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Plotting a scientific path to counter COVID-19

How COVID-19 response is stimulating global scientific collaboration

In a global online forum Tuesday night, scientific leaders from companies developing vaccines, therapies and diagnostics to address the COVID-19 outbreak discussed opportunities for collaboration, highlighted challenges, and called for sustained global initiatives to create medical countermeasures to emerging infections.

Participants in the forum, which was sponsored by WuXi Apptec Co. Ltd. (Shanghai:603259; HKEX:2359), provided updates on vaccine development progress, stressed the need to develop multiple vaccines, and called for the establishment of master protocols to efficiently test the candidates.

Vaccine developers and academic opinion leaders said the potential for a COVID-19 vaccine to enhance the severity of infections caused by other coronaviruses, including viruses that are likely to emerge in the future, is a contingency that must be addressed prior to widespread testing of candidate vaccines.

Scientists and business leaders on the ground in China described challenges with available diagnostic technologies and the need for point-of-care diagnostics.

Enhancement

The need to assess the potential of vaccine candidates to inadvertently worsen future coronavirus infections through a process called antibody-dependent enhancement was a major topic of discussion at the WHO COVID-19 R&D forum on Feb. 11-12, Xuefeng Yu, chairman and CEO of CanSino Biologics, said.

Yu noted that antibody-dependent enhancement has been a major problem with Dengue vaccines. When patients who have not previously been exposed to the virus are vaccinated, there is a risk that some of the antibodies they produce will facilitate virus entry into host cells upon Dengue exposure, causing a much more serious illness than would have occurred in the absence of vaccination.

Antibody-dependent enhancement has also been reported for SARS-CoV, HIV, influenza, other alpha and flaviviruses, and Ebola. SARS-CoV shares a high degree of similarity with SARS-2CoV, the virus that causes COVID-19.

“We should cautiously go into human Phase I trials before we have enhancement models.”

Xuefeng Yu, CanSino Biologics

The compressed vaccine development timeframe for COVID-19 is making antibody-dependent enhancement an urgent issue.

Yu said there was an extensive debate at the WHO forum, which he attended, about whether it is necessary to delay human clinical trials until animal models to test antibody-dependent enhancement have been developed.

The consensus, Yu told participants in the WuXi webinar, is that “we should cautiously go into human Phase I trials before we have enhancement models.” He added that there was also agreement about the need to “work on those models to be sure there will be a safe margin to allow us to move to the next phase” of clinical trials.

CanSino Biologics Inc. (HKEX:6185) is developing a viral vector-based COVID-19 vaccine.

Because vaccines will be administered to healthy people, there is little tolerance for safety risks. One way to minimize safety risks, Yu said, is to advance vaccine programs that are based on mature technologies, so the safety focus “is only on the antigen.”

Johan Van Hoof, who is leading COVID-19 vaccine development at Janssen, agreed that enhancement is a serious issue. Van Hoof, global therapeutic area head for infectious diseases and vaccines at the Janssen unit of Johnson & Johnson (NYSE:JNJ), noted that enhancement is “well known in RSV vaccines.”

“Regulators have worked with stakeholders on developing models that help to mimic and predict if a vaccine can induce this kind of phenomena,” Van Hoof said.

He added that it is “reassuring” that enhancement hasn’t been observed in other vaccine candidates under development with Janssen’s viral vector platform.

The platform has a safety database that includes over 47,000 patients, which should provide confidence to quickly advance a vaccine candidate from Phase I to Phase II trials, Van Hoof said.

Janssen hopes to have settled on a candidate vaccine based on immunogenicity studies in mice and primates “by the end of March,” Van Hoof said. The company plans to start large-scale manufacturing while Phase I trials are underway, so if the studies are successful it would have large quantities of vaccine available for Phase II trials and possible emergency use.

In addition to RNA and viral vector vaccines, forum participants received an update on a DNA vaccine candidate.

Joseph Kim, president and CEO of Inovio Pharmaceuticals Inc. (NASDAQ:INO), reported that the company is “seeing tremendous immunogenicity in animal models” with its DNA vaccine candidate.

