STAT United States of America
Race for Covid-19 vaccine slows as US officials tap the brakes - STAT
The FDA released strengthened rules for authorizing any vaccine, and a top official stressed manufacture supplies would be taken into account.
The race for a Covid-19 vaccine slowed on Tuesday, as both U.S. regulators and the head of the Trump administrations Operation Warp Speed initiative tapped ever so softly on the brakes. The Food and Drug Administration released strengthened rules for authorizing any Covid-19 vaccine on an emergency basis. And Moncef Slaoui, co-chair of Operation Warp Speed, revealed that the governments vaccine fast-tracking effort has urged manufacturers not to apply for emergency use authorization until they have significant amounts of vaccines to deploy. That could push back even the first such authorization expected to be for a vaccine being made by Pfizer and BioNTech, if it proves to be effective into sometime in mid- to late November. advertisement The one learning message that we came to was to recommend to the companies that we are supporting that if they achieve efficacy demonstration [of their vaccine] while there are no vaccine doses available at industrial scale to be able to immunize at least a relevant fraction of the population, that they should refrain or at least consider refraining for filing for an EUA, Slaoui said during a Covid-19 vaccines symposium on Tuesday. Approval of a vaccine that wasnt actually available to use would be a major disappointment to the public, Slaoui said. advertisement There has been deep concern in the public health world that President Trump would seek to force the FDA to approve Covid-19 vaccines before Election Day and before large clinical trials currently underway to determine safety and efficacy have reached statistically significant conclusions. Polls suggest many Americans are wary of the vaccines being produced through Operation Warp Speed, and public health experts fear political interference in the approval process would further undermine public confidence. The FDA has been attempting to strengthen the rules by which it would agree to issue an emergency use authorization, or EUA, for Covid-19 vaccines, but had been stymied by the White House. On Tuesday, the regulatory agency released the updated safety standards amid a number of guidance documents it posted online in advance of an important meeting on Oct. 22 of the vaccines and related biological products advisory committee, which advises the FDA on vaccine approvals. According to the revised rules, the FDA wants vaccine manufacturers to collect safety data on at least half of their clinical trial subjects for two months after they have received their second dose of vaccine, if the candidate vaccine is a two-dose vaccine. (Of the current frontrunners in the vaccine race, only the Johnson & Johnson vaccine, which only recently began its Phase 3 trial, uses a one-dose regimen.) Pfizer and BioNTech are viewed as most likely to deliver an early answer from trials of their vaccine, which uses a new technology called mRNA to mount an immune response to the virus. But at Pfizers virtual investor day on Sept. 15, the company said that 12,000 of its then-planned 30,000 volunteers had received a second dose meaning that Pfizer and BioNTech would not have enough data to apply for an EUA until mid-November at the earliest. Pfizer and BioNTech have since said they would expand their study to include 44,000 patients. Its not clear whether the FDA would want two months of data on half the patients on the larger number, or the original 30,000. Slaoui also stressed Tuesday that he expected the first efficacy data from Covid-19 vaccines to become available in November or December. Peter Marks, the FDAs top vaccine regulator, insisted Tuesday that the two-month follow-up timeline was guided by data showing that the majority of adverse events occur roughly within two to three months after vaccine administration. Theres something thats really amazing that you can actually use sometimes you can sometimes actually use data, Marks said during the symposium, staged by Johns Hopkins University and the University of Washington. We picked two months as something that was reasonably aggressive yet also somewhat kind of in the middle not too aggressive, not too conservative. Former FDA Commissioner Scott Gottlieb groused during the event over how much political dust was kicked up by political officials over the FDAs guidance, for, he said, little gain. Gottlieb, who served in the Trump administration from 2017 to 2019 and now serves on the board of Pfizer, appeared to be referencing reporting that White House officials were blocking release of the FDAs guidance, although he did not name specific officials nor specific media reports in his comments. In addition to the Pfizer-BioNTech vaccine, an mRNA vaccine being produced by Cambridge, Mass.-based Moderna, is expected to have data within that time frame. Slaoui told the symposium that though mRNA vaccines have never before been approved, both Moderna and Pfizer-BioNTech are now able to produce vaccine at industrial scale. We are in the process of stockpiling doses in the single-digit million doses in the months of October and then in the tens of millions of doses in November, Slaoui said. Nicholas Florko contributed reporting.
AstraZeneca Covid-19 vaccine study is put on hold - STAT
The large, Phase 3 study testing the vaccine has been put on hold due to a suspected serious adverse reaction in a participant in the U.K.
