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Search for key to beat virus

San Franscisco Chronicle

Bay Area at center of many promising treatment studies
By Peter Fimrite and J.D. Morris

The frenetic search for the miracle that will rid the world of COVID-19 is branching out in a thousand directions, and a large part of the microbial treasure hunt is going on in the Bay Area, where major progress has been made in the 100 days since residents were ordered to shelter in place.

Scientists at universities, laboratories, biotechnology companies and drug manufacturers are combing through blood plasma taken from infected patients for secrets that will help them fight the disease.

The key is likely a superstrength antibody found in some patients. But researchers must first figure out how those antibodies work and how they can be harnessed and used to stop the many health problems associated with COVID-19, particularly acute respiratory distress syndrome, or ARDS, which has killed more people than any other complication connected to the disease.

Other developments showing promise include injections of mesenchymal stem cells, found in bone marrow and umbilical cords, that doctors are studying to battle inflammation caused by ARDS. And a steroid called dexamethasone reduced the number of deaths by halting the overreactive immune responses in seriously ill patients in the United Kingdom.

In all, more than 130 vaccines and 220 treatments are being tested worldwide.

What follows is a list of some of the most promising elixirs, medications and vaccines with ties to the Bay Area:

Antibodies and immunity

Monoclonal antibodies / Vir Biotechnology, San Francisco: Scientists at Vir and several institutions, including Stanford and UCSF, are studying monoclonal antibodies, which are clones of coronavirusfighting antibodies produced by COVID-19 patients.

The idea is to utilize these “neutralizing antibodies” — which bind to the virus’ crown-like spikes — and prevent them from entering and hijacking human cells.

Only about 5% of coronavirus patients have these superstrength antibodies, and those people are believed to be immune to a second attack.

The trick for scientists at Vir is to identify these neutralizing antibodies, harvest, purify and clone them. If they succeed, the resulting monoclones could then be used to inoculate people and — it is hoped — give them long-term immunity against the coronavirus. The company recently signed a deal with Samsung Biologics, in South Korea, to scale up production of a temporary vaccine in the fall after clinical trials are complete.
 
Another monoclonal antibody, leronlimab, is being studied in coronavirus clinical trials by its Washington state drugmaker, CytoDyn. The company’s chief medical officer is in San Francisco, and the company that does laboratory tests of leronlimab is in San Carlos.

Interferon-lambda / Stanford University: Doctors at Stanford are running a trial to see if interferon- lambda, which is administered by injection, helps patients in the early stages of COVID-19. Interferon- lambda is a manufactured version of a naturally occurring protein that has been used to treat hepatitis. Stanford doctors hope it will boost the immune system response to coronavirus infections.

Dr. Upinder Singh, a Stanford infectious-disease expert, said the trial has enrolled more than 50 patients and is halfway finished. “We have noted that patients tolerate the drug very well,” she said.

Mesenchymal stem cells / UCSF and UC Davis Medical Center: UCSF Dr. Michael Matthay is leading a study about whether a kind of stem cell found in bone marrow can help patients with ARDS. Matthay hopes that the stem cells can help reduce the inflammation associated with some of ARDS’ most dire respiratory symptoms, and help patients’ lungs to recover.

Matthay is aiming to enroll 120 patients in San Francisco, the UC Davis Medical Center in Sacramento and hospitals in a handful of other states. He said the trial, which includes a small number ARDS patients who don’t have COVID-19, should have results within a year. So far 17 patients are enrolled in the trial, most of them in San Francisco.

Antiviral drugs

Remdesivir / Gilead Sciences (Foster City): Remdesivir, once conceived as a potential treatment for ebola, was the first drug to show some promise in treating COVID-19 patients. The drug interferes with the process through which the virus replicates itself. A large study led by the federal government generated excitement in late April when officials said hospitalized patients who received remdesivir intravenously recovered faster than those who received a placebo.

