The race is on to develop therapies and vaccines for the coronavirus outbreak

The coronavirus outbreak is creating a testbed for new vaccine and therapeutic technologies

Public release of the genetic sequence of the coronavirus first detected in Wuhan, China acted as a starter pistol, setting off a race to develop medical countermeasures.

Beyond the potential for containing and hopefully eradicating the 2019 novel coronavirus (2019-nCoV), this contest will serve as an experiment, testing competing scientific and technological approaches for rapidly responding to outbreaks or emerging infectious diseases.

In the two weeks since the first 2019-nCoV sequence was posted to a public database, biopharma companies and academic labs have launched at least eight vaccine development programs.

Several are based on technologies that have never been used in an approved vaccine, and some have never been tested in humans.

Three groups have announced plans to develop mAbs as potential 2019-nCoV therapeutics.

At least one company has started work on RNAi therapies that could treat or prevent 2019-nCoV infections, and companies and labs around the world are looking into opportunities to repurpose approved antiviral drugs.

Funding mechanisms created to respond to epidemics have been activated and are kickstarting product development, but it isn’t clear where money will come from to advance products beyond Phase I safety trials.

While a number of vaccines and therapies could be ready for Phase I trials as soon as April, moving into Phase II and deploying medicines on an emergency-use basis will require not only funding, but logistics and international coordination that are not yet in place.

Zero to sequence in rapid time

Unless an existing therapy can be repurposed, it is likely to be at least a year before safe, effective 2019-nCoV therapies can be made available on an emergency-use basis.

Vaccines will take longer.

That means that the best hope for containing the outbreak is the efficient application of public health practices - identifying and isolating infected individuals and providing supportive care.

Public health measures, including the development and deployment of diagnostics, will be key to containment, Luciana Borio, VP at IN-Q-Tel, a non-profit investment firm, told BioCentury. Borio is a former director for medical and biodefense preparedness at the White House National Security Council.

The rapid publication of a genetic sequence has allowed labs around the world to start working on medical countermeasures, and China’s response has been rapid compared to previous outbreaks of new pathogens, Borio said. “It is remarkable that China has been able to detect, diagnose, and share with the world the sequence of the virus.”

“The ideal would be an antibody-based ‘swab’ test that could be used at a doctor’s office.”

Scott Gottlieb, NEA

Health authorities in Wuhan issued a notice about a cluster of cases of pneumonia of unknown origin associated with a seafood market on Dec. 30, China reported the outbreak to the WHO on Dec. 31, and researchers at Fudan University in Shanghai posted a gene sequence to a public database on Jan. 9.

The Chinese government is taking extraordinary measures, including travel bans and the construction of dedicated hospitals. These steps may reduce transmission within China, but it is too late to contain it.

Borio predicted that the new virus will “spread around the globe pretty quickly. Within four to six weeks we could see cases all over the world.”

It is too early to determine if the outbreak will burn out quickly or if it will become a serious public health threat, she said.

CDC is sequencing the genome of the virus from the first reported case in the U.S. and will make it public. It is also growing the virus in cell culture. The agency has developed a PCR test for 2019-nCoV and is seeking emergency use authorization from FDA to share it with domestic and international health agencies. The test requires that samples be sent to central laboratories.

The development of rapid point-of-care diagnostics should be a top priority for containing the virus, former FDA Commissioner Scott Gottlieb told BioCentury. Gottlieb is a special partner at New Enterprise Associates, and holds a board seat at Pfizer Inc. (NYSE:PFE).

“The ideal would be an antibody-based ‘swab’ test that could be used at a doctor’s office,” he said.

A point-of-care test would make it possible to differentiate between cases of 2019-nCov and influenza, to isolate and track contacts of infected individuals, and to avoid flooding hospitals with patients who are not infected with the virus.

Borio said that it will also be critically important to study therapies in a controlled, systematic fashion. “Because there was no systematic clinical study undertaken, we learned very little from the SARS outbreak about countermeasures.”