A large, Phase 3 study testing a Covid-19 vaccine being developed by AstraZeneca and the University of Oxford at dozens of sites across the U.S. has been put on hold due to a suspected serious adverse reaction in a participant in the United Kingdom. A spokesperson for AstraZeneca, a frontrunner in the race for a Covid-19 vaccine, said in a statement that the companys standard review process triggered a pause to vaccination to allow review of safety data. It was not immediately clear who placed the hold on the trial, though it is possible it was placed voluntarily by AstraZeneca and not ordered by any regulatory agency. The nature of the adverse reaction and when it happened were also not immediately known, though the participant is expected to recover, according to an individual familiar with the matter. advertisement The spokesperson described the pause as a routine action which has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials. The spokesperson also said that the company is working to expedite the review of the single event to minimize any potential impact on the trial timeline. An individual familiar with the development said researchers had been told the hold was placed on the trial out of an abundance of caution.A second individual familiar with the matter, who also spoke on condition of anonymity, said the finding is having an impact on other AstraZeneca vaccine trials underway as well as on the clinical trials being conducted by other vaccine manufacturers. advertisement Clinical holds are not uncommon, and its unclear how long AstraZenecas might last. But the progress of the companys trial and those of all Covid-19 vaccines in development are being closely watched given the pressing need for new ways to curb the global pandemic. There are currently nine vaccine candidates in Phase 3 trials. AstraZenecas is the first Phase 3 Covid-19 vaccine trial known to have been put on hold. Researchers running other trials are now looking for similar cases of adverse reactions by combing through databases reviewed by a so-called Data and Safety Monitoring Board, the second person said. AstraZeneca only began its Phase 3 trial in the U.S. in late August. The U.S. trial is currently taking place at 62 sites across the country, according to clinicaltrials.gov, a government registry, though some have not yet started enrolling participants. Phase 2/3 trials were previously started in the U.K., Brazil, and South Africa. There are a number of different reactions that can qualify as suspected serious adverse reactions, symptoms that require hospitalization, life-threatening illness and even death. It was also not immediately clear which clinical trial the adverse reaction occurred in, though a clear possibility is the Phase 2/3 trial underway in the U.K. While its still unclear how severe and rare the adverse event may be, the finding could impact how quickly efficacy data from the U.K. trial will be available. Those data are considered integral to any bid to seek an emergency use authorization for the vaccine from the U.S. Food and Drug Administration and potentially jeopardize President Trumps efforts to fast-track a vaccine ahead of the November election. A Phase 1/2 study published in July reported that about 60% of 1,000 participants given the vaccine experienced side effects. All of the side effects, which included fever, headaches, muscle pain, and injection site reactions, were deemed mild or moderate. All of the side effects reported also subsided during the course of the study. The vaccine known as AZD1222 uses an adenovirus that carries a gene for one of the proteins in SARS-CoV-2, the virus that causes Covid-19. The adenovirus is designed to induce the immune system to generate a protective response against SARS-2. The platform has not been used in an approved vaccine, but has been tested in experimental vaccines against other viruses, including the Ebola virus. The Phase 3 trial in the U.S. aims to enroll about 30,000 participants at 80 sites across the country, according to a release last week from the National Institutes of Health. It was not immediately clear what steps were being taken at study sites across the U.S. in response to the hold. Clinical holds in ongoing studies often involve a pause in recruiting new participants and dosing existing ones, unless its deemed in the interest of participant safety to continue dosing. In the statement from AstraZeneca, the company spokesperson noted that in large trials illnesses will happen by chance but must be independently reviewed to check this carefully. The spokesperson also said the company is committed to the safety of our participants and the highest standards of conduct in our trials.
Steroids cut deaths of hospitalized Covid-19 patients by one-third - STAT
Use of inexpensive, readily available steroid drugs to treat people hospitalized with Covid-19 reduced the risk of death by one-third, a WHO analysis found.