A later study looking at dosage showed some benefit for moderately ill COVID-19 patients who received remdesivir for five days, but improvement among those who got it for 10 days was not statistically significant. Gilead, a drug company, recently announced that it will soon launch another clinical trial to see how remdesivir works on 50 pediatric patients, from newborns to teenagers, with moderate to severe COVID-19 symptoms. More than 30 locations in the U.S. and Europe will be involved in the trial, the company said.

Favipiravir / Fujifilm Toyama Chemical (Stanford University): This antiviral drug, developed in 2014 by a subsidiary of the Japanese film company to treat influenza, is undergoing numerous clinical studies worldwide, including a Stanford University trial that began this month. Unlike remdesivir, it can be administered orally, so it can be used to treat patients early in the disease, before hospitalization is necessary.

Stanford epidemiologists want to see if favipiravir, which has shown promising results in other trials, prevents the coronavirus from replicating in human cells, halts the shedding of the virus and reduces the severity of infection. The Stanford study, the only outpatient trial for this drug in the nation, is enrolling 120 people who have been diagnosed with COVID-19 within the past 72 hours. Half of them will get a placebo. People can enroll by emailing treatcovid@stanford.edu. Anti-inflammatory drugs


Colchicine / UCSF (San Francisco and New York): The anti-inflammatory drug commonly used to treat gout flareups is being studied in the U.S. by scientists at UCSF and New York University. The drug shortcircuits inflammation by decreasing the body’s production of certain proteins, and researchers hope that it will reduce lung complications and prevent deaths from COVID-19. About 6,000 patients are receiving colchicine or a placebo during the clinical trial, dubbed Colcorona, which began in March and is expected to be completed in September.

Selinexor / Kaiser Permanente: Kaiser hospitals in San Francisco, Oakland and Sacramento are studying selinexor, an anticancer drug that blocks a key protein in the cellular machinery for DNA processing, as a potential COVID-19 treatment. The drug has both antiviral and anti-inflammatory properties, and it’s administered orally, according to Kaiser’s Dr. Jacek Skarbinski. The trial aims to enroll 250 patients with severe symptoms at Kaiser and other hospitals that are participating nationwide.

Vaccines

VXA-COV2-1 / Vaxart, South San Francisco: The biotechnology company Vaxart is testing this drug to see if it is as effective at controlling COVID-19 as trials have shown it to be against influenza. VXACOV2-1, the only potential vaccine in pill form, uses the genetic code of the coronavirus to trigger a defensive response in mucous membranes. The hope is that the newly fortified membranes will prevent the virus from entering the body.

“It’s the only vaccine (candidate) that activates the first line of defense, which is the mucosa,” said Andrei Floroiu, Vaxart’s chief executive, noting that intravenous vaccines kill the virus after it is inside the body. “Our vaccine may prevent you from getting infected at all.”

The drug was effective against influenza and norovirus in trials and appears to work on laboratory animals, Floroiu said. He expects trials of VXA-COV2-1 on humans to begin later this summer.

VaxiPatch / Verndari (Napa and UC Davis Medical Center): Napa vaccine company Verndari makes a patented adhesive patch that can deliver a vaccine instead of a shot. Now, the company is trying to make a vaccine for COVID-19 that they can administer through that patch. At UC Davis Medical Center in Sacramento, Verndari researchers are developing a potential vaccine that relies on the coronavirus’ spike-shaped protein. When injected into a person, the substance would ideally train their body to recognize the virus and fight it off without becoming ill.

A spokeswoman told The Chronicle that the company’s preclinical tests have shown “early, positive data in developing an immune response.” Verndari hopes to move into the next phase of testing in the coming weeks and start clinical trials in humans this year.

If the vaccine is proved effective and safe, patients could receive it through the mail, according to company CEO Dr. Daniel Henderson. The patch would leave a temporary mark on the skin that patients could photograph and send to their doctor as proof they have taken the vaccine, Henderson has said.
 