She said that even if the outbreak reaches the U.S., trials may be conducted overseas. “It may be easier to do large-scale trials in countries where the U.S has established clinical trial networks.”

Therapeutics: antibodies and RNAi

Two companies have announced their intention to develop mAbs as potential therapeutics or preventative agents for 2019-nCoV infections.

Vir Biotechnology Inc. (Nasdaq: VIR) is interrogating its library of mAbs that bind and neutralize two coronaviruses, SARS and MERS, to determine if they could be effective against 2019-nCoV.

“As soon as the sequence became available, we initiated the necessary experiments to utilize those data” for screening its mAb library to find an existing molecule with the right profile, Vir CSO Herbert “Skip” Virgin told BioCentury. He declined to speculate on how long the process will take.

In parallel, Vir has started to develop a new mAb for 2019-nCoV, using the sequence form the Wuhan virus to create the “relevant viral protein,” said Virgin. “Then we're going to our bank of samples of persons who responded to previous infections with related viruses and screening for new monoclonal antibodies that would be potentially useful.”

“We can provide the immune response immediately rather than needing to wait for the vaccine to elicit the protective response.”

Skip Virgin, Vir Biotechnology

Vir’s platform screens up to hundreds of millions of B cells, and “utilizes the principle that certain individuals make unique, rare but very effective antibodies,” Virgin said.

He said the advantage is that the human mAbs in Vir’s sytem “have already been engineered by the immune system to be secreted, to be stable in the serum, and to at least have less of a chance of being cross-reactive with host tissues.”

mAbs also allow for a single molecule to have both fast-acting therapeutic and prophylactic effects.

“Vaccines require that the individual make the response that is protected,” Virgin said. “If we are able to find relevant antibodies, we can provide the immune response immediately rather than needing to wait for the vaccine to elicit the protective response.”

The trade-off, Virgin acknowledged, is the limited duration of protection provided by an antibody compared with a vaccine. He added, however, that Vir has technologies that use mutations in the Fc region to prolong efficacy.

“If those technologies can be applied, then the length of time of the putative protective effect of a monoclonal antibody can be extended to be long enough to be relevant in an epidemic setting,” said Virgin.

The dual properties of mAbs are being put to the test the Democratic Republic of Congo (DRC) in the fight against Ebola.

In a randomized trial, the survival rate of Ebola patients who received mAb114 soon after infection was 90%, and the overall mortality rate was 34%, compared with an overall mortality of 67% without treatment. mAb114 was developed in a collaboration including NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC), Vir, and researchers at the U.S. Army and the National Institute of Biomedical Research (INRB) in the DRC.

Ebola patients in DRC are being treated in an ongoing trial with mAb114 and with another mAb, REGN-EB3, from Regeneron Pharmaceuticals Inc. (NASDAQ:REGN), which produced similar efficacy in a multi-drug trial.

Regeneron has started working on a mAb for 2019-nCoV, Christos Kyratsous, the company’s VP of research for infectious diseases and viral vector technologies, told BioCentury.

Kyratsous noted that Regeneron also has a mAb in a Phase I trial for MERS. “We know how to get a specific and potent antibody against the coronavirus, so we can apply these lessons and hope to be able to get antibodies that are equally specific and potent” against 2019-nCoV.

Regeneron has synthesized the genome of 2019-nCoV based on one of the publicly available sequences and is using the spike protein to immunize mice, Kyratsous said.

Kyratsous declined to predict how long it will take to obtain a candidate mAb targeting 2019-nCoV, but said that for Ebola it took Regeneron six months to go from immunizing mice to obtaining positive data from an animal model. It took about another six months to generate a product that could be tested in humans.

NIH has also started work on a mAb against 2019-nCoV, NIAID Director Anthony Fauci told BioCentury.

At least one company is using RNAi. Sirnaomics Inc., a U.S. company with subsidiaries in Suzhou and Guangzhou, China, announced on Jan. 24 that it has “mobilized its research teams both in USA and China to develop novel RNAi-based prophylactics and therapeutics for treatment of patients,” infected by the virus.

