AstraZeneca Covid vax trial remains on hold in U.S., participants await 2nd dose

For the 20-something-year-old Hispanic man, volunteering for AstraZeneca’s Phase 3 Covid-19 vaccine study was an easy decision. His father, after all, had been briefly hospitalized with Covid-19, and, even beyond that personal motivation, signing up was “the right thing to do,” he told STAT.

The clinical trial participant, who lives in the western U.S., got his first shot in early September — he doesn’t know if he got the actual vaccine or a saline placebo, in line with the study’s double-blinded design — and he had been expecting to get a booster shot about four weeks later. But on Sept. 6, AstraZeneca, which is developing the vaccine with the University of Oxford, placed a halt on its studies of the vaccine around the globe due to safety concerns about a concerning illness in a participant in the U.K.

That hold has now been lifted everywhere except for the U.S. — meaning that study sites in the U.S. have not been administering second doses for the past month, and won’t do so until the trial resumes. It isn’t clear yet when that will happen, which has left the study participant who spoke with STAT and others in his situation in a sort of limbo. His scheduled appointment last week to get his booster shot was canceled, and he doesn’t know if he’ll ever be able to get the second dose.

Independent vaccine experts say there’s no need to worry about this group or their data, because such trials are carefully designed to account for situations in which participants can’t get a second dose. Asked about the participants who can’t currently get their second dose as scheduled, a spokesperson for AstraZeneca said: “We currently expect minimal impact based on the trial plans for 2nd dose timing.”

Still, such participants occupy an unusual position in a trial shutdown that is being closely watched as a potential indicator of the prospects of a frontrunner in the race to develop a vaccine to curb the devastation of the Covid-19 pandemic.

For the participant who spoke with STAT — and others in his same position who can’t currently get their booster shot — the trial halt has become a waiting game. “Now, we’re waiting as the lab rats in the corner,” said the participant, who requested anonymity because he was worried he could face consequences if study investigators found out he had spoken to the press.

It’s not clear how many participants fall into this bucket — AstraZeneca wouldn’t say — though it’s likely a small number, because the trial only officially started three weeks before the halt was placed, and dosing likely started later still. Some trial sites in the U.S. hadn’t yet begun enrolling participants at all by the time of the pause.

It’s also not clear whether participants whose second dose has been delayed will be able to get it at all. But according to the study protocol that AstraZeneca released last month, participants are due to get their second dose 28 days after the first, with leeway within a three-day window in both directions. It’s common for such trials to simply not give the second dose to participants who can’t get it within the established time frame, said Mark Slifka, a vaccine expert at Oregon Health and Science University whose research focuses on how long people are protected from a prior vaccination or infection.

There are many reasons why a vaccine trial participant may not be able to get their second dose as planned — they may become pregnant or move out of state, for example — and such trials are designed with the expectation that some fraction of them will be in that position, Slifka said. “There’s just unexpected circumstances that are not vaccine-related where a person just is unable to continue on with the study,” Slifka said. “It’s known that that happens.”

These circumstances, however, are vaccine-related. AstraZeneca has not said whether it will give participants a second dose if it would fall outside the prescribed window. But in this situation, it is possible that the trial investigators may feel they have an ethical responsibility to give these participants their second dose — or two doses of vaccine later, after unblinding, for participants who were randomized to the control arm.

In the event that does happen for some participants, there’s not reason to worry. “In general, spacing vaccines out with longer intervals between them is usually not associated with a decline in the immune response,” said Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.

While data from previous studies of the vaccine suggest that a second dose may be able to increase the effectiveness of the vaccine, preliminary results suggest a booster might not be strictly necessary for an immune response. In an earlier-stage study of the same vaccine in the U.K., some participants were given just one dose of the vaccine, while others got a second dose, too, between four and eight weeks later. The study found that a single dose could elicit immune responses, but that antibody responses were boosted following a second dose.

AstraZeneca wouldn’t say how the trial will handle data from participants who can’t get their second dose as scheduled when it restarts. Its study protocol states that all randomized participants who receive at least one dose, regardless of whether they adhere to the protocol or continue to participate in the trial, will have their data scrutinized in what’s known as the “full analysis set.”

