Virus World

For now, novel vaccine type needs to be frozen for storage and transport, with one requiring ultracold temperatures of –70°C. Today’s dramatic news that Moderna’s COVID-19 vaccine might work as well as one made by Pfizer and BioNTech means the world could have two powerful weapons to fight the COVID-19 pandemic. Now, the next hot vaccine topic is, well, heat. Both vaccines use a novel technology—strands of messenger RNA (mRNA), held within lipid particles—that is vulnerable to degradation at room temperature and requires doses to be frozen for transportation, then thawed for use. That’s where the Moderna vaccine may have an edge: Unlike Pfizer’s and BioNTech’s offering, it does not have to be stored at –70°C, but can tolerate a much warmer –20°C, which is standard for most hospital and pharmacy freezers. That difference means Moderna’s vaccine should be easier to distribute and store, particularly in the rural United States and developing countries that lack ultracold freezers. Moderna says years of development work enabled its vaccine to be stored at higher temperatures, but last week another mRNA vaccine company announced it is testing a COVID-19 vaccine that early studies suggest can survive at the even warmer temperatures of 2°C to 8°C found in refrigerators.  

Many types of vaccines must be stored and transported frozen, via a cold supply chain. Public health officials have even found ways to keep a vaccine ultracold, between –60°C to –80°C, in places like sub-Saharan Africa. There, for the past 5 years, a high-tech thermos called Arktek has helped distribute Ebola vaccines that must be kept ultracold. “In all likelihood, we’ll need a wide range of supply chain tools” to distribute COVID-19 vaccines, says Daniel Lieberman, a mechanical engineer with Global Health Labs in Seattle, a nonprofit created by the Bill & Melinda Gates Foundation, which funded Arktek’s development, and by a venture capital firm started by Bill Gates. Still, relying on an ultracold chain is expensive, and in some places it may make more sense to distribute a vaccine that can tolerate warmer temperatures even if it’s less effective. Both the Moderna and Pfizer/BioNTech vaccines give the body’s cells an mRNA template for making the spike protein of SARS-CoV-2, the virus that causes COVID-19. The protein then moves to the cell’s surface and triggers an immune response. This mRNA is relatively fragile compared with the proteins or protein fragments that often make up conventional vaccines, and it cleaves easily at room temperature, says Alana Gerhardt, who studies vaccine product development at the nonprofit Infectious Disease Research Institute (IDRI) in Seattle. Also, enzymes called ribonucleases that chew up mRNAs “are everywhere, even in the controlled environment of the lab,” from sources such as lab workers’ breath and skin, Gerhardt says.

The companies give the mRNA some protection during production and storage by inserting it into a carrier, a fatlike substance called a lipid nanoparticle. The lipid also shields the mRNA from enzymes in the blood once it has been injected. But the nanoparticle is deliberately designed to slowly degrade, so it won’t build up in the liver and cause harm, says Massachusetts Institute of Technology geneticist and chemical engineer Daniel Anderson.  Although the companies’ exact formulations are proprietary, Pfizer and BioNTech have so far said their vaccine has to be kept ultracold. But Barney Graham, a vaccine researcher at the U.S. National Institute of Allergy and Infectious Diseases who designed the mRNA used by both Moderna and Pfizer/BioNTech, says the temperature requirements are actually unclear. Pfizer and BioNtech started with –70°C when they first asked regulators to test their vaccine in humans, and Graham says the companies might ultimately be able to document that the mRNA survives warmer temperatures. In the meantime, at sites in Kalamazoo, Michigan, and Puurs, Belgium, Pfizer will pack shipments of 200 to 1000 vials each containing five doses in insulated boxes with thermal sensors on dry ice to provide the necessary chill. Pharmacies and doctor’s offices that lack $15,000 ultracold freezers can store it in the thermal box for about 2 weeks by refilling the dry ice every 5 days; once removed, the vaccine can be refrigerated for 5 days. Moderna’s vaccine, however, is stable for 6 months at –20°C, or in a standard freezer, and the company announced today its product can be kept at normal refrigerator temperatures for up to 30 days, longer than the 7 days initially expected....

Pfizer announced positive early results from its coronavirus vaccine trial, cementing the lead in a frenzied global race that has unfolded at record-breaking speed.  The drug maker Pfizer announced on Monday that an early analysis of its coronavirus vaccine trial suggested the vaccine was robustly effective in preventing Covid-19, a promising development as the world has waited anxiously for any positive news about a pandemic that has killed more than 1.2 million people. Pfizer, which developed the vaccine with the German drugmaker BioNTech, released only sparse details from its clinical trial, based on the first formal review of the data by an outside panel of experts. The company said that the analysis found that the vaccine was more than 90 percent effective in preventing the disease among trial volunteers who had no evidence of prior coronavirus infection. If the results hold up, that level of protection would put it on par with highly effective childhood vaccines for diseases such as measles. No serious safety concerns have been observed, the company said. Pfizer plans to ask the Food and Drug Administration for emergency authorization of the two-dose vaccine later this month, after it has collected the recommended two months of safety data. By the end of the year it will have manufactured enough doses to immunize 15 to 20 million people, company executives have said.

“This is a historical moment,” Kathrin Jansen, a senior vice president and the head of vaccine research and development at Pfizer, said in an interview. “This was a devastating situation, a pandemic, and we have embarked on a path and a goal that nobody ever has achieved — to come up with a vaccine within a year.” Independent scientists have cautioned against hyping early results before long-term safety and efficacy data has been collected. And no one knows how long the vaccine’s protection might last. Still, the development makes Pfizer the first company to announce positive results from a late-stage vaccine trial, vaulting it to the front of a frenzied global race that began in January and has unfolded at record-breaking speed. Eleven vaccines are in late-stage trials, including four in the United States. Pfizer’s progress could bode well for Moderna’s vaccine, which uses similar technology. Moderna has said it could have early results later this month. The news comes just days after Joseph R. Biden Jr. clinched a victory over President Trump in the presidential election. Mr. Trump had repeatedly hinted a vaccine would be ready before Election Day, Nov. 3. This fall, Pfizer’s chief executive, Dr. Albert Bourla, frequently claimed that the company could have a “readout” by October, something that did not come to pass.

