Beijing-based Sinovac, which makes a COVID-19 vaccine from inactivated virus, has efficacy trials underway in Brazil, Turkey, and Indonesia—but not in China.
The first people in the world to receive a COVID-19 vaccine were not part of a clinical trial. No TV stations or newspapers covered the historic event. No company issued a statement.
On 29 February, less than 2 months after the world awakened to the threat of the new disease, virologist Chen Wei, a major general in China’s army, and six military scientists on her team stood in front of a Chinese Communist Party flag and received injections of an experimental COVID-19 vaccine. Chen, a national hero for her work on Ebola vaccines, had come to the initial center of the pandemic, Wuhan, with her group from the Academy of Medical Military Sciences, in part to help make the candidate vaccine with a commercial company, CanSino Biologics. Commentators inside and outside of China later questioned whether the event, which received wide play on social media, was real. No less than People’s Daily, the Communist Party’s main newspaper, labeled a photo of Chen receiving the vaccine as “#FAKENEWS.” But Hou Li-Hua, a researcher at the academy who works on the vaccine project, says it was “true news”—an attempt to protect the scientists in the hard-hit city.
In the United States, the Trump administration’s $10.8 billion Operation Warp Speed accelerated vaccine R&D faster than many researchers thought possible, specifically for the U.S. population. But an equally massive effort unfolded in China. CanSino and two other Chinese companies—one owned by the government, the other working closely with its regulatory agency—are investing substantial resources, testing four candidates in tens of thousands of volunteers around the world, and are likely only days or weeks away from announcing the outcomes of efficacy trials, just behind the encouraging early results announced over the past month by Pfizer and BioNTech, Moderna, AstraZeneca and the University of Oxford, and Russia’s Gamaleya Research Institute of Epidemiology and Microbiology.
But the low profile of those historic first injections, the military collaboration with a “private” company, and the ethically fraught decision to start with vaccinations outside of a clinical trial telegraphed that aside from the similar scale and speed, China’s vaccine effort is following a very different course from those in the United States and Europe. Most leading Western vaccines rely on sexy technologies such as genetically engineered viral vectors, designer proteins, and snippets of RNA. Three of China’s four leading vaccine candidates use an unfashionable stalwart: the whole inactivated virus, an approach that dates back to the first successful flu vaccine in the 1930s. And China’s vaccine effort is cursed by its dramatic success with aggressive public health measures to stop the spread of the coronavirus SARS-CoV-2, including forced isolation of cases and testing of entire cities. Whereas the raging pandemic in the United States has enabled trials there to quickly deliver signals of efficacy, “China crushed the coronavirus epidemic early, so they lost the opportunity to test the efficacy of their vaccines there,” says epidemiologist Ray Yip, who closely follows COVID-19 vaccine development as an adviser to Bill Gates. “If they had plenty of cases in China, they could have finished an efficacy trial ahead of other people.”
So China’s vaccine developers have gone abroad. Although the United States has shut them out of Operation Warp Speed, they have brokered deals with 15 other countries on five continents. They have mounted massive trials in the Arab world—and given candidate vaccines to top government officials there—and navigated toxic politics in Brazil, where the pandemic is raging fiercely, to test a vaccine and explore producing it there.
But China isn’t just seeking promising venues for clinical trials. Not urgently needing the vaccines at home to fight a virus it has largely quashed, it is playing a global game by pledging to send any proven vaccine to countries that are conducting trials for its candidates, or to share the technologies behind them. “They know they don’t need a vaccine to contain the epidemic in China,” Yip says. “They can take their sweet time.”
The Chinese company CanSino Biologics had the first COVID-19 vaccine to enter clinical trials, and by April had already progressed to a phase II study in Wuhan.
Yanzhong Huang, a global health specialist at both Seton Hall University and the Council on Foreign Relations, says the country is “actually using the vaccine to promote the diplomacy of foreign policy objectives.” This “vaccine diplomacy” he says, contrasts starkly with Warp Speed’s “vaccine nationalism” and aims to “fill in the void left by the United States.”
“It is a very carefully executed and carefully thought out strategy,” says Stephen Morrison, who directs the Global Health Policy Center at the Center for Strategic & International Studies. “A strategic goal of the Chinese government is to achieve hegemonic influence in the bioeconomy within the next decade.”
At home, too, attitudes toward vaccines contrast with those in the United States and Europe, where mistrust is high, Morrison says. To the consternation of vaccine experts overseas, hundreds of thousands of people in China have already lined up to receive the experimental vaccines—even before their value and safety have been proved. “There has not been a collapse of faith and trust in science and in the state,” Morrison says. “There’s less fear about where this is all going.”