Peter Fimrite and J.D. Morris are San Francisco Chronicle staff writers. Email:
pfimrite@sfchronicle.com, jd.morris@sfchronicle.com Twitter: @pfimrite, @thejdmorris


Coronavirus vaccine could come from California, with no shot needed

San Franscisco Chronicle

Bay Area researchers’ proximity to leading health care centers and Silicon Valley has given them a leading role in developing drugs to treat COVID-19.

It could also give local companies and institutions a leg up in the global race to create a vaccine. Several have set out to create a highly effective product that can be distributed widely.

The stakes could not be higher. Even as doctors learn more about drugs to help patients who have contracted the virus, a vaccine remains potentially the most effective — and elusive — tool to fight the pandemic. Answers are likely still months away at the earliest, but government officials and health companies are trying to accelerate the process.

The odds are long: More than 130 vaccines are in development worldwide, according to the Milken Institute, a Santa Monica think tank. Only a small subset of those will likely be put to use. And successful companies must not only build a product that stops the virus, but also manufacture it on a truly enormous scale as fast as possible.

Some of the vaccines being studied locally would not be administered through a shot.

Verndari, of Napa, is working on a potential coronavirus vaccine to administer through an adhesive patch. The idea is to take away the pain component, thereby circumventing anyone’s aversion to shots, and to make something that can be kept at room temperature. That could make the vaccine easier to distribute, especially in developing countries.

Dr. Daniel Henderson, Verndari’s CEO, said the patches could even be sent through the mail and use temporary dye to leave a mark on a patient’s arm. The patient could then take a photo of the dye and send that to their health care provider as proof they were vaccinated.

“We really do want to change the way vaccines are perceived,” Henderson said. “And of course this goes far beyond COVID-19. It goes to the global distribution of vaccines everywhere. You could make them cheaper and have better efficacy and do away with the fear of vaccines.”

Verndari’s potential vaccine, which the company is developing at the UC Davis Medical Center in Sacramento, uses the virus’ “spike” protein, which the virus uses to attach itself to human cells. By introducing that protein into a person’s body, Verndari hopes it can train their immune system to recognize the virus when exposed to it and thereby prevent the person from becoming ill.

Henderson said he hopes to be able to start clinical trials that would test the vaccine on humans this summer. Forecasting when the vaccine might be rolled out, if it works and is safe, is more complicated given that the company is also proposing a new delivery method.

But Henderson said Verndari has already demonstrated that its patch is effective in humans when it was studying a potential flu vaccine. The company has also established a relationship with a California manufacturer.

South San Francisco’s Vaxart is another one of the local companies that is working on a potential coronavirus vaccine. Like Verndari, Vaxart also wants to protect people from COVID-19 without giving them shots. But instead of using a patch, the company is exploring a vaccine that could be taken in pill form.

Vaxart CEO Wouter Latour said the company has already shown efficacy through a clinical trial of a flu vaccine pill. Now, it’s trying to develop a similarly effective tool for the coronavirus.

Latour said the company wants to use an inactivated common cold virus as a vehicle for DNA that could help train the body to fight off the new coronavirus. He said Vaxart is on track to start clinical studies in the second half this year.

Vaxart doesn’t expect to create the first viable vaccine for COVID-19 — Latour thinks there will be many. Demand for a vaccine will be so high that the world won’t have enough resources to get one vaccine in the hands of everyone who needs it, at least not initially.

“Get those early vaccines out,” he said. “We could be right behind with this fantastic tablet and make life a lot easier and much more efficient in terms of implementing a large vaccination campaign and getting it to parts of the world where it’s harder to get vaccines.”

In order to make a vaccine pill effective, developers would have to figure out how to make it strong enough to not be killed by stomach acid before the vaccine can do its job, said Dr. Lee Riley, an infectious disease expert at UC Berkeley. But if effective, such a vaccine would be safe and easy to give to a lot of people, he said. A patch could work well because skin is the body’s largest organ and it’s good at producing a strong immune response, Riley said.