Operation Warp Speed, the federal effort to rush a vaccine to market, has promised Pfizer $1.95 billion to deliver 100 million doses to the federal government, which will be given to Americans free of charge. But Dr. Jansen sought to distance the company from Operation Warp Speed and presidential politics, noting that the company — unlike the other vaccine front-runners — did not take any federal money to help pay for research and development. “We were never part of the Warp Speed,” she said. “We have never taken any money from the U.S. government, or from anyone.” She said she learned of the results from the outside panel of experts shortly after 1 p.m. on Sunday, and that the timing was not influenced by the election. “We have always said that science is driving how we conduct ourselves — no politics,” she said. The data released by Pfizer Monday was delivered in a news release, not a peer-reviewed medical journal. It is not conclusive evidence that the vaccine is safe and effective, and the initial finding of more than 90 percent efficacy could change as the trial goes on. “We need to see the actual data, and we’re going to need longer-term results,” said Jesse Goodman, a professor of medicine and infectious diseases at Georgetown University....

Pfizer Press releaase (Nov. 09, 2020): 

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against

Pfizer and BioNTech are under a white-hot spotlight because their vaccine, by design, is likely to be the first to have any efficacy data. The announcement is both good news and bad news. Umer Raffat, a senior managing director at the investment bank Evercore ISI, wrote in an analyst note that the fact that Pfizer hasn’t conducted an interim analysis was “a good thing” because it means that, based on the details of the trial protocol, the vaccine had not failed to prevent more than 77% of Covid cases, the benchmark for success at this early juncture. But it also suggests that cases of Covid are being reported less frequently among participants in the Pfizer study than in the U.S. as a whole. That means that the study is progressing more slowly than Pfizer and its partner, BioNTech, originally expected. In August, Pfizer had thought that the first interim analysis could occur as early as September. Pfizer and BioNTech are under a white-hot spotlight because their Covid-19 vaccine, by design, is likely to be the first to have any efficacy data. But that first analysis will come when there have been a total of only 32 cases of Covid-19 across the company’s entire 42,000-volunteer study. It would be considered to be positive, Pfizer has said, if six or fewer of those 32 cases occurred in the group that received the vaccine, with the rest occurring in the group that received the placebo. The trial is expected to continue until 150 of the volunteers in the study have had Covid-19.

Pfizer CEO Albert Bourla set the goal of having a Covid-19 vaccine ready by October this spring, in what appeared to be a bid both to combat the pandemic and to make a statement about the company’s research prowess. Pfizer is in the midst of spinning off older, slower-growing parts of the company in a merger with Mylan, which will leave Bourla running a firm whose future will depend heavily on its research laboratories and the prospects of its experimental drugs.  The vaccine itself is expected to be a significant but not huge financial opportunity. Analysts at SVB Leerink estimate sales could peak at $3.5 billion in 2021, and then stabilize at $1.4 billion a year. In its third-quarter earnings, also announced Tuesday, Pfizer reported profits of $2.2 billion on sales of $12.1 billion. But the October time frame has put Pfizer squarely in the political maelstrom of the U.S. election, as President Trump repeatedly predicted that a vaccine would be available before Election Day. It has been clear for months that other companies developing Covid-19 vaccines, including Moderna, AstraZeneca, and Johnson & Johnson, had no chance of hitting that mark.

On Oct. 6, the Food and Drug Administration released new guidance on safety data that would be required before it would consider clearing a vaccine through an emergency use authorization, or EUA, its fastest path to making a vaccine available. The agency told drug makers not to file for an EUA until at least half the patients in their studies have been followed for two months. In an Oct. 16 public letter, Bourla confirmed that this would prevent Pfizer from filing for an EUA until the third week of November. At an advisory panel of outside experts the FDA held last week, the agency signaled that it was not certain it would grant an EUA for a vaccine until a sufficient amount of data had been accumulated to more fully understand the safety and efficacy of a vaccine prospect.

The U.S. Food and Drug Administration needs at least two months of safety data before authorizing emergency use of any experimental Covid-19 vaccine. Pfizer’s CEO Albert Bourla said the company would file for emergency approval as soon as safety data is available, assuming those results are positive. The FDA requires at least two months of safety data on half of trial participants to grant emergency approval, he said, as well as information on effectiveness and proof it can be manufactured safely. The safety data is likely to take the longest to collect — Bourla said Pfizer expects to have manufacturing data before that and should know whether or not the vaccine is effective by the end of October. The company will continue to monitor and report safety data for all trial participants for two years, Bourla said. Bourla said the November timeline reflects the company’s “best estimates,” noting that this could change.

Bourla’s statement cements Pfizer’s status as a frontrunner — alongside Germany’s BioNTech, who it is developing the vaccine with — in the global race to develop a safe and effective Covid-19 vaccine. Excluding Russia and China, which have licensed vaccines for domestic use, no manufacturer has been granted regulatory approval for a vaccine anywhere in the world. If Pfizer manages to stick to this timeline, it could be the first. Pfizer and other vaccine-makers have grown increasingly frustrated with the persistent politicization of potential Covid-19 vaccines by high-ranking officials, most notably President Trump, who has claimed one will be ready before the November 3 election. Bourla’s letter does little to hide this annoyance,stating: “To ensure public trust and clear up a great deal of confusion, I believe it is essential for the public to understand our estimated timelines for each of these three areas.”

We may not find out whether the vaccines prevent moderate or severe cases of Covid-19. If you were to approve a coronavirus vaccine, would you approve one that you only knew protected people only from the most mild form of Covid-19, or one that would prevent its serious complications? The answer is obvious. You would want to protect against the worst cases. But that’s not how the companies testing three of the leading coronavirus vaccine candidates, Moderna, Pfizer and AstraZeneca, whose U.S. trial is on hold, are approaching the problem. According to the protocols for their studies, which they released late last week, a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death. To say a vaccine works should mean that most people no longer run the risk of getting seriously sick. That’s not what these trials will determine.