In general it’s typical for such trials to analyze data from such participants in what’s known as an “intent-to-treat” analysis, which accounts for deviations from the protocol. That’s separate from the “per-protocol” analysis, which includes data from only those participants who followed the protocol precisely. AstraZeneca’s study protocol states that its per-protocol analysis will include those participants in the full analysis set who “receive the correct dose of randomized treatment and who do not have a serious protocol deviation.”

When it comes to the AstraZeneca trial participants who can’t currently get their second dose, “the good news is they’re not going to be ignored. The good news is they’re going to be followed for safety, and they’ll also be followed for protection,” Slifka said.

Slifka also pointed to the size of AstraZeneca’s trial — the U.S. study aims to eventually enroll 30,000 participants — as cause for reassurance. “By having such a large trial, it also helps buffer against small changes like this that might have been unexpected,” Slifka said.

https://www.statnews.com/2020/10/06/astrazeneca-covid19-second-dose-trial-vaccine/

'COVID-19 free' hospital areas could save lives after surgery

Setting up 'COVID-19 free' hospital areas for surgical patients could save lives during the second wave of the pandemic—reducing the risk of death from lung infections associated with coronavirus, a new global study reveals. 

Researchers working together around the world found that that patients who had their operation and hospital care in 'COVID-19 free' areas had better outcomes. 'COVID-19 free' areas improved the safety of surgery by having a strict policy that no patients treated for COVID-19 were mixed with those undergoing surgery. 'COVID-19 free areas' were set up both in smaller independent hospitals and large hospitals with emergency departments.

For fear that patients may contract COVID-19 in hospital, millions of operations around the world were cancelled during the first wave of the pandemic. As a second wave approaches, more patients face delays. When operations for cancer and other time-dependent are delayed, they can progress to be untreatable.

This research has shown, for the first time, that hospitals around the world can continue safe surgery by setting up COVID-19 free areas to minimise the risk from the coronavirus.

Researchers examined data from 9171 patients in 55 countries, across 5 different continents from the start of the pandemic up the middle of April 2020. Experts have discovered that pulmonary complication (2.2% vs 4.9%) and rates of death after surgery (0.7% vs 1.7%) were lower for patients who had their hospital treatment in 'COVID-19 free' areas. However, in this study, just 27% of patients had their care in these protected areas.

It is estimated that around 4.7 million operations take place in the UK each year, of which around 550,000 are for removal of a cancer. Setting up COVID-19 free hospital areas could prevent 6,000 unnecessary COVID-related deaths after cancer surgery in the UK alone over the next year.

Led by researchers at the University of Birmingham, the COVIDSurg Collaborative comprises of experts from over 130 countries. The group has published its findings today in the Journal of Clinical Oncology, which is a leading global cancer research journal.

Collaborative lead Dr. Aneel Bhangu, from the NIHR Global Health Research Unit on Global Surgery, at the University of Birmingham, commented: "As health providers restart elective cancer surgery, they must look to protect cancer surgery patients from harm by investing in dedicated COVID-19 free hospital areas. These can be tailored to the resources available locally, ensuring that patients treated for COVID-19 are not mixed with patients needing surgery.

"However, this represents a significant challenge to many hospitals around the world. Governments and hospital providers must help to fund this major international redesign of surgical services and provide protection for patients. COVID-19 free areas could save many lives during future waves, by allowing surgery to continue safely despite high rates of infection in the community."

The study was funded by a National Institute for Health Research (NIHR) Global Health Research Unit grant. It covered adult patients undergoing elective surgery with curative intent for a range of suspected cancers including bowel, gullet, stomach, head and neck, lung, liver, pancreas, bladder, prostate, kidney, womb, cervix, ovarian, breast, sarcoma and brain tumours.

Dr. James Glasbey, the study lead at the University of Birmingham, commented: "Major reorganisation of hospital services to provide COVID-19 free areas for elective surgery must be justified by evidence like this, as it redirects time and resources away from other services. We have proved that those efforts are essential in protecting patients undergoing surgery during the pandemic.

"Our data showed that COVID-19 free hospital areas were beneficial when the rate of infection in the community was both low and high. We recommend that COVID-19 free areas are set-up in all countries currently affected by the pandemic, including those likely to suffer from future waves.

