China emerging as a leader in COVID-19 vaccines
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China’s biotech sector may still be developing, but the COVID-19 crisis has revealed just how swiftly it can bring new vaccines to the clinic. The country has more COVID-19 vaccine candidates in human testing than any other, and was first to advance one to Phase II.
Arguably, China had a thin edge in the vaccine race, given that the outbreak was first reported in its Hubei province, putting patient samples in the hands of Chinese researchers first. But a group of those scientists published the virus’ genome within weeks, firing a starting gun for drug development around the globe (see “The Race Is on to Develop Therapies and Vaccines”).
It’s rare in biopharma to have a such clear starting line, and it showcases China’s capabilities in infectious disease.
The therapeutic area has long been a strong suit of the country. Researchers in China were active 18 years ago in the search for a SARS vaccine, with China’s Sinovac Biotech Ltd. (NASDAQ:SVA) among the first groups to take a SARS vaccine to the clinic.
Since then, China has remade its National Medical Products Administration (NMPA), enacted significant regulatory reforms and poured a huge amount of resources into growing its biotech sector, enabling an even broader and faster response to COVID-19.
As cases dwindle in China, and the chances of a subsequent outbreak remain unclear, one challenge for these companies is where to set up sites for late-stage trials.
Four of the nine clinical vaccines for COVID-19 are being developed in China.
CanSino Biologics Inc. (HKEX:6185) took Ad5-nCoV into Phase I testing in mid-March, putting it neck and neck with mRNA-1273 from U.S.-based Moderna Inc. (NASDAQ:MRNA).
CanSino reached Phase II first, on April 12, the same day the China National Biotec Group (CNBG) subsidiary of China National Pharmaceutical Group Corp. (Sinopharm) became first to bring an inactivated virus vaccine into the clinic (see “End of the Beginning for COVID-19 Vaccines”).
CNBG received clinical trial approval for its second inactivated virus vaccine on April 27. The other Chinese vaccine in the clinic comes from Sinovac, which started trials of an inactivated virus vaccine on April 17.
These companies have played to their strengths and benefited from unified government support.
China has actively coordinated development of medical countermeasures by forming connections between research institutes and supporting expansion of manufacturing capacity. All four of its clinical candidates are being developed in partnerships.
NMPA is expediting clinical development through emergency approval studies and allowing overlap of Phase I and Phase II trials.
“This is no longer an issue for one particular department, now it is an issue for the whole country.”
And China’s National Health Commission has set up special funds to promote research on five vaccine modalities: adenoviral vectors, recombinant subunits, inactivated virus, nucleic acids and attenuated influenza virus vectors. It has also made commitments to set up a future vaccine reserve mechanism.
According to China’s State Council, under the emergency IND process, R&D steps are changed from serial to parallel and research and review are linked through rolling submission of R&D materials to NMPA.
With overlapping Phase I and Phase II studies, candidates have moved into Phase II in as little as 12 days after beginning clinical testing.
“There is a national level joint effort to coordinate different departments, to have the same timelines and objectives,” said Helen Yang, senior director of investor relations at Sinovac. “This is no longer an issue for one particular department, now it is an issue for the whole country.”
Starting with adenovirus
CanSino is parlaying its experience in Ebola into COVID-19 by designing a vaccine that uses the same viral vector. The company received government support for both programs in the form of a partnership with the Institute of Biotechnology of the Academy of Military Medical Sciences.
In collaboration with Wei Chen’s group at the academy, CanSino produced Ebola vaccine Ad5-EBOV using its adeno-associated virus serotype 5 (AAV5) vector platform. The vaccine was approved for emergency use and national stockpile in 2017, validating the approach.
Chen is a major general and the researcher leading Ad5-nCoV development at the academy.
CanSino has reported the candidate, a replication-deficient AAV5 vector encoding a full-length SARS-CoV-2 spike protein, induced strong immune responses and was safe in animal models.
The decision to advance the vaccine to Phase II testing less than a month after starting Phase I was based on preliminary safety data. The Phase I study has enrolled 108 healthy volunteers and is continuing in parallel with the Phase II.
According to Chen, 508 volunteers had been inoculated in the Phase II trial as of April 25, and she expects the trial to be unblinded in May. Primary endpoints are the occurrence of adverse events and anti-spike and neutralizing antibody responses.
The company has not disclosed its timeline for Phase III testing, nor said if it expects emergency approval. In an April 27 regulatory filing, however, CanSino described its first steps toward clinical testing outside of China where disease incidence remains higher. The company plans to conduct Ad5-nCoV trials with undisclosed partners in Canada, saying that Health Canada had accepted a pre-CTA meeting request.
Inactivated virus yields the second wave
A flurry of trial approvals for inactivated virus candidates from the CNBG and Sinovac have followed CanSino’s dive into the clinic.
Sinovac leveraged its experience in creating a vaccine for the SARS coronavirus to develop its chemically inactivated virus vaccine for COVID-19, Yang said. In 2004, Sinovac was the first company to complete Phase I testing of a SARS vaccine, before halting development when the epidemic subsided.
“A mature technology may provide more certainty in an uncertain situation.”
Yang noted that the maturity of Sinovac’s technology platform, which it has used to produce multiple inactivated virus products, takes away some of the risk. “A mature technology may provide more certainty in an uncertain situation.”
