ACC 2021 – Novartis Entresto far from Paradise trial endpoints

 Novartis managed to get Entresto approved in patients with heart failure with preserved ejection fraction despite the failure of the Paragon trial. But it looks unlikely to be able to repeat the trick in post-myocardial infarction patients, full results from the Paradise MI trial suggest. The study, presented at the American College of Cardiology meeting today, found a 10% relative risk reduction in its primary endpoint, a composite of cardiovascular death, first heart failure hospitalisation or outpatient heart failure, with Entresto versus the angiotensin-converting enzyme ramipril. This was well below the 15% target. However, the lead investigator, Dr Marc Pfeffer of the Brigham and Women's Hospital, still seems to believe that there could be a path forward for Entresto in this pre-heart failure population. He highlighted a secondary endpoint, time to both first and recurrent events, where Entresto showed a bigger benefit – however, given the primary endpoint miss, this can only be considered exploratory. When asked whether this might convince regulators, he said that “remains to be seen. I’d like to pursue that. But that’s going to be a question for the sponsor.” Over to Novartis, though this looks like a lost cause even by the company’s standards.

Source: ACC via Dr Marc Pfeffer

Source: ACC via Dr Marc Pfeffer

https://www.evaluate.com/vantage/articles/news/snippets/acc-2021-entresto-far-paradise

CDC Limits Review of Vaccinated but Infected, Draws Concern

 Federal health officials this month decided to limit how they monitor vaccinated people who have been infected with Covid-19, drawing concern from some scientists who say that may mean missing needed data showing why and how it happens.

At the end of April, more than 9,000 Americans were reported to be infected after being vaccinated, according to the U.S. Centers for Disease Control and Prevention. While that’s a tiny percentage of the 95 million people fully inoculated at the time, researchers still want to find out what specific mechanisms may be spurring the infections.

Rare breakthrough cases are expected since no vaccines are 100% effective. But tracking and sequencing the cases helps in figuring out who may be more at risk, whether new variants evade the vaccines and when protection from the shots begins to wane. At the same time, those infected -- some of whom are suffering widespread medical issues, even if they’re not hospitalized -- say they feel lost as a result of the lack of information.

“We shouldn’t be narrowing the focus, we should be broadening and develop a systematic plan,” said Eric Topol, director of the Scripps Research Translational Institute in La Jolla.

At the start of May, the CDC shifted from monitoring all reported breakthroughs to only those that result in hospitalization or death, Tom Clark, head of the vaccine evaluation unit for the CDC’s vaccine task force, said in an interview. The goal of the new strategy, according to the agency: maximize the quality of data collected on cases.

TOTAL NUMBER OF BREAKTHROUGH INFECTIONS REPORTED TO CDC	9,245
Females	5,827 (63%)
People aged 60 and older	4,245 (45%)
Asymptomatic infections	2,525 (27%)
Hospitalizations	835 (9%)
Deaths	132 (1%)

The CDC says its numbers are probably an undercount, since their surveillance system is passive and relies on voluntary reporting from state health departments that may not be complete.

The agency shifted its strategy because there’s few worrying patterns in the data collected so far, suggesting the focus should be on the most severe cases, Clark said. He added that the agency has planned other vaccine studies, including one with a network of health centers, to compare disease severity and frequency of variant infections between vaccinated and unvaccinated people.

“I don’t think we’re missing out on this data,” Clark said. “It’s just sort of a package of how we’re looking at these questions.”

Michael Kinch, a former drug developer who’s now associate vice chancellor at Washington University in St. Louis, says as much information as possible should be recorded on breakthroughs. Cases that don’t rise to hospitalization are still important to track, he said, since symptoms that aren’t as severe for someone could eventually lead to hospitalizations. Non-life-threatening symptoms can impact someone’s life greatly, and evolve over time, Kinch said.

“It’s essential that we stay on top of this,” he added. “If we let our guard our down, we will pay the price.”

Huge Price

In late March, several days after she began feeling headaches and light-headedness, Melissa Muldoon, a 35-year-old resident of Buffalo, New York, went on a run and lost consciousness.