The speed at which Chen and her colleagues were able to get those first shots is all the more remarkable given that CanSino was arguably slow off the mark.
Although some COVID-19 vaccinemakers launched their projects the day after the sequence for SARS-CoV-2 became public on 10 January, CanSino CEO Yu Xuefeng had reservations. “We started to look into it in the middle of January, but there was a hesitation,” he says. COVID-19, Yu worried, might be a blip, like severe acute respiratory syndrome (SARS), another coronavirus-caused disease, which alarmed the world in 2003 but disappeared a year later, after companies and governments had poured resources into developing vaccines.
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Yu, who is originally from China, completed his Ph.D. in microbiology at McGill University in Canada in 1997, and then stayed, working on vaccines for nearly 9 years at a Sanofi Pasteur branch there. He co-founded CanSino—a portmanteau of Canada and China—in 2009. A team led by Chen back in China helped develop its only previous product to receive approval: an Ebola vaccine based on a widespread and largely harmless virus known as adenovirus 5 (Ad5), into which they stitched a gene for the surface protein of the Ebola virus.
Yu and his team considered making a COVID-19 vaccine with messenger RNA (mRNA) for the new coronavirus’ surface protein, called spike—the innovative approach taken by Pfizer and its partner BioNTech, the “winner” of the race to report preliminary efficacy data. But CanSino decided to go with what it knew, using the Ad5 vector to carry the spike gene. “I thought that’s the quickest and the mature way of developing a new vaccine,” Yu says.
In just 1 month, CanSino’s candidate was ready to be given to Chen and her team, and on 16 March the company launched the world’s first COVID-19 vaccine trial, in Wuhan, to test its safety and ability to provoke immune responses. CanSino had beaten Moderna by 8 hours—though a world transfixed by the vaccine race among Western companies paid little attention.
Several U.S. and European contenders, including AstraZeneca, have also adopted adenoviruses to carry the spike protein, some opting for an Ad5 vector similar to CanSino’s, despite several concerns about the approach. In 2007, two disastrous efficacy trials of an Ad5-based AIDS vaccine found that—for still-debated reasons—it actually raised the risk of HIV infection. The other worry is that preexisting immunity to Ad5 can attack the vaccine vector, which could explain why, in early trials, the CanSino vaccine elicited a weaker-than-expected antibody response. “We do see there’s some impact,” Yu concedes, “but it’s not black and white.” (The AstraZeneca/Oxford vaccine’s preliminary efficacy data suggest immunity against its adenovirus vector may have compromised that candidate’s performance, as well.)
China’s vaccine road trip
With few COVID-19 cases at home, Chinese vaccinemakers have had to test the worth of their candidates abroad and four are in efficacy trials in 15 countries.
(GRAPHIC) N. DESAI/SCIENCE; (DATA) WORLD HEALTH ORGANIZATION; CLINICALTRIALS.GOV; CHINESE CLINICAL TRIAL REGISTRY; WCG CENTERWATCH
The two other Chinese players, Sinovac Biotech and China National Biotec Group (CNBG)—a subsidiary of one of the world’s largest vaccinemakers, the state-owned Sinopharm—are taking a different approach: vaccinating people with the whole, “killed” virus. This requires no sophisticated protein or RNA design or genetic engineering: Scientists simply inactivate the virus with a chemical (beta propiolactone) and mix it with an adjuvant (alum) that effectively puts the immune system on full alert by irritating it. In theory, such vaccines can produce broader antibody and T cell responses, because they contain the full set of viral proteins, rather than a single one such as spike. And unlike mRNA vaccines, which have to be stored at subzero temperatures, inactivated viruses requires no more than ordinary refrigeration.
But many scientists view inactivated virus vaccines as outmoded, difficult to make in high volume, and potentially dangerous. Warp Speed outright rejected the approach. “I really don’t think the inactivated vaccine is a good idea,” says Moncef Slaoui, scientific head of Warp Speed.
A major worry is that inactivated SARS-CoV-2 vaccines might trigger more severe illness, known as “enhanced respiratory disease,” in immunized people who do get infected. Basically, if a vaccine triggers ineffective antibodies, they can form immune complexes that clog the lungs. This occurred with a vaccine against respiratory syncytial virus given to children in the 1960s, and in animal experiments with vaccines against SARS and another coronavirus disease, Middle East respiratory syndrome. The prospect of growing large batches of virus before killing it also poses challenges; twice in the past 5 years, live poliovirus has escaped from European plants making inactivated virus vaccines for that disease.