Several of the other leading COVID-19 vaccines are based on modalities that haven’t yet been validated, such as mRNA and DNA (see “BioCentury’s COVID-19 Resource Center”).
Sinovac began the first part of its Phase I/II trial on April 17. According to ClinicalTrials.gov, it will enroll 144 volunteers and the Phase II part will add 600 more, investigating safety and neutralizing antibody seroconversion rates.
In rhesus macaques, the vaccine avoided one safety issue by demonstrating it does not cause antibody-dependent enhancement (ADE), a process by which antibodies made in response to vaccination or infection worsen disease (see “Animal Studies Show Sinovac’s COVID-19 Vaccine is Protective”).
Yang said the Phase II study is expected to begin in May or June.
“Right now, our biggest challenge is Phase III,” said Yang, adding that it is difficult to design and implement a study to determine protective efficacy when the number of reported cases in China is low.
Sinovac is in discussions with regulators in China as well as the WHO and other countries that still have reported cases, but the company does not yet have a Phase III timeline, said Yang.
“Right now, our biggest challenge is Phase III.”
Last month, Sinovac partnered with Dynavax Technologies Corp. (NASDAQ:DVAX) to evaluate its CpG 1018 adjuvant with the vaccine, but does not yet have data on the effects of the adjuvant, Yang said.
CNBG, which is testing two inactivated virus vaccines, said its first candidate had shown “good safety” in the 96 volunteers enrolled in the Phase I portion of its Phase I/II trial as of April 23. CNBG is developing the vaccine in partnership with the Wuhan Institute of Virology.
The Phase I trial is expected to enroll 288 volunteers. In the meantime, CNBG started the Phase II portion of the trial on April 24, which will enroll 1,108 subjects and is focusing on safety and the vaccination procedure, according to state-run news outlet Xinhua.
The company said it may take a year to demonstrate safety and efficacy in Phase III.
According to the company, the vaccine was simultaneously approved for Phase I and II testing based on the strength of the preclinical data and the severity of the global outbreak. Preclinical testing of the vaccine included viral challenge studies in rabbits, guinea pigs, three kinds of mice and two kinds of monkeys.
As of April 28, CNBG had enrolled 32 volunteers in a Phase I/II trial of its second inactivated virus vaccine. The candidate is being developed in collaboration with the China’s Center for Disease Control and Prevention.
CNBG also has a recombinant protein vaccine in preclinical testing and has allocated RMB1 billion ($141.6 million) in R&D funding for all three programs.
At least five other candidates have advanced into the clinic globally, but manufacturing capacity could become a rate-limiting factor.
China’s manufacturers producing vaccines for trials each have the potential to produce nearly 100 million doses annually.
CanSino’s annual production capacity is approximately 70-80 million doses. The company did not respond to inquiries regarding how much capacity might be used for its COVID-19 vaccine or if it is developing additional capabilities.
CNBG has completed construction of a Beijing facility for production of a COVID-19 vaccine that should have an annual capacity of 100 million doses.
Sinovac has obtained an RMB60 million credit line from the bank of Beijing for construction of a Beijing-based manufacturing plant, said Yang, adding that the government also provided financial grants and the company has invested “much more”.
“Some portion of that facility can be used for other purposes, but the main focus will be on COVID-19,” she said. Although the primary goal is to produce 50-100 million doses annually, the company will have a better capacity estimate once it moves into commercial scale production, she added. Sinovac expects to complete construction of the facility within the next two months.
Yang said that emergency use is a possibility if Sinovac’s vaccine is demonstrated to be safe in humans.
If China experiences another outbreak, a Phase II or Phase III vaccine could be made available for emergency use in the country as early as September, and could be used to help medical staff and other “special groups,” according to George Gao, director general of China’s Center for Disease Control and Prevention (CDC). A vaccine for widespread public use could be available next year, he said.
That timeline would be on par with anticipated emergency approval of candidates outside of China (see “Pfizer Joins Front of Pack in COVID-19 Vaccine Race”).
There are over 70 vaccine candidates in preclinical development globally; some of the other Chinese companies joining the effort include Chongqing Zhifei Biological Products Co. Ltd. (SZSE:300122), Shenzhen Kangtai Biological Products Co. Ltd. (SZSE:300601) and Stemirna Therapeutics Co. Ltd.
At least two Chinese groups, Shenzhen Genoimmune Medical Institute and Sichuan Clover Biopharmaceuticals Inc., have disclosed timelines to enter the clinic.
Although ClinicalTrials.gov says Genoimmune is recruiting patients for a Phase I trial of universal artificial antigen presenting cells (aAPCs) and a Phase I/II trial of LV-SMENP-DC, a combination of engineered dendritic cells and antigen-specific cytotoxic T lymphocytes, Genoimmune President Lung-Ji Chang told BioCentury its candidates are still in “final testing” in rhesus macaques before moving to human studies.
Clover plans to initiate a Phase I trial of COVID-19 S-Trimer, a trimeric spike protein subunit vaccine, in Australia by mid-2020 (see “Clover: Trimerizing Fusion Proteins”).
“Everyone is trying to provide a solution,” said Yang. Although three inactivated virus vaccines have made it to the clinic, “I don’t think differentiation is something we want to pursue; we want to come up with a vaccine as good as we can, as soon as we can,” she said. “I don’t think one or two companies can solve the problem for the whole world.”