Use of inexpensive, readily available steroid drugs to treat people hospitalized with Covid-19 reduced the risk of death by one-third, according to an analysis encompassing seven different clinical trials conducted by the World Health Organization and published Wednesday in the Journal of the American Medical Association. The positive steroid findings the result of a pooled look at data known as a meta-analysis confirm a similar survival benefit reported in June from a single, large study. Corticosteroids are the first, and so far only, therapy shown to improve the odds of survival for critically ill patients with Covid-19. Based on the newly published data, the WHO on Wednesday issued new treatment guidelines calling for corticosteroids to become the standard of care for patients with severe and critical Covid-19. Such patients should receive 7-10 days of treatment, a WHO panel said. But it cautioned against use of the steroids in patients with non-severe illness, saying that indiscriminate use of any therapy for COVID-19 would potentially rapidly deplete global resources and deprive patients who may benefit from it most as potentially life-saving therapy. advertisement The consistent findings of benefit in these studies provide definitive data that corticosteroids should be first-line treatment for critically ill patients with COVID-19, said Hallie Prescott and Todd Rice, professors of medicine at the University of Michigan and Vanderbilt University, respectively, in an accompanying JAMA editorial. Nahid Bhadelia, medical director of the Special Pathogens Unit at the Boston University School of Medicine, said there has been widespread adoption of steroids in the care of critically ill patients with Covid-19 since the first trial results in June. This is particularly true in many resource-limited countries where I work. This meta-analysis adds further confidence to those results, she added. advertisement Other groups, including the National Institutes of Health and the Infectious Diseases Society of America, have already issued similar guidelines recommending the use of steroids to treat patients with severe Covid-19. The new analysis included data on 678 patients randomized to treatment with steroids and 1,025 patients to usual care or a placebo. All of the patients had a confirmed diagnosis of Covid-19 and were admitted to the hospital. Most were on mechanical ventilation. Twenty-nine percent of the patients were women, but a breakdown by race was not disclosed. After 28 days, 33% of the steroid-treated patients had died, compared to 41% of the patients on usual care or a placebo. In the meta-analysis, the difference in absolute mortality translated into a 34% reduction in the risk of death for those given steroids a statistically significant result. The survival benefit remained consistent regardless of the type of steroid administered, the dose, or whether patients were receiving mechanical ventilation or supplemental oxygen only, researchers found. Eighteen percent of patients on steroids reported side effects compared to 23% of patients on usual care or placebo. Adverse events varied across trials but there was no suggestion that the risk of serious adverse events was higher in patients assigned to corticosteroids except for the two smallest trials, in which the total number of serious adverse events was one and three. Corticosteroids do not directly attack the novel coronavirus. Instead, the drugs work by dampening the activity of a patients immune system to prevent it from attacking the lungs a serious and often fatal condition called acute respiratory distress syndrome, or ARDS. The first evidence that common steroids could improve the survival of patients with severe Covid-19 came in June when British researchers conducting a large clinical trial called RECOVERY reported that the use of dexamethasone reduced the death rate by 35% in patients requiring ventilation and by 20% in patients who needed oxygen but were not ventilated. Prior to the public announcement of the RECOVERY trial results, physicians had been reluctant to use steroids to treat severely ill Covid-19 patients due to concerns about side effects. Clinical trials involving other immune-suppressing drugs like IL-6 inhibitors were also yielding disappointing results. Patrick Vallance, the U.K. governments chief scientific adviser, speaking in June, called the dexamethasone survival benefit from the RECOVERY study tremendous news and a groundbreaking development in our fight against Covid-19. But the findings also hampered efforts to confirm the results. Other randomized and controlled clinical trials investigating the use of steroids at that time were unable to enroll additional patients. For that reason, the WHOs Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group stepped in to coordinate the meta-analysis of these incomplete but randomized and controlled trials. The analysis was done prospectively, meaning that data and outcomes from the seven individual trials were not known in advance, but were shared for the first time with the WHO team in order to reduce the chance of bias. Three of the individual clinical trials of steroids were published in JAMA Wednesday, alongside the WHOs meta-analysis. The efforts of the clinical trial groups for the launch and conduct of high-quality trials in the midst of a pandemic should be acknowledged as an important accomplishment. The agreement among the trialists to share unpublished data with WHO is an example of how science can advance and is critical in the midst of what is likely to be numerous underpowered [randomized controlled trials], write Prescott and Rice in their JAMA editorial. The WHOs meta-analysis leaves some questions about steroids and Covid-19 unanswered, said Boston Universitys Bhadelia. It still remains unclear if there is any use in starting [steroids] earlier. Most clinicians, including myself, would not do so with the current data, she said, adding that theyre also uncertain whether to use biomarkers to guide therapy rather than oxygenation only. One of the concerns about steroids is, given too early in the course of Covid-19, they might hamper the bodys ability to eliminate the virus, leading to worse outcomes. But steroids might also benefit a subset of Covid-19 patients who dont yet need oxygen but have lab tests indicating early signals of their immune system going into overdrive. It would be interesting to know if co-administration of an antiviral may help reduce viral load while the earlier steroids work on the inflammatory component in that group of people, Bhadelia said. We also need more data around co-infections in the setting of steroid use.
