Virus World

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

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.