The Moderna and AstraZeneca studies will involve about 30,000 participants each; Pfizer’s will have 44,000. Half the participants will receive two doses of vaccines separated by three or four weeks, and the other half will receive saltwater placebo shots. The final determination of efficacy will occur after 150 to 160 participants develop Covid-19. But that is only if the trials are allowed to run long enough. Pfizer will look at the accumulating data four times, Moderna twice and AstraZeneca once to determine if efficacy has been established, potentially leading to an early end to the trials. Knowing how a clinical trial defines its primary endpoint — the measure used to determine a vaccine’s efficacy — is critical to understanding the knowledge it is built to discover. In the Moderna and Pfizer trials, even a mild case of Covid-19 — for instance, a cough plus a positive lab test — would qualify and muddy the results. AstraZeneca is slightly more stringent but would still count mild symptoms like a cough plus fever as a case. Only moderate or severe cases should be counted. There are several reasons this is a problem. First, mild Covid-19 is far more common than severe Covid-19, so most of the efficacy data is likely to pertain to mild disease. But there is no guarantee that reducing the risk of mild Covid-19 will also reduce the risk of moderate or severe Covid-19. The reason is that the vaccine may not work equally well in frail and other at-risk populations. Healthy adults, who could form a majority of trial participants, might be less likely to get mild Covid-19, but adults over 65 — particularly those with significant frailty — might still get sick. This is the case with influenza vaccines, which reduce the risk of mild disease in healthy adults. But there is no solid evidence they reduce the number of deaths, which occur largely among older people. In fact, significant increases in vaccination rates over the past decades have not been associated with reductions in deaths.

Second, Moderna and Pfizer acknowledge their vaccines appear to induce side effects that are similar to the symptoms of mild Covid-19. In Pfizer’s early phase trial, more than half of the vaccinated participants experienced headache, muscle pain and chills. If the vaccines ultimately provide no benefit beyond a reduced risk of mild Covid-19, they could end up causing more discomfort than they prevent. Third, even if the studies are allowed to run past their interim analyses, stopping a trial of 30,000 or 44,000 people after just 150 or so Covid-19 cases may make statistical sense, but it defies common sense. Giving a vaccine to hundreds of millions of healthy people based on such limited data requires a real leap of faith.  Declaring a winner without adequate evidence would also undermine the studies of other vaccines, as participants in those studies drop out to receive the newly approved vaccine. There may well be insufficient data to address the aged and underrepresented minorities. There will be no data for children, adolescents and pregnant women since they have been excluded. Vaccines must be thoroughly tested in all populations in which they will be used. None of this is to say that these vaccines can’t reduce the risk of serious complications of Covid-19. But unless the trials are allowed to run long enough to address that question, we won’t know the answer.

The trials need to focus on the right clinical outcome — whether the vaccines protect against moderate and severe forms of Covid-19 — and be fully completed. It is not too late for the companies to do this, and the Food and Drug Administration, which reviewed the protocols, could still suggest modifications. These are some of the most important clinical trials in history, affecting a vast majority of the planet’s population. It’s hard to imagine how much higher the stakes can be to get this right. Cutting corners should not be an option.

The companies hope to earn the trust of the public and of scientists who have clamored for details of the studies.  Two drug companies that are leading the race to develop coronavirus vaccines bowed to public pressure on Thursday, abandoning their traditional secrecy and releasing comprehensive road maps of how they are evaluating their vaccines. The companies, Moderna and Pfizer, revealed details about how participants are being selected and monitored, the conditions under which the trials could be stopped early if there were problems, and the evidence researchers will use to determine whether people who got the vaccines were protected from Covid-1. Moderna’s study will involve 30,000 participants, and Pfizer’s 44,000.  Companies typically share these documents after their studies are complete. The disclosures while the trials are still underway, a rare move, are aimed at addressing growing suspicion among Americans that President Trump’s drive to produce a vaccine before the election on Nov. 3 could result in a product that was unsafe.  The plan released by Moderna on Thursday morning included a likely timetable that could reach into next year for determining whether its vaccine works. It does not jibe with the president’s optimistic predictions of a vaccine widely available to the public in October.

Pfizer’s plan does not appear to estimate when its results could be available. Its chief executive has said repeatedly that the company hopes to have an answer as early as October. Moderna has said only that it could have a result before the end of the year. Moderna’s 135-page plan, or protocol, indicated that the company’s first analysis of early trial data might not be conducted until late December, though company officials now say they expect the initial analysis in November. In any case, there may not be enough information then to determine whether the vaccine works, and the final analysis might not take place until months later, heading into the spring of next year. Moderna’s timeline meshes with the cautionary estimates from many researchers, including Dr. Robert R. Redfield, the director of the Centers for Disease Control and Prevention, who told senators on Wednesday that a vaccine would not be widely available until the middle of next year. Hours later, Mr. Trump sharply contradicted him, making unsubstantiated projections that a vaccine could become widely available weeks from now. On Wednesday, Joseph R. Biden Jr., the Democratic presidential nominee, said in Wilmington, Del., that the process used to evaluate and approve a vaccine would have to be “totally transparent” to win public confidence. He has said that Mr. Trump’s calls for companies and regulators to speed the process have shaken the public’s faith in vaccines and that politics has no place in vaccine development. Researchers in particular have been urging vaccine makers to share the detailed blueprints of their studies so that outside experts can evaluate them. At least one expert, after reading the plans, has already raised questions about the way the trials were designed. “I want to acknowledge a good deed done,” said Peter Doshi, who is on the faculty at the University of Maryland School of Pharmacy in Baltimore and an editor with The BMJ, a medical journal. He previously requested the plans from Moderna and Pfizer. “They have opened up, for the first time, the ability for researchers not involved in the trial to form their own independent judgment about the design of this study.”

Until now, none of the nine companies that are testing vaccines in large clinical trials had released this level of detail. Moderna, AstraZeneca and Pfizer, which is collaborating with the German company BioNTech, are among the front-runners in the global race to produce a vaccine to fight the pandemic. A spokeswoman for AstraZeneca said the company intended to publish its protocol shortly. Novavax, which is expected to start a large, advanced clinical trial later this year, also did not comment. Johnson & Johnson, which has said it plans to begin a large trial this month, said it would have “more information to share” when the trial starts.AstraZeneca’s trial was stopped temporarily because of serious illness in a participant. It has resumed in Britain and Brazil, but not in the United States. Earlier studies of both vaccines in small numbers of people found that after the second shot, they developed so-called neutralizing antibodies, which can inactivate the virus in lab tests. The vaccines also produced a favorable response involving T-cells, another part of the immune system...