Muldoon was taken to an emergency room, where she took a Covid-19 test, she said in an interview. The next day, it came back positive more than a month after she had been fully vaccinated. A week later, she began developing new symptoms, she said, including a loss of smell for certain foods, a racing heart and muscle twitches.

She said some health professionals questioned how much of a role Covid played, given she was inoculated. But Muldoon wonders how it could be anything else given the quick onset and combination of symptoms.

“I’m anxious about what happens if there’s no answer,” she said, “and it just keeps up with random problems or strange things happening with my body that I haven’t experienced before.”

What’s Known

What’s known so far about breakthroughs is encouraging for the vaccination effort, scientists say, with current research indicating that people in breakthrough cases tend to be either asymptomatic or to have only mild symptoms. There is some evidence as well that vaccination may make illness less severe, according to the CDC, and scientists have also detected infectees that don’t spread Covid to others. But little else is known.

Clinical trials weren’t designed to study how the vaccines perform in specific subgroups and people with certain medical conditions weren’t included, said Lee Harrison, a professor of medicine and epidemiology at the University of Pittsburgh.

At a more granular level, the specific mechanisms that explain how breakthroughs occur should be further investigated, said Alex Greninger, assistant director of the clinical virology laboratories at the University of Washington Medical Center. The conventional thinking is that those who mount less of a response to vaccines would be more susceptible to getting breakthroughs infections, he said. But Greninger said he’s seen a few cases where people developed strong immune responses to the vaccines, yet still got infected.

Link to Variants

Scientists are also trying to figure out whether a disproportionate number of breakthroughs are linked to variants. However, studying all this is difficult given that number of cases is small and some may not be detected at all since many are asymptomatic or have only mild symptoms, said Stefan Green, co-principal investigator at the Regional Innovative Public Health Laboratory at Rush University.

Green said he’s also seen in a few cases that viral loads are too low to conduct whole genome sequencing on, similar to what some other researchers have found.

Breana Landon, a 23-year-old Utah resident, has also been experiencing ongoing symptoms.

Landon tested positive for Covid in late March after being fully vaccinated, she said. It was her second time testing positive, and her second shot came six days later than is recommended. She was told, though, that missing the deadline didn’t matter.

The first time she was infected came last fall, before she got vaccinated. She had respiratory problems then that developed into pneumonia. This time, she experienced a whole new set of symptoms, including persisting heart palpitations and pain.

‘Dead End’

“I feel a little lost, almost, kind of at a dead end,” Landon said in an interview. She recognized it’s possible she never fully recovered from the first round of Covid, but she had gotten multiple negative tests before she tested positive again.

https://www.bloomberg.com/news/articles/2021-05-09/cdc-limits-reviews-of-vaccinated-but-infected-spurring-concerns

Anti-Androgen Meds May Disarm Coronavirus Spike Protein, Stop COVID Disease Progress

 A new Penn Medicine study shows how anti-androgen drugs disrupt key receptors required for viral invasion of cells.

Hormone drugs that reduce androgen levels may help disarm the coronavirus spike protein used to infect cells and stop the progression of severe COVID-19 disease, suggests a new preclinical study from researchers in the Abramson Cancer Center at the University of Pennsylvania and published online in Cell Press’s iScience.

Researchers show how two receptors — known as ACE2 and TMPRSS2 — are regulated by the androgen hormone and used by SARS-CoV-2 to gain entry into host cells. Blocking the receptors with the clinically proven inhibitor Camostat and other anti-androgen therapies prevented viral entry and replication, they also showed in lab studies.

The findings provide more insight into the molecular mechanisms of the virus but also support the use of anti-androgen therapies to treat COVID-19 infections, which are currently being investigated in clinical trials and have produced promising results. They also support data showing increased mortality and severity of disease among men compared to women, who have much lower levels of androgen.

“We provide the first evidence that not only TMPRSS2, which is known to be regulated by androgen, but ACE2 can also be directly regulated by this hormone,” said senior author Irfan A. Asangani, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. “We also show that the SARS-CoV-2 spike relies on these two receptors to impale and enter cells, and that they can be blocked with existing drugs. That’s important because if you stop viral entry, you reduce the viral load and disease progression.”

Camostat is a drug approved for use in Japan to treat pancreatitis that inhibits TMPRSS2. Other anti-androgen therapies, including androgen deprivation therapy used to treat prostate cancer, serve similar functions.