First Covid-19 reinfection documented in Hong Kong, researchers say - STAT
The case raises questions about the durability of immune protection from the coronavirus, though it remains unclear whether it's an outlier.
Researchers in Hong Kong on Monday reported what appears to be the first confirmed case of Covid-19 reinfection, a 33-year-old man who was first infected by SARS-CoV-2 in late March and then, four and a half months later, seemingly contracted the virus again while traveling in Europe. The case raises questions about the durability of immune protection from the coronavirus. But it was also met with caution by other scientists, who questioned the extent to which the case pointed to broader concerns about reinfection. There have been scattered reports of cases of Covid-19 reinfection. Those reports, though, have been based on anecdotal evidence and largely attributed to flaws in testing. advertisement But in this case, researchers at the University of Hong Kong sequenced the virus from the patients two infections and found that they did not match, indicating the second infection was not tied to the first. There was a difference of 24 nucleotides the letters that make up the virus RNA between the two infections. This is the worlds first documentation of a patient who recovered from Covid-19 but got another episode of Covid-19 afterwards, the researchers said in a statement. advertisement Experts cautioned that this patients case could be an outlier among the tens of millions of cases around the world and that immune protection may generally last longer than just a few months. They said that ongoing studies tracking patients who had recovered from Covid-19 would help reach more definitive conclusions. Theres been more than 24 million cases reported to date, Maria Van Kerkhove, a coronavirus expert at the World Health Organization, said at a briefing Monday, when asked about the Hong Kong report. And we need to look at something like this at a population level. The question of how long someone is protected from Covid-19 after being infected and recovering looms large. Studies are increasingly finding that most people who recover from the illness mount a robust immune response involving both antibodies (molecules that can block the virus from infecting cells again) and T cells (which can help clear the virus). This has suggested that people would be protected from another case for some amount of time. But based on what happens with other coronaviruses, experts knew that immunity to SARS-CoV-2 would not last forever. People generally become susceptible again to the coronaviruses that cause the common cold after a year or even less, while protection against SARS-1 and MERS appears to last for a few years. What we are learning about infection is that people do develop an immune response, and what is not completely clear yet is how strong that immune response is and for how long that immune response lasts, Van Kerkhove said. She added she was still reviewing the Hong Kong case. The strength and durability of the immune response is also a crucial factor in how long vaccines will be effective for, and for how often people might need a booster dose. In the Hong Kong case, the man had traveled to Spain and returned to Hong Kong via the United Kingdom. A saliva sample was taken upon arrival in Hong Kong as part of a screening protocol and tested positive for SARS-CoV-2 on Aug. 15. During his second infection, the man did not have any symptoms. Some patients go through their course of Covid-19 without showing symptoms, but researchers have also hypothesized that secondary cases of the coronavirus will generally be milder than the first. Even if immune systems cant stop the virus from infecting cells, they might still rally some level of response that keeps us from getting sicker. During his first case, the patient had classic Covid-19 symptoms of cough, fever, sore throat, and headache. Experts said it was also important to consider the immune response the patient generated after his first infection. While most people seem to mount a solid response, there has been indication that some people do not produce neutralizing antibodies those that can block the virus from infecting cells at very high levels, for unclear reasons. The fact that somebody may get reinfected is not surprising, said Malik Peiris, a virologist at the University of Hong Kong, who is not an author of the paper describing the reinfection but is familiar with the case. But the reinfection didnt cause disease, so thats the first point. And the second thing is that it is important to know whether the patient mounted a neutralizing antibody response to the first infection or not. Because the vast majority of patients in our experience do mount a good neutralizing antibody response. So is this person an outlier or is he likely to be the average person infected? Even if the Hong Kong case is an outlier, it points to a few implications: For one, people who have recovered from Covid-19 should also be vaccinated, the researchers said. And they should continue following precautions like wearing a mask and physical distancing. Helen Branswell contributed reporting.