Now, a new study by researchers from Pfizer, University of Arizona, Purdue University, The Scripps Research Institute, and UC San Diego School of Medicine and published on the preprint server bioRxiv in September 2020 reports that an enzyme inhibitor may act in synergism with the approved antiviral remdesivir to suppress viral replication in COVID-19. Remdesivir is an RNA-dependent RNA polymerase (RdRp) inhibitor that has received emergency use authorization by the US Food and Drug Administration (FDA) in May 2020 for the treatment of SARS-CoV-2. Remdesivir trials have revealed that this drug reduces the time to recovery for COVID-19 patients, but not the severity of the disease. To enhance its clinical impact, it is necessary to find other drugs that may add to its therapeutic efficacy. The drug candidate PF-00835231 discussed in the current study acts on the SARS-CoV-2 main protease or 3C-like protease (3CL protease or 3CLpro). This is required for viral replication since it causes the large viral polyprotein p1a/p1ab to be cleaved at 10 or more junctions. The result is the production of several non-structural proteins that play a crucial part in viral replication and transcription. These include RdRp, the helicase, and the 3CLpro itself. Also, viral 3CLpro has no comparable human analogs. These two properties make it an ideal candidate for further investigation as a potential COVID-19 therapeutic.

Protease inhibitors have played a similar role in HIV and HCV therapeutics. Following this lead, the current researchers identified a small molecule protease inhibitor PF-00835231 that was active against SARS-CoV, the virus responsible for the earlier respiratory illness outbreak of 2002.  Produced by structure-based drug design, this drug never saw the light of day because of the rapid termination of the outbreak by stringent public health measures. Now, the researchers are taking a fresh look at it because of the high degree of identity between the SARS-CoV and SARS-CoV-2 3CLpro. In fact, they have entirely identical active sites. The researchers found that both PF-00835231 and its phosphate prodrug has antiviral activity against a broad spectrum of coronaviruses (CoVs). It binds tightly to the enzyme at the catalytic cysteine residue, potently suppressing its activity. This enzyme being conserved across several CoVs. This allows it to inhibit several CoV 3CLpro enzymes in vitro, from alpha-, beta- and gamma-CoVs. However, it is inactive against human and HIV proteases, indicating its specificity of activity.

The researchers examined the ability of PF-00835231 to exert antiviral activity against SARS-CoV-2 in cell culture, using a cytopathic effect (CPE) assay. As expected from experience with other viral protease inhibitors, they found that there was a dose-dependent but steep suppression of viral activity with this molecule. When repeated using cell lines, which are more similar to the human lung cells, they obtained similarly promising results. Thus, this drug candidate has in vitro antiviral activity even as a single agent.  When antiviral agents are combined, especially when they act on different steps of the replication cycle, the effects are often much more significant than when used alone. Evaluation of the combined activity of these drugs led to the finding that while the in vitro EC50 for PF-00835231 alone was 0.14 μM, and for remdesivir, it was 0.074μM, in combination, they showed a mix of synergistic and additive effects. This could be because different convalescent sera were used for the detection process...

Preprint available at bioRxiv (Sept.13, 2020):

https://www.biorxiv.org/content/10.1101/2020.09.12.293498v2

Through Operation Warp Speed, the U.S. has backed seven vaccine candidates with $11 billion, securing preorders for some 800 million doses. Scientists, drugmakers and governments are moving with unprecedented haste to deliver a vaccine to protect against the new coronavirus. The fastest of them have already delivered early data from human studies, and further results from others should come quickly as the year progresses. The goal, at least in the U.S., is to have a vaccine ready for use in some fashion by the end of the year, or early next. Doing so would be a scientific feat with few parallels. No vaccine has ever been developed so quickly, never mind manufactured for the world. Researchers' success or failure could determine whether the virus becomes endemic, recurring in countries around the world year after year, or is ultimately checked.  With the health of their citizens at stake, governments are investing enormous sums of money into vaccine research and development, and to prepare for manufacturing and distributing what will likely need to be hundreds of millions of doses necessary to keep infection at bay.

Although none of the coronavirus vaccines under development has proved its efficacy yet in clinical trials, at least 5.7 billion doses have been pre-ordered  around the world. First shipments of a COVID-19 vaccine created by Western laboratories have often been snapped up by the United States. Five vaccines — three Western and two Chinese — are in Phase 3 efficacy trials involving thousands of people. In a surprise announcement, Russian President Vladimir Putin claimed Tuesday that a vaccine dubbed Sputnik V — after the Soviet satellite — conferred “sustainable immunity” against the novel coronavirus. As research laboratories around the world race to develop a vaccine, manufacturers have received financing to help them prepare to have millions of doses ready to administer in 2021 or even before the end of the year.

Oxford University, working with the Swedish-British pharmaceutical group AstraZeneca, hopes to have results by September, while the US biotech company Moderna, partnering with the U.S. National Institutes of Health (NIH), is aiming for the end of the year, possibly November. U.S. President Donald Trump has launched “Operation Warp Speed” in a bid to develop, manufacture and distribute a COVID-19 vaccine to all Americans by January 2021. Hundreds of millions of dollars have been directed to vaccine developers, including nearly $500 million to Johnson & Johnson at the end of March. The United States has allocated funding to more companies than any other nation in the hope that one of them will come up with the vaccine to counter the highly contagious virus. So far, Washington has handed out at a total of at least $9.4 billion to seven vaccine developers and signed manufacturing contracts with five of them to provide 700 million doses. The companies involved are: Johnson & Johnson, Moderna, Oxford/AztraZeneca, Novavax, Pfizer/BioNTech, Sanofi/GSK, Merck Sharp and Dohme.  Two vaccine developers — Oxford/AztraZeneca and Sanofi/GSK — have signed or are in advanced negotiations with the European Commission to provide a combined 700 million vaccine doses. Britain, because of Brexit, is negotiating a separate pre-order of 250 million doses from four developers.  Japan is counting on 490 million doses from three suppliers, including 250 million from Novavax of the United States. Pharmaceutical giant Takeda bought the rights to a Novavax vaccine for Japan, which has funded the research. It would be produced locally.