Inovio is developing the vaccine in partnership with Beijing Advaccine Biotechnology.

Inovio expects to start a Phase I trial in “early summer,” Kim said. At the same time, it plans to start a parallel study in China and possibly in other regions. The Phase I trial will rapidly be extended into an “efficacy signal-generating study,” Kim said.

“Mice lie.”

Mark Esser, AstraZeneca

George Scangos, CEO of Vir Biotechnology Inc. (Nasdaq:VIR), said it will be important for any vaccine that protects against COVID-19 “to ensure it doesn’t enhance the next coronavirus.”

Vir is pursuing a therapeutic mAb approach. While a mAb could also produce enhancement, the risk is mitigated by the shorter persistence of an antibody, Scangos said. mAbs can provide protection for weeks or months, while vaccines may protect - and potentially pose enhancement risks - for a lifetime, he said.

Caution from veterans

Vaccine development veterans who participated in the WuXi webinar sounded other notes of caution.

Mark Esser, VP of microbial sciences at AstraZeneca plc (LSE:AZN; NYSE:AZN), said creating “vaccines is not for the faint of heart.”

He noted that animal studies are not always predictive. “Mice lie,” Esser said. “We developed an RSV vaccine at AZ that in animal models [including mice and ferrets] was 100% effective in preventing disease. When tested in a large clinical trial” it was not effective.

Gregory Poland, director of the Mayo Clinic Vaccine Research Group, said that the mRNA technology Moderna Inc. (NASDAQ:MRNA) is using to develop a COVID-19 candidate vaccine is promising, but it also raises concerns.

Moderna announced Feb. 24 that it had delivered a candidate vaccine to NIH’s National Institute for Allergy and Infectious Diseases. A Phase I trial is scheduled to start March 6 (see "U.S. Testing of Coronavirus Vaccine, Therapeutic Begin").

Particularly for RNA viruses like coronaviruses, Poland said he is “a little concerned about vaccines that are limited to one protein [because the virus] could certainly mutate through that.”

Poland added that “we need more than one kind of vaccine. We are going to have to consider subjects who are immuno-immature, immuno-senescent, and immuno-compromised,” as well as individuals “who are pregnant, who smoke, who have diabetes,” and other conditions.

Van Hoof agreed that several vaccines with different profiles should be developed. He added that “speed is of the essence, but we should be mindful of potential pitfalls.” Vaccine developers, the Janssen scientist said, should be completely transparent, use standardized tests so their products can be readily compared, and should “learn from each other’s successes and failures.”

Esser called on companies to join together to support the creation of a master protocol for testing COVID-19 vaccine candidates in the “most streamlined fashion possible.”

Advantages and disadvantages of mAbs

Vir has identified two mAbs that bind a region of the SARS-CoV-2 spike protein that the virus uses to infect cells, and is using a pseudovirus expressing the SARS-CoV-2 spike protein to assess whether these and other mAbs can neutralize viral entry (see “COVID-19 mAb Menagerie”).

mAbs can be “exquisitely specific” to a pathogen, and compliance with a single administration can be higher than with an oral drug that has be taken daily, Scangos said.

It “remains to be seen” if a mAb would be useful as a COVID-19 therapy or prophylaxis, Scangos noted.

Disadvantages include the challenge of finding antibodies that have the required characteristics, especially a high level of potency, and mAbs can be difficult to manufacture, Scangos said.

Vir is collaborating with WuXi Biologics Inc. (HKEX:2269) on the manufacturing of COVID-19 mAbs.

WuXi Biologics will be responsible for cell line development, process and formulation development, and initial manufacturing for clinical development.

Vir and WuXi could be ready to submit an IND for a Phase I trial in five to seven months, a WuXi spokesperson told BioCentury. The process usually takes 12-18 months.

Because it could provide immediate protection, a mAb could serve as a bridge to a vaccine, Zhi Hong, co-founder and CEO of Brii Biosciences suggested.

At least six other groups are developing mAbs against COVID-19 (see “COVID-19: A growing list of new vaccines and therapies in development”).