But finding a vaccine that works is only one part of the equation. Once proved effective, the product has to be made widely available — which will be a major challenge if it needs to reach billions of people.
George Talbott, left, works on a coronavirus vaccine patch with Verndari CEO Dr. Daniel Henderson in Sacramento in May.

“It will take years to be able to have a production capacity to make that many vaccines,” Riley said. “It’s not just coming up with a vaccine that works. It’s also the production that’s going to take some time.”

Dynavax Technologies of Emeryville is taking a slightly different approach to vaccine development than some of the other companies. Instead of building a vaccine on its own, Dynavax is lending a helping hand to others.

The company has created a federally-authorized vaccine for hepatitis B that uses a modifying ingredient to improve the immune response in patients. So Dynavax is providing that ingredient, called CpG 1018, to help other companies that are developing potential vaccines.

“We have a technology that’s proven in our vaccine that can be possibly very valuable to helping address this issue, and therefore it has to be evaluated,” said Dynavax CEO Ryan Spencer. “We have, I think, a responsibility to be in the game here.”

At UCSF, immunology Professor Raul Andino is taking his time to study exactly how the coronavirus works before trying to devise a new way to protect people. He’s closely examining how the virus progresses in animals, and he thinks he’s at least six months away from moving into the clinic.

“While everybody is trying to jump ahead and get the answer in humans, basic studies are very important to understand the mechanisms by which this virus causes the disease,” Andino said.

He knows the world can’t wait for him to finish his work before advancing ways to make people immune to COVID-19. But his ultimate goal is still to create a live-attenuated vaccine, which uses a weakened form of a virus to create immunity.

That type of vaccine has proved broadly effective at combating other dangerous illnesses such as polio, mumps and smallpox, Andino said. Because using a weakened form of the virus is so similar to a natural infection, live-attenuated vaccines have the power to induce long-lasting immunity — but they require a sophisticated understanding of how the virus works.

“I understand everybody wants a vaccine yesterday,” he said. “But what I’m thinking of is the second generation of vaccines ... maybe a live-attenuated vaccine will be better in the long run.”

An ideal coronavirus vaccine might look like previous vaccines developed for hepatitis B and whooping cough that used certain proteins to provide protection, said Dr. Yvonne Maldonado, an epidemiologist and infectious disease specialist at Stanford University’s School of Medicine. Part of the challenge now is that doctors do not yet fully understand the virus that caused the current pandemic.

“It’s like the normal coronaviruses that cause colds in human beings, but it’s much more likely to cause serious disease as well,” she said. “We’re trying to understand why that is.”

One way to speed up the vaccine development process may be to let volunteers be given a potential vaccine or placebo, then injected with the virus or placebo while researchers study the effects. A new campaign called 1 Day Sooner has sprung up in support of that goal. It’s already registered thousands of people, including hundreds in California, who have said they’re willing to participate in “challenge trials” — if and when they occur in humans.

Josh Morrison, a New York resident who co-founded the campaign, said the goal is to have a list of people who are willing to participate should researchers take the step of asking for volunteers. More screening would be required if that happens.

While such trials would only accept people who are at lower risk of developing severe or deadly cases of COVID-19, Morrison knows that asking people if they are willing to be injected with a live coronavirus may sound like a dicey proposition.

“This is definitely a significant risk ... but it’s also a type of risk that is consistent with other risks we let people take,” he said. “We think, if you have intelligent and well-educated volunteers, we should let those people make those choices if it’s likely that you have a meaningful gain in vaccine development, which to us is as little as one day.”

J.D. Morris is a San Francisco Chronicle staff writer. Email: jd.morris@sfchronicle.com Twitter: @thejdmorris


Napa company begins testing a potential COVID-19 vaccine

Napa Valley Register

Could a vaccine for COVID-19 come from Napa?

Daniel Henderson, John H. Brown and Jan Van Prooyen, founders of Verndari, a Napa- based biotechnology company, hope so.

The three men have been working on a potential vaccine that could potentially save millions of lives around the world.