"However, overcoming the challenges of setting up such pathways, including separate hospitals to provide elective surgery, may lead to unintended consequences.

Consequences for hospitals must be carefully monitored to achieve the best balance of healthcare for patients."

Data included in this study represented a wide variety of different surgeries for patients of all ages, genders and ethnicities. 

More information: 'Elective cancer surgery in COVID-19 free surgical pathways during the SARS-CoV-2 pandemic: An international, multi-centre, comparative cohort study' Journal of Clinical Oncology (2020). 

https://medicalxpress.com/news/2020-10-covid-free-hospital-areas-surgery.html

Recent endemic coronavirus infection is associated with less severe COVID-19

Manish Sagar,¹ Katherine Reifler,¹ Michael Rossi,¹ Nancy S. Miller,² Pranay Sinha,¹ Laura White,³ and Joseph P. Mizgerd¹ 

PDF: https://www.jci.org/articles/view/143380/pdf

Abstract

Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal “common cold,” and these eCoVs share extensive sequence homology with human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we show that individuals with as compared to without a relatively recent documented eCoV were tested at greater frequency for respiratory infections but had similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less severe coronavirus disease-2019 (COVID-19) illness. Our observations suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.

Graphical Abstract

https://www.jci.org/articles/view/143380

Are New COVID-19 Treatments More Important Than a Vaccine?

• The ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiative is a public-private partnership through the National Institutes of Health to support a coordinated research strategy to develop promising COVID-19 treatments and vaccines.

• Developing COVID-19 drugs could help people live longer and slow the spread of the virus. They could also be used as prophylactic treatment.

• People who have severe COVID-19 are treated in the hospital with such drugs as remdesivir and dexamethasone. However, there is not a single treatment for people who show early signs or mild symptoms of COVID-19.

• Making monoclonal antibodies that specifically target SARS-CoV-2 is expensive and complicated. However, about 20 companies are working on creating these drugs, and we could expect an effective treatment by the end of 2020.

• Developing COVID-19 drugs to treat people with mild cases is critical and may be more important than developing a vaccine, which will probably not protect everyone nor last long-term in an individual.

John Whyte, MD, MPH: Welcome, everyone. You're watching Coronavirus in Context. I'm Dr Whyte, chief medical officer at WebMD.

You can't turn on the news and not hear about a potential COVID vaccine. Should we really be talking more about potential treatments? Is that one of the most effective strategies to return to some sense of normal?

To help provide answers and insights into the role of therapeutics, I've asked Dr Davey Smith, the head of the Division of Infectious Disease and Global Health at UC San Diego in La Jolla, California. Dr Smith, thanks for joining me.

Davey Smith, MD: Thanks for having me, John.

Whyte: I want to start off talking about the ACTIV trial. Doctors are always good for acronyms, and I want to get it right. ACTIV stands for "Accelerating COVID-19 Therapeutic Interventions and Vaccines."

Smith: That is correct.

Whyte: Is it a public-private partnership with NIH?

Smith: That's a good question. So, there's a program at the US government called Operation Warp Speed. They developed this public-private partnership that they termed ACTIV to develop these coronavirus vaccines and treatments, basically as a way to efficiently and very quickly get some good vaccines and therapies out to the public.

Whyte: You're a big proponent of therapeutics, that we need to get treatments more accelerated, as well as any potential vaccine. Is that right?

Smith: That is correct. I'm very much a fan. If we could get a vaccine, that would be absolutely great, but we also need therapies. From our HIV experience, we know that therapies can really help people live longer, but they can also be used to control an epidemic. They both decrease the chance of somebody getting sick and decrease the chance of somebody spreading it. Those treatments could also be used as prophylaxis. They could really be very good tools in our toolbox to stop the pandemic.

Whyte: Do you think HIV/AIDS is a good comparison? In many ways, that's multidrug therapy as well. There's been some preliminary data to suggest that one-drug therapy is not going to be sufficient for COVID.

Smith: I don't really know. Those trials still need to be done. In the hospital setting, it is probably going to take more than one drug to treat COVID. In the outpatient setting, one drug might be enough.