Driven by the disparity in COVID-19 rates between men and women, the cancer researchers sought to better understand the role androgen and its receptors played in infections, which has long been known to be a driver of prostate cancer.

The researchers performed experiments with a pseudotype SARS-CoV-2, which carries the spike proteins of the virus but not its genome.

In mice with significantly reduced androgen levels and cells treated with anti-androgen treatments, the researchers found little to no expression of TMPRSS2 and ACE2, suggesting both are regulated by the hormone. They also observed how inhibiting TMPRSS2 with Camostat blocked priming of the spike for entry into cells. That drug, as well as enzalutamide, an anti-androgen therapy used to treat prostate cancer, also blocked the virus’ entry into lung and prostate cells. Combining these therapies, they found, significantly reduced virus entry into cells.

“Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors, androgen-deprivation therapy / androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression,” the authors wrote.

In March, researchers from Brazil reported preliminary results of 600 hospitalized patients in a clinical trial investigating proxalutamide, a new anti-androgen therapy, for the treatment of COVID-19. The drug reduced mortality risk by 92 percent and shortened the median hospital stay by nine days versus the standard of care, the researchers reported.

Next, Asangani and his colleagues will partner with Susan R. Weiss, PhD, a professor of Microbiology and co-director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens, to investigate the findings further using live SARS-CoV-2, as well as anti-androgen therapies’ ability to block different variants of the virus, which continue to emerge and are often differentiated by their spike proteins.

Reference: “Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19” by Qu Deng, Reyaz ur Rasool, Ronnie M. Russell, Ramakrishnan Natesan and Irfan A. Asangani, 1 March 2021, iScience.
DOI: 10.1016/j.isci.2021.102254

Penn co-authors of the study include Qu Deng, Reyaz ur Rasool, Ronnie M. Russell, and Ramakrishnan Natesan.

https://scitechdaily.com/hormone-drugs-may-disarm-coronavirus-spike-protein-and-stop-covid-19-disease-progression/

How gut microbes educate the immune system

 The immune system's main job is identifying things that can make us sick. In the language of immunology, this means distinguishing "self" from "non-self": The cells of our organs are self, while disease-causing bacteria and viruses are non-self.

But what about the billions of bacteria that live in our guts and provide us with benefits like digesting food and making vitamins? Are they friend or foe?

This isn't only a philosophical question. An immune system that mistakes our good gut bacteria for an enemy can cause a dangerous type of inflammation in the intestines called colitis. An immune system that looks the other way while gut microbes spill past their assigned borders is equally dangerous. Understanding how the immune system learns to make a brokered peace with its microbial residents, called the microbiota, is therefore an important area of research.

"Right now, each of us has immune cells in our body that can recognize and attack specific members of our gut microbiota," says Gretchen Diehl, an immunologist in the Sloan Kettering Institute. "So, it's a puzzle why more of us don't have colitis caused by these cells attacking our gut microbes."

To try to solve that puzzle, Dr. Diehl and her colleagues, including SKI postdoctoral researcher Daniel Zegarra-Ruiz and immunologist Matthew Bettini at the University of Utah, recently conducted a study using lab mice to explore what happens to microbe-specific T cells (a type of immune cell) when mice are exposed as young pups to a common gut microbe.

"We thought that maybe T cells specific for this microbe would be eliminated from the mice, or perhaps the mice would develop anti-inflammatory T cells that would protect them from developing colitis," Dr. Diehl says. In other words, they hypothesized the bacteria would be seen as self.

Surprisingly, that wasn't the case. Not only were the microbe-specific T cells not deleted, they actually grew in number. The results, which were published May 12, 2021, in Nature, document a previously unknown way that gut microbes interact with the immune system and raise yet more questions about what goes awry in autoimmune disease.

Hidden Highway

The scientists focused their attention on an immune system organ called the thymus, which is located in the upper chest behind the breastbone. The thymus's main role is "educating" T cells about which markers, or antigens, in the body are self versus non-self. T cells that recognize self are actively culled while those that do not recognize self are spared. The non-self-recognizing T cells are then released into the circulation where they patrol for viruses, bacteria, and other invaders.