Covid-19 vaccine from Pfizer and BioNTech shows positive results - STAT
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 were testing other candidates as well, said Philip Dormitzer, the chief scientific officer for viral vaccines at Pfizers research laboratories. However, what we can say at this point is there is a viable candidate based on immunogenicity and early tolerability safety data. advertisement 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. advertisement 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. Its 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 is testing four different versions of the vaccine, but only one will advance to larger studies. The current study did not include pregnant women, and no other information on the ethnic diversity of participants was noted, although the paper does say that future studies will need to include a more diverse group. The second dose, a booster shot, was required for immunity. The patients who received the single 100-microgram dose had lower antibody levels than those who received two shots of the lower doses. Fourteen Covid-19 vaccines are currently in human trials, according to the Milken Institute, including entrants from Inovio, CanSino, AstraZeneca, and Moderna. More are expected to start soon, including entrants from Merck, Johnson & Johnson, and Sanofi. In total, 178 vaccines are in various stages of development. The Pfizer/BioNTech vaccine, like the Moderna vaccine, is based on a technology called messenger RNA, which uses a key genetic messenger found in cells to create protein that the immune system then learns to attack. Moderna has not yet published data on its vaccine but is expected to do so soon.
New study likely closes door on use of hydroxychloroquine for Covid-19 - STAT
A major clinical trial showed the malaria drug hydroxychloroquine had no benefit for patients hospitalized with Covid-19.
A major clinical trial showed the malaria drug hydroxychloroquine had no benefit for patients hospitalized with Covid-19, likely closing the door to the use of the highly publicized medicine in the sickest patients a use for which it was widely prescribed as the pandemic hit the U.S. The results come from a study called RECOVERY, funded by the U.K. government, that sought to randomly assign large numbers of patients to multiple potential treatments in the countrys National Health Service. The goal was to rapidly get answers as to what worked and what didnt. Todays preliminary results from the RECOVERY trial are quite clear hydroxychloroquine does not reduce the risk of death among hospitalized patients with this new disease, University of Oxford epidemiologist Martin Landray, one of the studys leaders, said in a statement. This result should change medical practice worldwide and demonstrates the importance of large, randomized trials to inform decisions about both the efficacy and the safety of treatments. advertisement A total of 1,542 received hydroxychloroquine, and 3,132 received usual care. After 28 days of treatment, 25.7% of those on hydroxychloroquine and 23.5% of those received usual care had died, meaning those on hydroxychloroquine were 11% more likely to die. That difference was not statistically significant. There was no beneficial effect on how long patients stayed in the hospital, or on other outcomes. advertisement The results were shared via a press release, which the studys lead authors shared on Twitter. They have not been peer-reviewed or published in a medical journal. The researchers said that full results would be shared as soon as possible. Still, experts said even the top-line results showed they were meaningful. This is a hugely important finding that will likely end use of the drug in hospitalized Covid patients, given the other existing data as well, said Walid Gellad, director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. Gellad said that he is curious to see the results of other ongoing studies, and that it is still an open question whether the medicine might work earlier in the disease. We need real answers there as well, he said. Robert Califf, the former Food and Drug Administration commissioner and Alphabet employee, tweetedthat the study essentially rules out benefit of [hydroxychloroquine] in critically ill hospitalized patients. He wrote that the results showed no benefit; no major risk. In addition to being used for malaria, hydroxychloroquine is prescribed to treat conditions including rheumatoid arthritis and lupus. But it was known to increase the risk of arrhythmias. The FDA still authorized emergency use of the drug in hospitalized patients in March, citing the possible safety issues. Concerns were heightened by a May 22 study in British medical journal the Lancet. That study, which claimed to use a database from hundreds of hospitals around the world, seemed to indicate that treatment with hydroxychloroquine increased the death rate and the rate of arrhythmias. But on Thursday, the Lancet retracted that study at the request of the authors after widespread questions about the database the study used and the company, Surgisphere, that had provided it. The authors not associated with Surgisphere had asked for the data to be audited, and Surgisphere refused. As such, they wrote, we can no longer vouch for the veracity of the primary data sources. On Wednesday, another group of researchers released results from another randomized study, testing whether giving people hydroxychloroquine shortly after they have been exposed to someone with Covid-19 could prevent disease transmission. That study also showed no benefit, thought some researchers, including Gellad and Califf, say some effect is still possible. It could still have an effect given very early in disease, although less and less likely every day that passes, Gellad said. There are dozens of studies ongoing with hydroxychloroquine, more than for any other potential Covid-19 treatment, including studies that combine it with antibiotics such as azithromycin or doxycycline. But the results appear to show the benefit of putting resources into testing medicines in large randomized trials, the medical gold standard, during a pandemic. The RECOVERY trial represented an early and large effort at such studies, testing not only hydroxychloroquine but also a pair of HIV drugs, lopinavir and ritonavir, and the steroid dexamethasone. The study was later expanded to also test using plasma from recovered patients to treat those who are still ill.