Whyte: Tell us where we are on treatments. People are talking about remdesivir, dexamethasone, and monoclonal antibodies. Where exactly are we?

Smith: Right now, when somebody gets severely sick in the hospital, we have some therapies that seem to have a good signal for working, such as remdesivir or dexamethasone. There's also this new drug called baricitinib that's coming out.

We do not have a single treatment for outpatients before they get sick. They have early COVID, and some will progress to needing the hospital, but we just don't have a treatment for those people yet. That's one of the reasons that ACTIV-2 is testing those drugs.

Whyte: What are some of the drugs they are testing? Are they mostly drugs that are already approved and indicated for some other disease, or are you also thinking about new molecules?

Smith: Right now, we are looking at drugs that were made specifically to target SARS-CoV-2. The first ones that are going to be used are called "monoclonal antibodies." They are humanized antibodies that are specifically targeted to SARS-CoV-2 and are not repurposed drugs.

Whyte: Those drugs are hard to make, are they not? There are challenges in manufacturing. We have to sometimes worry about potential side effects, given the immune response. Can you give us a quick primer on the role of monoclonal antibodies?

Smith: Monoclonal antibodies are made from people who got the virus, and some of those people made really potent antibodies. We were able to select out and grow those antibodies and turn them into drugs. That process is complicated and can be very expensive to make. About 20 companies or groups out there have made these monoclonal antibodies specifically targeting SARS-CoV-2.

We've progressed a long way into figuring out how to safely produce those monoclonal antibodies now. I'm very optimistic that one or more of those will be ready to use soon for treating COVID-19.

Whyte: I'm going to put you on the spot a little. What does "soon" mean? Six months, a year, or 3 months? What's your best bet?

Smith: December. My best bet is that by the end of the year, we will have a pretty good new monoclonal antibody that will keep people out of the hospital. I'm optimistic, and I do believe that.

Whyte: Can we drive manufacturing for monoclonal antibodies to the level that we need?

Smith: That's a good question. We really need to figure out how much capacity each of these companies has to drive manufacturing. Operation Warp Speed has stepped in to say, "OK, if we find a good target, they are going to help drive manufacturing as well, especially for some of these smaller companies that might not have the resources to be able to do so."

Whyte: I'm looking at some of the information on Operation Warp Speed. It's interesting that you point out how Operation Warp Speed is also about therapeutics, but all the news seems to be around just vaccine development. Is that a disservice to innovation?

Smith: I don't know that it's a disservice, but I do know that the oxygen in the room is all being taken up by coronavirus vaccines. I get it, because we talk about vaccines so much in terms of everybody needs to get their flu vaccines and there's the antivaxxers with measles, and so on. We think that having a good vaccine will get us out of the pandemic. I am less optimistic on that point.

I think we also need treatments. The reason that I say that is the US Food and Drug Administration (FDA) has said that they will approve a coronavirus vaccine that works 50% of the time. If I get a coronavirus vaccine (which I will if it works 50% of the time) and then get exposed in the hospital, I still have a 50% chance of getting sick. I really need to have a therapy that's going to keep me from getting sicker and perhaps dying, even if we do have a vaccine that works 50% of the time.

Whyte: That might be 50% effective with two immunizations as well, correct?

Smith: That's right; it might be two immunizations. We also don't know how long that vaccine might last. In regular circulating coronavirus infections, we know that immunity wanes pretty quickly. We don't know what the duration is of these vaccines that will actually work. If I had a treatment, I would be a lot more optimistic of opening up businesses and so on. When somebody gets sick, I have something that I can do for them.

I'm an infectious disease doctor, and I see lots of people with coronavirus infections that get pretty sick. I want to be able to help them. But at the moment, I really have nothing to offer them before they get into the hospital.

Whyte: If people aren't willing to take the vaccine (because of concerns that it was rushed or about its safety), then we concomitantly have to be developing treatments, correct?

Smith: That is correct. We talk a lot about herd immunity. But if you have a vaccine that only works half the time, and only half the people take it, you're never going to have enough immunity within a population to get rid of that epidemic spread with this virus. We still need a treatment, and that's what ACTIV-2 is doing. We're really hoping that we can develop a treatment that can keep people out of the hospital.