The education process is thought to be primarily about protecting the body from self-attacking T cells that could cause trouble in the form of autoimmunity. Dr. Diehl and her colleagues were taken aback to find that rather than eliminating T cells that recognize gut bacteria, the thymus was giving them the green light.

"We were very, very surprised that when we colonized mice with gut bacteria, instead of seeing the development of regulatory T cells that calm immune reactions or loss of microbe-specific T cells, we saw an expansion of them," she says. "As far as we are aware, this is the first time anyone has shown the thymus playing this role in the expansion of microbe-specific T cells."

Next they asked: How is information about gut bacteria making its way to the thymus?

Using standard gut microbiota detection techniques, they could see that bacterial DNA was showing up in the thymus, suggesting that the gut is somehow in communication with this organ via DNA. But that only raised the further question of how this DNA was getting there.

One possible explanation is that bacterial DNA is carried there by immune cells called dendritic cells, whose main job is, in fact, to carry suspicious antigens from tissues to lymph nodes. Traveling from the gut to the thymus hadn't been seen, but the scientists couldn't rule out that possibility.

To track the movement of dendritic cells, Dr. Diehl and her colleagues took advantage of a hi-tech lab mouse developed by Kat Hadjantonakis's lab at MSK. The mouse had been engineered to make a fluorescent marker called green fluorescent protein (GFP) in its cells. When GFP-containing cells are hit with light from a laser, they change from emitting green fluorescence to emitting red. By shining the laser in the intestine of the mouse, the scientists could turn gut dendritic cells red and then watch and see if red cells turned up in the mouse thymus. Sure enough, they did.

"The dendritic cells are clearly migrating that whole way, which is kind of crazy," Dr. Diehl says.

A Temporary Window

The gut-to-thymus journey only happens in very young animals. When the scientists looked at older animals, they didn't see the red cells turning up. Nor did they find any gut microbe DNA in the thymus or expansion of gut-specific T cells.

What might be the purpose of this gut-to-thymus traffic that only happens during a specific developmental window in the mice?

"What we think is happening is a kind of templating on the immune system," Dr. Diehl says. "In that timeframe, the mouse immune system is very underdeveloped and the most relevant thing for it to recognize is microbes. So, it brings gut antigens to the thymus to educate the T cells about these and related dangers."

As evidence for this possibility, they showed that the T cells that recognize the introduced bacteria also afford protection against pathogens the mice hadn't yet seen. But because they recognize gut microbes, these T cells can also cause inflammation that can lead to colitis.

What the scientists next want to understand is whether this process differs in people who are more susceptible to colitis.

Dr. Diehl wonders: "Do you have this happening for a more extended period of time in people with colitis? Do you have it happening for less? Does it restart in someone with colitis? These are all questions we want to explore."

This work was supported by the National Institutes of Health (grants R01AI136963, R01AI125264, R01DK114456, R01AI130152, R01 DK114252, P30 CA125123, and S10 RR024574), the Kleberg Foundation, Rainin Foundation, and a Leukemia and Lymphoma Society Scholar Award.

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Story Source:

Materials provided by Memorial Sloan Kettering Cancer Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Daniel F. Zegarra-Ruiz, Dasom V. Kim, Kendra Norwood, Myunghoo Kim, Wan-Jung H. Wu, Fatima B. Saldana-Morales, Andrea A. Hill, Shubhabrata Majumdar, Stephanie Orozco, Rickesha Bell, June L. Round, Randy S. Longman, Takeshi Egawa, Matthew L. Bettini, Gretchen E. Diehl. Thymic development of gut-microbiota-specific T cells. Nature, 2021; DOI: 10.1038/s41586-021-03531-1

https://www.sciencedaily.com/releases/2021/05/210512164011.htm

India's Cipla says supply of remdesivir catching up with demand

 India's Cipla said on Saturday that its manufacturing of the COVID-19 remdesivir drug was beginning to catch up with demand after the company sought to boost production amid a massive second wave of coronavirus infections in the country.

Backorders and complaints over low supply started moderating in the second week of May, the drugmaker said, after it began ramping up production of the antiviral drug last month.