On Thursday the company announced that it will begin preclinical testing at UC Davis of a potential COVID-19 coronavirus vaccine, which will be administered using its patented microneedle array dermal patch.

“This is what I’ve trained to do,” said Daniel R. Henderson, Ph.D., CEO, and chief scientific officer of Verndari, Inc., during a phone interview. “The need is great.”

The medical scientist is optimistic about finding a vaccine, noting, “I’m working as hard now as I ever have in my life.”

However, “The scary thing is that we’re not in control,” said Henderson. “The virus is in control. The virus has no purpose in life other than to replicate.”

“We’re passing 60,000 deaths (in the U.S.) and we’re still in the second inning. This isn’t anywhere close to over.”

Verndari, Inc. was founded in 2015 after the three men met through connections at St. Mary’s Episcopal Church in Napa. Verndari is an Icelandic word that means guardian or protector, said Henderson.

The company has since developed the potential COVID-19 vaccine using single, purified protein antigens produced by genetic engineering, said a news release.

The vaccine candidate uses the COVID-19 “spike” protein that enables the virus to infect human cells.

Verndari, Inc. was founded “to enable a rapid response to new viral threats as well as to produce more effective vaccinations for existing viruses, such as seasonal flu, while sharply reducing costs and making vaccine administration much simpler,” said Henderson.

The testing will be conducted in laboratories at the University of California, Davis. “Our new approach and previous vaccine work have enabled us to quickly develop a potential vaccine for COVID-19. UC Davis provides a world-class forum for testing,” said the news release.

Preclinical testing begins this week at UC Davis’ Mouse Biology Program.

Verndari, Inc. is also in discussions with the California National Primate Research Center at UC Davis to conduct further testing in nonhuman primates.

If the preclinical testing meets safety and efficacy goals, Phase 1 human clinical trials would begin.

Verndari estimates that testing from inception through Phase 1 human clinical trials will take approximately six months. The company is in consultation with the U.S. Food and Drug Administration using its Investigational New Drug (IND) submission.

The company isn’t the only one working on a possible vaccine. There are as many as 70 other such companies racing towards that goal, he said.

“We are excited to work with Verndari, Inc. to move its vaccine candidate through preclinical, and potentially clinical, studies,” said Prasant Mohapatra, vice chancellor for research at UC Davis.

“This collaboration illustrates one of many ways that UC Davis is leveraging our unique expertise and established platform built on previous research for HIV, Zika and human cytomegalovirus in order to advance knowledge and solutions specific to COVID-19,” he said.

“When we founded Verndari, Inc. we set about to transform the entire vaccination process, from development through vaccination,” said John H. Brown, president, and co-founder of Verndari, Inc.

“Our goal is to enable more rapid development of more effective vaccines for both existing and emerging diseases that can be delivered at lower cost to populations around the world.”

Verndari’s VaxiPatch is a complete single-dose vaccination kit that uses a dermal patch with a microneedle array to deliver vaccines to the arm.

The patch itself is a big deal because the technology eliminates the need for refrigeration, a major cost factor in vaccination, and facilitates high-volume, automated manufacturing of vaccines. The vaccine technology can be used for both existing vaccines and new vaccines developed to meet emerging threats.

The VaxiPatch kit reduces or eliminates the reliance on healthcare professionals to administer vaccines and the need for sterile use of a needle and syringe, said a news release. The vaccination is accomplished with a painless microneedle patch applied to the arm, which can potentially be self-administered.

The single-dose vaccination kit has the potential to be shipped around the world to enable simple shelter-in-place inoculation using a microneedle patch placed on the back of the arm.

What does Henderson want Napans to know about the company’s possible vaccine?

“I’d like them to know that one of their neighbors is trying to help. And that I’m optimistic that we will come up with a vaccine,” he said.

“You’ve got a bunch of guys in Napa that are trying to help and by the way we might really transform the way we do vaccines going forward,” with the VaxiPatch, “and that’s pretty cool.”