Whyte: So therapeutics along with immunization is the real way to return to some sense of normal. Is that right?

Smith: I think we need both. It would be very good if we at least had a treatment so that when people got sick, we could keep them out of the hospital and from dying. That would really buy us a lot of time to have a good, well-developed, safe and effective vaccine.

Whyte: Why haven't we gotten a vaccine for HIV? We have this commitment toward COVID. People have been working 20 years [on an HIV vaccine].

Smith: HIV is just such a different virus. It has so much more genetic mutability and mutates so much better than coronavirus. I do have some skepticism about coronavirus vaccines. I think that maybe the first generation will work a little bit, but not very well. They may have some duration problems, which is also what we see with HIV vaccine issues.

Whyte: Why do you have that skepticism?

Smith: Because I know that in regular coronavirus infections, our immunity wanes pretty quickly. The other thing is that people who don't have severe SARS-CoV-2 infection — so they don't get COVID and are asymptomatic — we don't see them mounting much of an immune response at all.

I'm not sure how a vaccine that basically introduces some viral antigens in there to stimulate an immune response can really generate a durable immune response. That's what I'm worried about.

Whyte: Dr Smith, I want to thank you for taking the time today to help educate us all about what's happening in terms of therapeutics, especially in relation to vaccines. Hopefully, we'll have the timeline that you're suggesting.

Smith: Yeah, I really hope so. Thank you so much for allowing me to come and talk to you.

Whyte: I want to thank everyone for watching Coronavirus in Context.

https://www.medscape.com/viewarticle/938578

FDA career experts will handle coronavirus vaccine reviews: commissioner Hahn

With numerous COVID-19 vaccines in late-stage testing, the FDA may soon face critical decisions on whether the candidates are safe and effective enough for emergency use or widespread distribution. While the agency has come under political pressure during the pandemic, Commissioner Stephen Hahn, M.D., on Monday stressed its procedures are adequate to maintain independence for the forthcoming reviews.

Career experts at the Center for Biologics Evaluation and Research, an organization within the FDA, will have the authority to “make the assessment around safety, effectiveness, [and] quality manufacturing,” Hahn said during a virtual interview with the CEO of AdvaMed, the medtech industry’s trade group.

The FDA has “processes in place to make sure that the centers are protected from any outside pressure, and that they’re focused solely on looking at the science and the data,” he said, adding “I have absolute faith and confidence in those decisions.” 

Hahn's reassurance comes right after COVID-19 vaccines came up during the recent presidential debate between President Donald Trump and Democratic nominee former Vice President Joe Biden. Trump has repeatedly said vaccines could be available in the coming weeks, while his administration's health officials have said they won't be widely available until next year. Biden said he doesn’t trust the president on the process and would listen to scientists.

After the debate, Pfizer CEO Albert Bourla wrote in an open letter that he was “disappointed” the vaccine progress was "discussed in political terms," warning politics could threaten uptake for a safe and effective vaccine. Pfizer could be the first to report phase 3 data, as the CEO has said he expects early results late this month. Aside from Pfizer, AstraZeneca, Moderna, Johnson & Johnson and Novavax have also reached late-stage testing.

At times during the pandemic, the FDA has run into controversy and faced criticisms that politics affected its decision-making. 

Perhaps most notably, when the FDA issued an emergency use authorization for convalescent plasma, Hahn said the treatment was associated with a “35% improvement in survival.” Experts pointed out that the data were from a single-arm observational study, and that the survival figure was a comparison of benefit for patients who received plasma with a high dose of antibodies versus a low dose. That's not sufficient evidence to claim a survival benefit at all, experts said. Hahn later walked his claim back.

Before that, Trump accused the FDA of harboring “deep state” employees who are seeking to hurt the administration’s response to the pandemic. That statement—and Hahn’s lack of a response—bothered several lawmakers, who wrote (PDF) to the commissioner that it’s his “responsibility to lead and defend the agency.” In their letter, the lawmakers pointed out several instances of “science being politicized" during the Trump administration's COVID-19 response, including the hydroxychloroquine saga in the spring.

https://www.fiercepharma.com/vaccines/fda-career-experts-will-handle-coronavirus-vaccine-reviews-commissioner-says