Sirnaomics said it has identified “potentially potent siRNAs, specifically targeting the viral genes critical for the viral infection and replication.” The company reported that it will collaborate with laboratories that have cell culture models of 2019-nCoV infection to develop multiple siRNA drug candidates.

Vaccines

Release of the 2019-nCoV sequence has also made it possible for groups around the world to start developing vaccines.

At least eight initiatives have been announced, utilizing a variety of technologies to develop vaccines that could protect against the virus.

“The question is, when we get the vaccine, what will we do with it?”

Gregory Glenn, Novavax

The Coalition for Epidemic Preparedness Innovations (CEPI) is funding 2019-nCoV vaccine programs at Moderna Inc. (NASDAQ:MRNA), Inovio Pharmaceuticals Inc. (NASDAQ:INO) and The University of Queensland. CEPI is a non-profit organization founded by the governments of Norway and India, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the World Economic Forum.

Moderna’s platform is RNA-focused, while Inovio’s is DNA-focused. Nucleic acid vaccines have advantages of ease and speed of manufacturing, as well as safety compared with live viral vaccines -- a benefit they, as well as RNA company CureVac AG, sought to demonstrate during the Zika epidemic.

RNA- and DNA-based vaccines also have greater potential to stimulate T cell responses than inactivated virus- or protein-based vaccines because they more readily result in antigen presentation on the HLA molecules required to activate T cells (see "Fever Pace for Zika").

Between RNA and DNA vaccines, the former has the advantage of only needing to cross the plasma membrane to trigger production of protein antigens; the latter must cross both the plasma membrane and nuclear envelope, reducing efficiency. DNA's advantage is its greater stability, which could make it more practical to distribute in developing countries and provinces.

Moderna is developing its mRNA vaccine in partnership with the Vaccine Research Center (VRC) at NIH’s National Institute of Allergy and Infectious Diseases. NIAID has committed to conduct IND-enabling studies and a Phase I clinical study, the company said.

Inovio has received a grant of up to $9 million from CEPI for preclinical and Phase I testing of INO-4800, an investigational 2019-nCoV DNA vaccine. The company has developed an electroporation device that increases the efficiency of DNA transduction via a quick procedure, but adds a layer of complexity to product distribution.

CureVac is joining the 2019-nCoV effort as well. It announced on Jan. 24 that it is “in contact with several key players in the field such as CEPI, the Bill and Melinda Gates Foundation and others to investigate how we can contribute to the fight against this potential health emergency.”

CureVac said it is working on a vaccine, to get it to the point it could be tested in humans; it will likely collaborate at that point. “From earlier preclinical work on another Coronavirus, we know that our mRNA vaccines are suitable to induce an immune response in animals for this type of viruses. Furthermore, our recent clinical results with a rabies vaccine show that we can induce an immune response in humans with very low amounts of mRNA.”

Protein-based approaches are also under way.

CEPI is funding an initiative at the University of Queensland to use its “molecular clamp” vaccine platform to develop a 2019-nCoV vaccine. The technology involves “synthesizing viral surface proteins, which attach to host cells during infection, and ‘clamping’ them into shape, making it easier for the immune system to recognize them as the correct antigen,” CEPI said.

Novavax Inc. (NASDAQ:NVAX) has announced that it has started development of a 2019-nCoV vaccine using its recombinant protein nanoparticle technology. Like the Queensland program, Novavax's technology seeks to stabilize immunogenic conformations of viral antigens; the nanoparticle platform that delivers these proteins is similar in size to actual viruses, a strategy that has been reported to enhance immune responses.

“The question is whether our SARS vaccine will cross-protect against the new virus or if we’ll have to develop a new vaccine.”

Peter Hotez, Baylor Medical School

Novavax expects to have an investigational 2019-nCoV vaccine ready for a Phase I trial in 90 days, Gregory Glenn, the company’s president for R&D, told BioCentury. “When we make our first batch, it will be at a scale where we have a significant number of doses."