Brazil chose a similar model, ordering 100 million doses from AstraZeneca and partnering with China’s Sinovac to produce 120 millions of CoronaVac, which is already undergoing testing with Brazilians. Clinical tests of two Chinese vaccine candidates — Sinovac and Sinopharm — are well underway but only a few international partnerships have been announced, the one with Brazil and a possible one with Indonesia. Russia said 20 nations have pre-ordered 1 billion doses of Sputnik V and that with foreign partners it would be able to produce 500 million doses a year in five countries. The Coalition for Epidemic Preparedness Innovations, launched in 2017 by Norway, India, the Bill and Melinda Gates Foundation and the Wellcome Trust, seeks to ensure that there is “equitable access” to future vaccines. It has pre-ordered 300 million doses from AstraZeneca for dozens of developing countries in a partnership with The Vaccine Alliance. Billions of doses would be produced for Asia and elsewhere by the giant Serum Institute of India (SII), the largest vaccine producer in the world. Novavax and AstraZeneca have separately signed agreements with SII to produce a billion doses each for India and low- and middle-income countries on the condition that they prove their efficacy in clinical trials.

Watchdogs expressed concern that Pfizer and BioNTech's recent vaccine supply deal with the U.S. could lead to price gouging on the final shot. The U.K. pumped $127 million into its vaccine manufacturing capacity, plus the EMA formed a multi-pronged COVID-19 research initiative. And the NIH will launch a suite of large-scale coronavirus therapeutics trials. 

With a new U.S. vaccine supply deal under their belts, Pfizer and BioNTech are taking heat from some watchdogs concerned that the partners' shot is overpriced—and worried by Pfizer's refusal to promise a no-profit vaccine. China's Sinopharm said its shot could release to the public before year's end; plus, the U.K. poured nearly $127 million into manufacturing "for any successful" COVID vaccine, approval pending. Meanwhile, the National Institutes of Health is gearing up to launch a "flurry" of large-scale COVID-19 therapeutics trials, and the European Medicines Agency established a new coronavirus research initiative. 

Pfizer and BioNTech's $1.95 billion deal to supply 100 million vaccine doses to the U.S. drew ire from watchdogs, who warned that the move could lead to price-gouging later. The agreement includes an option for 500 million more doses at an as-yet-undetermined price. AstraZeneca and Johnson & Johnson both pledged to sell vaccines at no profit to the U.S.—which has shelled out funding for development in both cases—while Pfizer has expressed interest in making at least a marginal return on its shot.....

The first human trials of a coronavirus vaccine developed by researchers at the University of Oxford will start today in the U.K. Making the announcement at a recent press briefing, U.K. government Health Secretary Matt Hancock pledged £20 million in government funding to support Oxford University’s ChAdOx1 nCoV-19 coronavirus vaccine program, and another £22.5 million to fund Phase II testing of a coronavirus vaccine in development by Imperial College London, which is projected to start human testing in June. The Imperial College London funding will also be used to help prepare for Phase III studies. “We will throw everything we’ve got at developing a vaccine,” Hancock added. “The U.K. is at the forefront of the global effort … and for all of the efforts around the world, two of the leading vaccine developments are taking place here at home, at Oxford and Imperial.”

The start of human testing in the U.K. coincides with Germany’s regulator, the Paul-Ehrlich-Institut, giving German biotech BioNTech and partner Pfizer the green light to start the first coronavirus vaccine clinical trial in the country. “This is the fifth authorized clinical trial worldwide in which a preventive specific COVID-19 vaccine candidate is tested in humans,” the Federal Institute for Vaccines and Biomedicines said. The Phase I/II study will evaluate the BNT162 vaccine program. Clinical trials are also expected to start in the United States upon regulatory approval, which is anticipated shortly, Pfizer said. The first part of the clinical study in Germany will test variants of the vaccine in 200 healthy volunteers aged 18–55 years. The second part of the study will be expanded to include volunteers who are at an increased risk of infection or increased risk of serious COVID-19 disease.

A week after Pfizer posted impressive early coronavirus vaccine efficacy numbers, Moderna took the spotlight early Monday with impressive findings of its own. But separate from its big announcement, the mRNA biotech said its vaccine can be kept at refrigerated temperatures for 30 days, reducing hurdles for a potential large-scale rollout. Moderna’s mRNA vaccine, mRNA-1273, can be stored at 36 degrees to 46 degrees Fahrenheit for up to 30 days, the company reported Monday, up from a prior estimate of just a week. It's also stable for 12 hours at room temperature. For longer-term storage and shipping, the vaccine needs to be kept at freezer temperatures of -4 degrees Fahrenheit, a temperature that distributors are familiar with, Moderna CEO Stéphane Bancel said on CNBC Monday. Bancel also stressed that Moderna’s vaccine won’t require dilution before it's administered to patients. That's a “big differentiator of our product," Bancel said on CNBC.

Pfizer’s vaccine, another frontrunner, requires colder storage at -94 degrees Fahrenheit and will only last for 24 hours at refrigerated temperatures. But the company has an aggressive plan to tap experienced shipping partners to transport doses in newly designed, GPS-enabled storage containers. Moderna’s stability profile will “likely make it easier to widely distribute compared to Pfizer’s BNT162b2,” Barclays analysts wrote to clients Monday. Pfizer is working on a powder version of its vaccine that's stable at room temperature, the analysts noted.  While Moderna and Pfizer are the only two players to post early efficacy numbers so far, a host of other players are advancing vaccines expected to be stable at refrigerated temperatures.  CureVac, a German biotech in mid-stage testing, said last week its vaccine is stable for at least three months at refrigerated temperatures, and up to 24 hours at room temperature. The stability profile “has the potential both to enable decentralized storage and to significantly facilitate large-scale vaccination efforts during the current pandemic," chief production officer Florian von der Mülbe said in a statement. Other vaccines using various technologies, such as programs from Sanofi, AstraZeneca, Novavax and Johnson & Johnson, are also eying refrigerated storage.  On the heels of its early data release Monday, Moderna said it’s on track to have about 20 million doses of its vaccine ready to ship in the U.S. by the end of the year. It’s expecting to be able to produce 500 million to 1 billion doses next year.  