Hospitals have faced shortages of the drug, which is being widely used and was sold in April for over 10 times its listed price in the black market.

Cipla's production of remdesivir is currently 5 times higher than the monthly output of 200,000 to 300,000 vials seen in the last wave of the pandemic last year, the company's Chief Financial Officer Kedar Upadhye told Reuters. Remdesivir was originally developed by U.S.-based Gilead Sciences Inc.

Future supply of the drug will also depend on the course of the pandemic in India but "manufacturing is no longer the bottleneck," Upadhye said.

The number of complaints about supply has dropped, Upadhye said, adding that Cipla was working with state governments to tackle ongoing supply shortages in parts of the country.

Cipla, one of India's oldest drug manufacturers, has a deal to make and supply remdesivir to more than 100 countries. Several other Indian drug producers have similar agreements.

The company has also signed licensing agreements with U.S. companies Merck and Eli Lilly to make and sell Merck's experimental COVID-19 drug molnupiravir and Lilly's arthritis drug baricitinib, which is also being used to treat COVID-19, in India.

https://www.livemint.com/companies/news/indias-cipla-says-supply-of-covid-19-drug-remdesivir-catching-up-with-demand-11621073953773.html

Probiotics Protect Overweight, Older Patients From Coughs and Wheeze

 Daily doses of certain probiotics appeared to keep upper respiratory tract symptoms somewhat at bay, especially in patients older than 45 and with a body mass index (BMI) in the obesity range, secondary results of a small trial indicated.

Overall reports of such symptoms -- including cough, sore throat, headache, muscle ache, and wheeze -- were 27% lower among 110 people taking a probiotic mix called Lab4P than in 110 assigned to placebo in the randomized study, said Benjamin Mullish, MD, of Imperial College London, during a press briefing held in advance of the annual Digestive Disease Week meeting.

The findings were also published recently in Gut Microbes.

The reduction was more pronounced in subgroups defined by age and BMI. In participants age 45 and older, Mullish and colleagues found an incidence rate ratio for respiratory symptoms of 0.60 (P<0.0001) for probiotics versus placebo, as opposed to 0.90 (not significant) in younger people.

And those with BMI values of 30-34.9, indicating obesity, showed an incidence rate ratio of 0.57 (P<0.0001) with probiotics versus placebo, compared with 0.78 (P=0.006) for those with BMI values of 25-29.9, considered overweight.

Kaplan-Meier curves showing time to first respiratory tract symptom indicated advantages for the probiotic group developing early in the 6-month study. In the 45-and-older group, nearly 80% of those taking probiotics remained symptom-free at day 50, whereas half of the placebo participants had shown symptoms at that point. A similar though less dramatic difference was seen among obese participants. Probiotics provided no benefit for this metric in overweight participants or in those younger than 45.

Mullish said previous studies had suggested that probiotics could protect against upper respiratory tract symptoms, but had not examined the effect in older or overweight people specifically.

Those earlier studies had established that there is a "gut-lung axis" connecting the intestinal microbiome to respiratory function, with which the current research firmly aligns.

The so-called PROMAGEN trial randomized 220 patients to daily placebo or the Lab4P probiotic mix (including two Lactobacillus and two Bifidobacterium species), chosen on the basis of earlier findings that these were particularly capable of affecting overall metabolism and also had a good safety record. Primary outcomes were body weight and lipid parameters (results of which were published last year in Scientific Reports); however, patients also completed daily diaries tracking the five types of respiratory symptoms, analyzed for the current analysis.

Although these results document an apparent transaction whereby modifications to the intestinal microbiome affect respiratory health, Mullish emphasized in a press release that it's a two-way street: "It's not just the gut sending out signals that affect how the lungs work. It works in both directions."

Notably, PROMAGEN did not examine immune parameters nor identify pathogens, allergens, or other proximate causes for the respiratory symptoms.

Nevertheless, the researchers did suggest in their Gut Microbes paper that probiotics should be tested specifically for preventing viral upper respiratory tract infections "and possibly also COVID-19."

"We feel that a compelling case exists for further randomized studies to prospectively explore the potential impact of probiotics on prevention of respiratory infection in particular for those at higher risk, including obese and older people," the team wrote.