The Texas Children's Hospital Center for Vaccine Development at Baylor College of Medicine is part of a consortium that developed a preclinical recombinant protein SARS vaccine candidate. It will evaluate that vaccine to determine if it is likely to protect against 2019-nCoV, Peter Hotez, dean of the National School of Tropical Medicine at Baylor Medical School, told BioCentury.

NIAID has been funding coronavirus vaccine research at the Baylor-led consortium since 2012. “The question is whether our SARS vaccine will cross-protect against the new virus or if we’ll have to develop a new vaccine,” Hotez told BioCentury. “Whether anything will be ready for this outbreak is hard to know.”

“The sequence homology looks good so far. We’ve published that our vaccine seems to protect against some other SARS-like coronaviruses.”

Hotez said it will take “days to weeks” to determine if the consortium’s SARS candidate vaccine is a good match for 2012-nCov.

If the SARS vaccine isn’t promising, the consortium, which includes the University of Texas Medical Branch, the New York Blood Center and the Virology Center at Fudan University in Shanghai, will develop a 2019-nCoV vaccine, Hotez said.

The SARS vaccine consists of a recombinant version of the SARS-CoV spike (S) protein with an amino acid deletion that enables high yield protein expression and purification.

The University of Saskatchewan's Vaccine and Infectious Disease Organization - International Vaccine Centre has also started developing an engineered protein-based vaccine.

Codagenix Inc. has started work on a 2019-nCoV vaccine using the company’s computationally designed live attenuated virus technology, J. Robert Coleman, the company’s co-founder and CEO, told BioCentury.

“Unlike technologies that require the physical virus, our digital platform was able to take the genome and modify it synthetically, and we have begun in collaboration with synthetic DNA companies to construct fragments of the genome” for use in a vaccine, Coleman said.

A live-attenuated vaccine might produce more robust protection than a single antigen vaccine, Coleman said. “The key questions to ask are scalability and how broad an immune response the vaccine candidate can induce. Our live-attenuated vaccine will essentially be a replica of the entire virus, presenting all of the proteins, unlike other single-antigen vaccines.”

Like some of the other new technologies that are being applied to meet the 2019-nCoV challenge, Codagenix says it can produce a candidate vaccine rapidly.

“The next milestone will be the recovery of a vaccine candidate in the manufacturing suite, which we're hoping to happen in the next few weeks or earlier if everything goes according to plan,” Coleman said.

Moving into Phase II

If the 2019-nCoV outbreak is active in the spring when Phase I studies have been completed on several of the vaccine candidates, the governments and philanthropic organizations around the world will have to make decisions about funding additional development.

Few if any of the companies that have started vaccine development programs are likely to have the resources to fund Phase II trials.

“The question is, when we get the vaccine, what will we do with it?” Novavax’s Glenn said. “That's going to depend a lot on funders.”

There isn’t a market for vaccines for emerging diseases, “so funding is really important,” he added.

For now, Codagenix is investing its own funds, but it will need external funding to advance a vaccine beyond Phase I, Coleman said. “The speed with which we are moving will require us to find some partners in the near future to help with scale-up manufacturing and probably some toxicology testing that must be done before it can go into the human trials.”

Coleman said Codagenix is “in discussions with government agencies and other manufacturing partners in real time, trying to figure out how to get this vaccine candidate manufactured as quickly as possible.”

The U.S. government’s Biomedical Advanced Research and Development Authority (BARDA) is dedicated to funding the development of medical countermeasures, but does not have funding available for 2019-nCoV.

BARDA has “contracts in place that could be considered for use to initiate product development activities if funds become available,” an HHS spokesperson told BioCentury. “However, it is important to note that BARDA does not currently have adequate funding to initiate product development activities for this novel coronavirus or other emerging infection diseases. If funding becomes available, we would be positioned to be able to initiate activities quickly.

Further analysis of the coronavirus crisis can be found at https://www.biocentury.com/coronavirus. The 2019-nCoV content is free to all who visit the site.

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