Moderna's release  (November 16, 2020):

https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-longer-shelf-life-its-covid-19-vaccine

AstraZeneca Plc said on Sunday Britain's health regulator had started an accelerated review of its potential coronavirus vaccine. “We confirm the MHRA’s (Medicines and Healthcare Products Regulatory Agency) rolling review of our potential COVID-19 vaccine,” an AstraZeneca spokesman said. In rolling reviews, regulators are able to see clinical data in real time and have dialogue with drug makers on manufacturing processes and trials to accelerate the approval process. The approach is designed to speed up evaluations of promising drugs or vaccines during a public health emergency. AstraZeneca’s COVID-19 vaccine is being developed along with the University of Oxford. Bloomberg reported on Friday that MHRA had also begun an accelerated review for the COVID-19 vaccine candidate from Pfizer Inc. AstraZeneca and Pfizer are among the frontrunners in the race to develop a vaccine for the coronavirus, with the race also including Johnson & Johnson and Moderna Inc. Their vaccine candidates are in late-stage trials, interim data from which are expected in the coming weeks.

The British drug maker said on Monday its COVID-19 experimental vaccine produces an immune response in both old and young adults. The vaccine also triggers lower adverse responses among the elderly, it said.  The novel coronavirus has killed more than 1.19 million people globally, damaged the world economy and turned normal life upside down for billions of people. Work began on the Oxford vaccine in January. Called AZD1222 or ChAdOx1 nCoV-19, the viral vector vaccine is made from a weakened version of a common cold virus that causes infections in chimpanzees.

The vaccines are ready to be rolled out worldwide should regulators approve it. The coronavirus vaccines are being made at the company’s factory in Puurs, Belgium, according to the Mail on Sunday, who interviewed Pfizer’s U.K. head, Ben Osborn and showed a video that appears to show Pfizer’s manufacturing process, although it is not clear whether the clip shows the Covid-19 vaccine being manufactured.  The company says it hopes to make 100 million doses available this year, should the vaccine be granted regulatory approval, with plans to manufacture 1.3 billion in 2021. 

Every patient will need to receive two doses of the vaccine, according to the Mail on Sunday. The vaccines produced are now being stockpiled, and are ready to ship worldwide when given the go ahead, the Mail on Sunday report. A Pfizer spokesperson told Forbes that the video accompanying the Mail on Sunday’s article was not Covid-19 vaccine production. 

Pfizer is a frontrunner in the global race to develop a safe and effective Covid-19 vaccine, which it is developing with Germany’s BioNTech. While not yet approved, production comes ahead of an anticipated approval in the U.S. when the company applies in the middle of November. Last week, the company’s CEO publicly clarified its best estimates for when it could apply for emergency approval, a thinly veiled critique of President Trump, who has been insisting a vaccine will be ready and available before the November 3 election. By Pfizer’s best estimate, the third week of November will be the earliest they will be able to apply for approval.

BioNTech and Pfizer have started a rolling submission of their COVID-19 vaccine BNT162b2 to the European Medicines Agency (EMA). The news comes days after EMA named AstraZeneca's AZD1222 as the first COVID-19 vaccine to start the rolling review process. The EMA uses rolling reviews to start assessing data on an experimental candidate before all the evidence needed to make a final decision is available, cutting the time it takes to decide whether to approve a prospect once the pivotal clinical trial results are submitted to the agency. The pressing need for COVID-19 vaccines potentially makes the mechanism important to the current crisis. After receiving the first part of a rolling submission, the EMA’s Committee for Medicinal Products for Human Use has begun evaluating the preclinical evidence on mRNA vaccine BNT162b2. The rolling review format provides opportunities to file additional data before the complete application. Each cycle typically requires a two-week review. The duration of the review of the final application will depend on the proportion of data already assessed by EMA under the rolling review. 

The EMA accepted BNT162b2 for rolling review on the strength of the preclinical and early clinical data on the vaccine. BioNTech and Pfizer have linked BNT162b2, which encodes a SARS-CoV-2 spike glycoprotein, to antibody and T-cell responses in people dosed in early-phase trials. The data led the partners to start a phase 3 clinical trial. That trial has now enrolled around 37,000 participants at sites in countries including the U.S., Brazil, South Africa and Argentina, with centers in Turkey coming online to help push BioNTech and Pfizer to their enrollment target of 44,000 subjects. More than 28,000 participants have received their second dose. BioNTech and Pfizer originally planned to enroll 30,000 subjects. The enrollment figures suggest BioNTech and Pfizer are closing in on the release of top-line data from the trial. Exactly how long the partners need to wait for efficacy data will depend on the extent to which participants have been exposed to the virus and the effectiveness of the vaccine. BioNTech and Pfizer are set to perform interim efficacy analyses when there are 32, 62, 92 and 120 COVID-19 cases in the trial...

The Covid-19 vaccine trial designed by Pfizer Inc. and its German partner BioNTech SE may allow them to find whether their shot works before their fastest-moving rivals. The companies plan a first look after a mere 32 coronavirus infections have accumulated in their massive 44,000-person trial. That case total could be reached as soon as Sept. 27, according to Airfinity Ltd., a London-based analytics firms tracking vaccine trials. Pfizer has also given itself four chances to get a preliminary result, before reaching the final goal of 164. Some trial experts say the company appears to be looking for a leg up in a race against frontrunners such as Moderna Inc. and AstraZeneca Plc to be first with a vaccine. “I’ve never seen a trial where there were four interim analyses; that may be the Olympic record,” said Eric Topol, editor-in-chief of Medscape, a website offering clinical information for health-care professionals, and director of the Scripps Research Translational Institute in La Jolla, California. “It’s obvious why it is being done: so you can just keep looking at the data to try to win a race.”

A wide range of symptoms and severity makes the evaluation of Covid-19 vaccines tricky. The U.S. Food and Drug Administration has said that to be approved, vaccines should cut the number of symptomatic cases by half. Yet documents released by the drugmakers show each has its own approach to defining which symptoms count, and when to count them. Big drug studies usually allow a panel of monitors to get an early peek at the data once or twice before the planned end. The panel can stop the trial early if a treatment is judged overwhelmingly effective -- or alternatively, a total dud. Four early looks may give Pfizer an “easy route” to making sure it has results soon, said Marie-Paule Kieny, a former World Health Organization official who’s now a research director at the French health-science institute Inserm. “It seems that there are different levels of stringency,” she said in an interview. “I wouldn’t say that Pfizer-BioNTech comes out as a star of stringency.” Moderna, working with the U.S. National Institute of Allergy and Infectious Diseases, won’t dive in until 53 cases have occurred; its ultimate goal is to make a judgment at 151 diagnoses. Cancer powerhouse AstraZeneca, collaborating with the University of Oxford, will take its first look at 75 cases, and not again until the trial is complete with 150.

