partnership, BioNTech secured one of the world’s largest and most sophisticated pharmaceutical companies as its partner. Now Pfizer was all in with its global vaccine research and development, regulatory, manufacturing and distribution infrastructure.
On April 23, TrialSite News announced a series of activities including a Phase 1/2 clinical trial to evaluate BNT162 to prevent COVID-19 infection. The first COVID-19 vaccine candidate to start a clinical trial in Germany, with the Pfizer partnership the pair would embark on a global clinical development initiative.
Hence, the BioNTech and Pfizer partnership now has two clinical trials disclosed on Clinicaltirals.gov; the first study NCT04380701 is a study of the safety, tolerability and potential efficacy of the RNA vaccine candidate against COVID-19 in healthy adults in Germany. With a start date of April 23, the clinical trial in Germany targeted 200 healthy volunteers in the multi-site, dose-escalation trial investigating the safety and immunogenicity of the four RNA-based vaccine candidates.
The second trial NCT04368728 commenced just a week after the German trial. This study was designed to investigate the safety, tolerability, immunogenicity and potential efficacy of the RNA vaccine candidates targeting COVID-19 in healthy adults. Based in the United States, the sponsors leveraged deep Pfizer site connections and recruited the following sites: Diablo Clinical Research, Research Centers of America, Clinical Neuroscience Solutions, Inc., Meridian Clinical Research LLC, Clinical Research Atlanta, Kentucky Pediatric/Adult Research, University of Maryland, Center for Vaccine Development and Global Health, Boston Medical Center, Sundance Clinical Research, Quality Clinical Research, NYU Langone Health, Rochester Clinical Research, M3 Wake Research Inc., PMG Research of Wilmington, LLC, Cincinnati Children’s Hospital Medical Center, Aventiv Research, Inc., Benchmark Research, Ventavia Research Group LLC, Texas Center for Drug Development, Inc. and Jean Lewis Research Inc. /Foothill Family Clinic.
TrialSite News recently covered the medRxiv uploaded pre-peer review summary data describing the preliminary clinical data for BNT162b1 as it will undoubtedly be concurrently reviewed by scientists around the world.
The data reveals a robust immunogenic response and promising safety profile of the novel vaccine candidate targeting SARS-CoV-2. The promising data supports proceeding with the clinical development imperative but there isn’t nearly enough data to come to any conclusion.
INO-4800 (Inovio Pharmaceuticals’ INO-4800 shows promise with recent data as it readies for Phase 2/3 Study)
Inovio Pharmaceuticals’ (Nasdaq INO) INO-4800, a DNA plasmid vaccine with electroporation, could be the “dark horse” in the race as the only nucleic-acid based investigational candidate that is stable at room temperature for over a year. Hence making distribution and storage less cumbersome, a significant advantage when considering the implementation of a mass immunization, reports the company. The vaccine product is accompanied by CELLECTRA,® a device used to open small pores in the cell reversibly to facilitate entry of plasmids. Hence, the company positions a novel platform delivering optimized DNA into human cells where then translated into proteins that trigger a human immune response, in theory, to generate a robust and targeted T cell and antibody reaction against SARS-CoV-2.
Most recently, the company disclosed positive interim clinical data based on the first of two Phase 1 clinical trial cohorts. The company reported in a preliminary analysis that 94% of Phase 1 clinical trial participants demonstrated overall immune responses at Week 6 post two doses of INO-4800 in the study with 40 healthy volunteers. Moreover, after week 8, the INO-4800 regimen was reported safe and well-tolerated and no serious adverse events occurred. Any reported adverse events were grade 1 in severity level. Moreover, the company shared that in a preclinical animal challenge that INO-4800 afforded full protection against COVID-19 replication in the lungs in mice.
The Phase 1/2 clinical trial NCT04336410 worked with the University of Pennsylvania, Central Kentucky Research Associates and Center for Pharmaceutical Research as investigational sites.
The company is planning on a Phase 2/3 efficacy study in the summer pending regulatory approval. Moreover, the company recently received $71 million from the U.S. Department of Defense (DOD) to support scale up manufacturing of the company’s CELLECTRA 3PSP smart device and the procurement of CELLECTRA 2000 devices, again used for the administration of the actual vaccine. That the DOD was outlaying such capital to this firm was another positive indicator of the potential.
A handful of other candidate companies were not covered here but should be understood by those tracking these vaccines. These companies and their candidates include China’s Sinovac and Sinopharm, also headed to Phase 3 clinical trials soon. Other candidates include Johnson and Johnson (Janssen) and GlaxoSmithKline (actually supplying adjuvant to many vaccine makers) to Novavax and Genexine. Again, see the WHO COVID-19 vaccine list for a comprehensive update as well as Precision Vaccinations for good additional details. The leading candidate moving into Phase 3 trials could be considered AstraZeneca/Oxford as Phase 3 activity has commenced in the UK, South Africa and Brazil as well as CanSino Biologics as the military has given the greenlight to test the experimental candidate on military personnel in that country. Moderna’s in a slight delay but is a nimble company with a powerful platform and should kick into Phase 3 gear by late July at the latest. The world has never needed a safe and effective vaccine as badly as now.