During the DDW press briefing, Mullish noted that the case for probiotics as a COVID-19 preventive or treatment is built largely on "strands of circumstantial evidence."

Preclinical studies have pointed to "perturbation of the gut microbiome" as an influence on immune response, he said. But he also pointed to a small study from Italy in which COVID patients received probiotics, and none progressed to needing respiratory support. On the other hand, he said he was unaware of any studies of probiotics as prophylaxis against COVID-19. "It would be really interesting to look into," Mullish said.

Disclosures

The study was funded by Cultec, which manufactures the Lab4P probiotic; several investigators were Cultec employees.

Primary Source

Digestive Disease Week

Source Reference: Mullish B, et al "Daily probiotic use is associated with a reduced rate of upper respiratory tract symptoms in overweight and obese people" DDW 2021; Abstract 739.

Secondary Source

Gut Microbes

Source Reference: Mullish B, et al "Probiotics reduce self-reported symptoms of upper respiratory tract infection in overweight and obese adults: Should we be considering probiotics during viral pandemics?" Gut Microbes 2021; DOI: 10.1080/19490976.2021.1900997.

https://www.medpagetoday.com/meetingcoverage/ddw/92591

History of MIS-C Doesn't Preclude COVID Vaccination: CDC

 People with a history of multi-inflammatory syndrome for children or adults (MIS-C or MIS-A) may choose to be vaccinated against COVID-19, CDC staff said in a call with clinicians on Friday.

However, these patients should consider delaying vaccination for 90 days until after the date of their diagnosis. Other factors may include clinical recovery from MIS-C or MIS-A, including a normal return to cardiac function, as well as personal risk of severe acute COVID-19 due to age or underlying condition, level of community transmission, and the timing of any immunomodulatory therapies.

Kate Woodworth, MD, MPH, of the CDC, added that there is "no data specifically on the safety of COVID-19 vaccine after MIS-C."

When asked if there was other specific guidance for people with primary immune disorders, such as Kawasaki syndrome, Woodworth noted guidance for immunosuppressed people can be found under clinical considerations on the agency's website.

Another special population clinicians were curious about was the effect of COVID-19 vaccination on menstruation in female adolescents.

"At this time, there haven't been any studies on changes to the menstrual system," Woodworth said, though she added there were reports of heavier menstrual periods, earlier or later onset of menstrual periods and cramps. However, she said many things can affect the menstrual cycle, and clinicians should talk to patients about their concerns.

Sara Oliver, MD, MPH, of the CDC, responded to a question on whether different adverse events were being observed in adolescents versus adults. Oliver said that because adolescents are younger, healthier, and likely have fewer underlying medical conditions, there were less serious adverse events seen in this population following vaccination in general.

Clinicians also heard the new guidance on co-administration of the COVID-19 vaccine and other vaccines, in both adolescents and adults.

Agency staff reiterated the clinical guidance from Wednesday's Advisory Committee on Immunization Practices (ACIP) meeting, stating that COVID-19 vaccines and other vaccines may now be administered simultaneously or can be co-administered within 14 days.

They also offered specific guidance for administration, reminding clinicians the deltoid muscle can be used for more than one intramuscular injection. Other best practices included:

• Labeling each syringe to identify the vaccine it contains
• Separating injection sites by an inch or more, if possible
• Administer COVID-19 and vaccines more likely to cause a local reaction (such as tetanus toxoid vaccines) in different limbs, if possible

CDC staff also reiterated that the Pfizer/BioNTech vaccine dose is the same for adolescents as adults (two intramuscular injections, delivered 3 weeks apart), and is not a "weight-based dose." They added it is also appropriate for adolescents to take over-the-counter pain relievers to alleviate mild post-vaccination symptoms.

When a question arose about how soon the vaccine will be available for even younger populations, Oliver explained that the process was more complicated than going from adults to adolescents.

"As we go younger, both Pfizer and Moderna are doing dose-finding" studies, making sure the dose is correct for a younger and physically smaller population, she said. They will then do safety and immunobridging studies, similar to the adolescent vaccine.

Oliver said it's harder to pinpoint the timing on that, but researchers are hopeful that data will be available by the end of the year or early 2022.

"We'll see how the data evolves," she said.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/92600