“All trials have set the bar quite low for what they test against,” said Rasmus Bech Hansen, Airfinity’s chief executive officer. Pfizer’s trial was designed to evaluate its vaccine candidate “as fast as possible,” said Amy Rose, a spokeswoman, in an email. The company has worked with government scientists to develop best practices for testing and based its schedule for interim analyses on the vaccine’s “strong profile” in early human trials and animal tests, she said. Moderna’s plan was agreed upon with U.S. regulators, and the company has been open about the numbers since before the trial began in late July, spokesman Ray Jordan said in an email. Case totals for interim analysis were based on probabilities of success and “were not selected based on timeframes,” he said. AstraZeneca said its trials are conducted under regulatory oversight and its plans have evolved over time to make sure they produce robust information in a timely way. All the companies said their trials will continue beyond points such as a preliminary readout or potential authorization. Pfizer says its study will likely yield conclusive results in October. None of the drugmakers will likely know whether their vaccines lower hospitalizations until February, according to Airfinity. But it’s the earlier assessments that have observers most concerned.

Safety has been a paramount concern since AstraZeneca paused tests of the vaccine it's co-developing with the University of Oxford following an adverse event in a U.K.  Researchers monitoring Pfizer Inc.’s giant trial of an experimental COVID-19 vaccine have reported no safety problems even after more than 12,000 people received their second of two doses. “So far there has been no safety signal reported,” said Mikael Dolsten, Pfizer’s chief scientific officer, in an online meeting with investors. The trial, now targeted at enrolling 44,000 people, has reached its initial goal of 30,000 subjects, Pfizer executives said. The drugmakers have expanded the trial to to allow inclusion of teenagers and people with certain medical conditions, like HIV. 

The trial compares two shots of the vaccine Pfizer is co-developing with Germany’s BioNTech SE to two doses of a placebo. While the doctors and subjects in the trial don’t know who got the vaccine — a measure to avoid bias — a committee of outside experts that knows which people received the shot is reviewing safety data on a weekly basis, Pfizer executives said during the investor meeting.  “They would notify us if they had any safety concerns and have not done that to date,” Kathrin Jansen, Pfizer’s head of vaccine research, said during the meeting. The company’s own scientists are also looking for worrisome adverse events that haven’t appeared so far. Fatigue has been the most common side effect seen in the trial thus far, according to the Pfizer presentation.  Pfizer confirmed it expects to get conclusive data on the vaccine’s efficacy by the end of October. The board monitoring the trial will conduct its first review of the data for efficacy when a total of 32 coronavirus cases have been seen among participants, Pfizer executives said during the investor meeting.

Drugmakers on the hunt for a COVID-19 vaccine have promised massive supply rollouts in the coming months if their candidates pass regulators' scrutiny. But promises and results are very different things:for two highly touted mRNA-based shots, storage concerns could derail those plans. A pair of frontrunner mRNA-based COVID-19 vaccines from Moderna and Pfizer could run into supply logistics issues over the ultra-cold storage needs for both shots, SVB Leerink analysts said in a pair of client notes Thursday. Citing discussion at a CDC advisory committee meeting Wednesday, analysts pointed out that experts expressed concern that the temperatures required to store mRNA vaccines were "severely limiting" to distributors' ability to ship the shots and to clinics' ability to administer them to a wide swath of patients.

Pfizer and BioNTech's mRNA hopeful, dubbed BNT162b2, specifically raised eyebrows: The vaccine reportedly needs to be held in storage at -94° Fahrenheit, and will last for only 24 hours at refrigerated temps between 35.6° and 46.4°. Meanwhile, most protein subunit vaccines—the type being developed for COVID-19 by Sanofi and Novavax, among others—can be held at refrigerated temps for months, analysts said. Given those constraints, the analysts argued that Pfizer's shot could only be used at certain hospitals and clinics with the proper equipment, and would require "intensive one-day vaccination events at such sites ... (that would) cover a fraction of the healthy population." In a statement, Pfizer argued that its vaccine could be stored at refrigerated temps for up to 2 days, instead of the 24 hours cited by analysts. The drugmaker has also developed shipping containers using dry ice that it believes will solve some shipping worries.  "We are confident of our capability to deliver and store doses to the destination's governments designate, according to product shipping and storage requirements," a spokeswoman said. Despite similar storage issues, Moderna is pursuing stability data showing its vaccine, mRNA-1273, can be stored at -4° Fahrenheit—which would be a big leg up over Pfizer's candidate. On a Wednesday call with investors, Moderna CTO Juan Andres said the -4° mark was a "very normal storage condition" comparable to home freezers. 

"Of course, industrial, well-monitored freezers for pharmaceuticals will be used for storage and shipment, Andres said. "The point here is that the infrastructure is widely available, and we do not need special equipment to use our vaccine." In the meantime, though, Moderna is likely to pursue an emergency use approval with cold-storage requirements similar to Pfizer's—and analysts said Moderna's eventual advantage over its rival might not be much of an advantage given the range of competitors in the hunt. "We note that storage/distribution temperature may be less of an advantage–and may in fact still be substantially inferior to non-mRNA competitors utilizing a protein sub-unit approach with much more permissive storage conditions," analysts wrote. The ability to successfully distribute their vaccines will come as a big challenge for both companies, which have promised hundreds of millions of doses within months if an approval comes through....

People between 18 and 55 had adverse events thought to be related to the vaccine 16.7% of the time, and none was reported in older recipients. Pfizer and BioNTech surprised many industry watchers on July 27 when they announced they would conduct a large-scale study of a vaccine for Covid-19. The surprise? The vaccine that would be tested in a 30,000-patient trial wasn’t the one for which the companies had presented data on July 1. The reason, the companies said, was that a second vaccine seemed to generate a similar immune response, but fewer side effects. On Thursday, they posted the results from all 332 people who received either vaccine, referred to as vaccines B1 or B2 — and indeed, B2 recipients experienced markedly fewer adverse events tied to the vaccine. The study tested doses of each vaccine ranging from 10 micrograms to 100 micrograms. The 30-microgram dose of B2 is being taken forward in clinical trials.