Developing diagnostics in the midst of an outbreak

Even with the extraordinary pace of development, new therapies and vaccines will not be ready for many months.

Improving diagnostics is the most immediate technological need for containing and treating COVID-19.

“Our true enemy is the virus.”

Joseph Kim, Inovio Pharmaceuticals

Victor Shi, CEO of Adicon Clinical Laboratories Inc., provided a compelling account of the front lines of testing for COVID-19. Adicon, which operates one of the largest clinical laboratory networks in China, has been conducting COVID-19 tests of samples from Wuhan for four weeks, Shi said. He noted that Adicon and other commercial labs are “performing twice as many tests as all the hospitals put together in Wuhan.”

All of the COVID-19 diagnostic testing in China is being conducted with commercially available PCR kits, Shi said. At least 11 test kits have been approved by Chinese regulators.

The approvals reflect extraordinary efforts by test companies and government. It normally takes years to clinically validate and gain approval of a PCR kit, Shi said.

Every step in the testing process is problematic, he noted.

It takes skill to take nasal or throat samples, and because the samples are “relatively messy compared to a blood draw” there is potential for contamination.

Once a sample has been obtained, it must be stored and transported to a lab. The SARS-CoV-2 virus that causes COVID-19 “is an RNA virus, it is very unstable, so storage conditions are critical,” Shi said.

As a result of the compressed development time and difficulty accessing samples, there was a “very limited amount of clinical validation” of PCR kits, Shi reported.

“Any issues in these steps could contribute to false negatives,” he said. “Do we know the false negative rate? The answer is ‘not really.’” The entities that are conducting testing have limited access to patient records and testing is not as standardized as it could be. “It is difficult in this explosive outbreak to conduct and validate these tests.”

Shi’s observations about diagnostic gaps are relevant in the U.S. and around the world.

“There is no gold standard for COVID-19 testing,” Shi said. There is a critical need, he said, for an inter-lab quality control program.

He said there’s also a need for a “multiplex or panel test for multiple pathogens” that can detect influenza and COVID-19. Outside Wuhan, most patients with fever are infected with influenza. It is important, he said, to quickly distinguish between influenza and COVID-19 so patients can receive appropriate treatment.

As employees start to return to workplaces in China, manual PCR testing at central labs is unable to cope with testing needs. Simply lining people up to provide samples creates opportunities for cross infections, and the two to three hour turn-around time for PCR tests creates difficulties when hundreds of thousands or millions of people must be tested, in some cases multiple times.

“The need for rapid tests and self-administered sampling is great,” Shi said. “I hope we can see such tests being developed very quickly, not only for patients but also for monitoring healthy populations.”

CRISPR pioneer Feng Zhang reported that he and other groups are “developing a diagnostic method based on CRISPR proteins” for COVID-19. “The idea is one day to have a paper strip-based test [using] blood, urine or saliva,” he said.

Feng is an investigator at the Howard Hughes Medical Institute, core member of the Broad Institute of MIT and Harvard, and co-founder of CRISPR diagnostics company Sherlock Biosciences Inc.

Looking forward

There was a strong consensus among participants in the WuXi webinar that even if the COVID-19 outbreak wanes or disappears, it is essential for researchers, industry, funders and governments to continue developing medical countermeasures.

COVID-19 is the third zoonotic coronavirus to emerge in 18 years and there is no reason to believe it will be the last.

Poland called on governments to commit to funding product development. He said that representatives of companies that are developing vaccines “should be congratulated” for “diverting resources to try to develop vaccines at their own risk that if successful would benefit all of us.”

He added that this work “shouldn’t be totally at-risk,” and that funding must not dry up when the crisis drifts off the front pages and cable TV chyrons.

Inovio’s Kim spotlighted industry’s willingness to collaborate, as well as the importance of sustained funding. “Our true enemy is the virus,” not other companies, he said. “Many of us have mobilized to be able to rapidly respond in a very responsible and collaborative way. We need resolve and resources to execute all the way to commercialization.”

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