With the original vaccine, called BNT162b1, or B1 for short, patients between the ages of 18 and 55 had adverse events thought to be related to the vaccine 50% of the time at the 30-microgram dose. Those between the ages of 65 and 85 had related adverse events 16.7% of the time. For the second vaccine, BNT162b2, or B2, patients between 18 and 55 had adverse events thought to be related to the vaccine 16.7% of the time, and no adverse effects thought to be related to the vaccine were reported in those between the ages of 65 and 85. Both vaccines use mRNA — the genetic messenger the body uses to make the DNA code into proteins — packaged inside a fatty capsule, called a lipid nanoparticle, that allows it to get into cells. The mRNA instructs cells to make a protein, which then triggers the immune system into action. For the B1 vaccine, the mRNA coded for the part of a protein on the SARS-CoV-2 virus that binds to a receptor on human cells in order to gain entry to them. The B2 vaccine makes the entirety of this protein, known as the spike protein.

Using the full spike protein may allow the immune system to figure out more ways to detect and attack the virus. Chemical modifications to the mRNA may also explain some of the difference. Although the same dosage, by weight, was given to patients with each vaccine, the B2 vaccine would include fewer particles, because the full-length mRNA is heavier. The side effects tracked were mostly those one would expect from a vaccine injection, including soreness at the injection site, fever, chills, headache, and muscle or joint pain. No older adult who received B2 reported redness or swelling at the injection site. The average level of antibodies to the virus in older adults was only 41% that seen in younger participants. However, it was still higher than the level of antibodies seen in recovered patients, the authors said. All patients in the study of B2 were white and non-Hispanic, with more older women than older men participating. The younger patients were a median of 37 years old, while the older ones were a median of 69. Pfizer has said that some data from its large study of the B2 vaccine could come as early as October.

Preprint of new report available at medRxiv:

https://www.medrxiv.org/content/10.1101/2020.08.17.20176651v1.full.pdf

The companies started a large study of a vaccine candidate for Covid-19 aimed at securing approvals — but it’s not the one for which results were released. Pfizer and BioNTech are starting a large study of a vaccine candidate for Covid-19 aimed at securing approvals — but it’s not the one for which results were released earlier this month. The companies always said that they planned to pick from among four different candidates, all of which use a technology called messenger RNA to produce a protein on SARS-CoV-2, the virus that causes Covid-19. The vaccine is designed to lead the immune system to recognize the protein, and, it is hoped, to attack the virus. On July 1, the companies announced results in a preprint publication showing that one vaccine candidate, BNT162b1, prompted an immune response in patients. That vaccine encoded a key portion of the spike protein, which SARS-CoV-2 uses to enter cells. The vaccine being taken forward, BNT162b2, encodes an optimized version of the whole spike protein, which should lead to “more consistent responses across diverse populations and in older adults,” Pfizer said in a statement. Philip Dormitzer, a Pfizer vice president in charge of vaccines, said the selected vaccine appears to generate a stronger response, in part because it includes more of the spike protein. That could mean less variability in how people respond to the vaccine. It also seemed to cause fewer side effects. “It just seemed a bit milder,” Dormitzer said in an interview. “There were fewer reactions to immunization, and that was an important mark in its favor.”

The study, which began today, will recruit about 30,000 healthy volunteers between 18 and 85, randomizing half to get the vaccine and the rest to get placebo. Pfizer will recruit from about 120 sites in countries around the world, including the U.S., Germany, and Brazil. The primary goal is preventing patients from developing Covid-19, and the secondary endpoints include preventing severe cases of the disease and protecting volunteers against asymptomatic infections. The announcement came hours after Moderna began a 30,000-participant trial of its own. Like Pfizer and BioNTech, Moderna’s vaccine uses messenger RNA to compel the body to produce spike proteins, leading to an immune response that will ideally protect subjects from Covid-19. Pfizer and BioNTech said that they are on track to file for regulatory review as early as October, and that they plan to supply up to 100 million doses by the end of 2020 and 1.3 billion doses by the end of 2021.

It’s not yet clear whether the antibody levels produced will lead to immunity to the virus. To prove that, the companies will need to conduct large studies. An experimental Covid-19 vaccine being developed by the drug giant Pfizer and the biotech firm BioNTech spurred immune responses in healthy patients, but also caused fever and other side effects, especially at higher doses. The first clinical data on the vaccine were disclosed Wednesday in a paper released on medRXiv, a preprint server, meaning it has not yet been peer-reviewed or published in a journal. “We still have a ways to go and we’re testing other candidates as well,” said Philip Dormitzer, the chief scientific officer for viral vaccines at Pfizer’s research laboratories. “However, what we can say at this point is there is a viable candidate based on immunogenicity and early tolerability safety data.” 

The study randomly assigned 45 patients to get one of three doses of the vaccine or placebo. Twelve received a 10-microgram dose, 12 a 30-microgram dose, 12 a 100-microgram dose, and nine a placebo. The 100-microgram dose caused fevers in half of patients; a second dose was not given at that level. Following a second injection three weeks later of the other doses, 8.3% of the participants in the 10-microgram group and 75% of those in the 30-microgram group developed fevers. More than 50% of the patients who received one of those doses reported some kind of adverse event, including fever and sleep disturbances. None of these side effects was deemed serious, meaning they did not result in hospitalization or disability and were not life-threatening.

The vaccine generated antibodies against SARS-CoV-2, the virus that causes Covid-19, and some of these antibodies were neutralizing, meaning that they appear to prevent the virus from functioning. Levels of neutralizing antibodies were 1.8 to 2.8 times the level of that in the recovered patients. It’s not certain that higher antibody levels will lead to immunity to the virus. To prove that, Pfizer will need to conduct large studies that aim to prove that people who have received the vaccine are at least 50% less likely to become infected. Those studies are expected to begin this summer, mostly in the United States. Pfizer and BioNTech are testing four different versions of the vaccine, but only one will advance to larger studies....

Preprint available at medRxiv (July 1, 2020):

https://doi.org/10.1101/2020.06.30.20142570