But inactivated SARS-CoV-2 vaccines, unlike mRNA and other technologies handsomely supported by Warp Speed, have a solid track record. “There are lots of different ways that vaccines are made, and it’s great that innovation is occurring alongside tried-and-true approaches,” says Nicole Lurie, a strategic adviser to the Coalition for Epidemic Preparedness Innovations (CEPI) who formerly served as U.S. assistant secretary for preparedness and response. “Inactivated vaccines are one of several tried and true approaches.” Meng Weining, a senior director at Sinovac, says they compared the inactivated approach—which they already use to make six vaccines—with two other strategies in animal models. “The inactivated whole virus vaccine gave a much, much better result,” Meng says.
Although it is easier, in theory, to produce mRNA in vast quantities than it is to grow the virus on a similar scale, vaccine experts say producing the inactivated virus vaccines is unlikely to be a hurdle. CNBG, for example, has “enormous resources: 10,000 employees and scientists, huge manufacturing capability,” says Nicholas Jackson, who heads CEPI’s China office and previously worked on vaccine R&D at Pfizer. “They are a very competent beast.” And, crucially for China’s vaccine diplomacy, many other countries have manufacturers that have produced inactivated virus vaccines for decades.
If China’s COVID-19 vaccines work, manufacturers say they could turn out 1.5 billion doses in total next year. And countries that cannot access vaccines bankrolled by Warp Speed—especially those that hosted China’s efficacy trials—might have a more secure vaccine supply.
Sheikh Mohammed bin Rashid Al Maktoum, prime minister of the United Arab Emirates (UAE), on 3 November tweeted a photo of himself in Dubai, the right sleeve of his kandura rolled high, being injected with a CNBG COVID-19 vaccine. “We wish everyone safety and great health, and we are proud of our teams who have worked relentlessly to make the vaccine available in the UAE,” Al Maktoum wrote. Two of the country’s top ministers had received the vaccine 3 weeks earlier.
Mohammed bin Rashid Al Maktoum (left), prime minister of the United Arab Emirates, on 3 November received a COVID-19 vaccine from CanSino Biologics under his country’s emergency use authorization.
UAE has become the cornerstone of CNBG’s efficacy trials and is following China’s controversial lead in allowing people to receive the vaccine outside of clinical trials.
In a video conference on 23 June that linked Abu Dhabi, Beijing, and Wuhan, health officials, ambassadors, and CNBG executives sat at long tables in rooms decorated with each country’s flags and celebrated their decision to stage an efficacy trial together. The trial has since expanded to Bahrain, Egypt, and Jordan and hopes to recruit 45,000 people. CNBG says it came to UAE to test its two whole virus vaccines—similar inactivated preparations made by two independent, and even competitive, laboratories, one in Wuhan and the other in Beijing—because the high SARS-CoV-2 infection rate there should speed an efficacy signal. But diplomacy and commerce also drove the decision. UAE’s enormous foreign workforce means trial participants come from 125 different countries. “If you can prove these vaccines work in UAE,” Huang says, “that means everybody in the world would think that the vaccine would work in their countries, too.”
China may be hoping for a public relations (PR) benefit as well: UAE and many of the other collaborating countries have large Muslim populations, which Huang says could help mitigate human rights complaints about China’s treatment of Uyghur Muslims in Xinjiang province. “They certainly don’t want to have more enemies overseas,” he says.
Huang adds that through its array of overseas trials, China hopes to build goodwill for its Belt and Road Initiative (BRI), a massive investment in infrastructure in more than 100 countries to increase trade. Critics have charged that the BRI is “debt-trap” diplomacy that’s a form of neocolonialism. “China wants to work with these countries and prioritize them to have the vaccine because I think they believe this is going to facilitate the implementation of the BRI,” he says.
China’s vaccine diplomacy has not always gone smoothly. On 9 November, after Brazil suspended a trial of Sinovac’s vaccine following the death of a participant, President Jair Bolsonaro took to Facebook. “Morte, invalidez, anomalia,” he wrote, quoting from a Brazilian health agency that had listed possible reasons for the suspension: death, disability, genetic anomalies. Bolsonaro’s message was clear: This Chinese vaccine, called CoronaVac, was dangerous.
Brazilian President Jair Bolsonaro and his supporters have protested the decision of his political rival, São Paulo’s governor, João Doria, to invest in Sinovac’s vaccine and allow its testing in efficacy trials. The mask pictured says, “No vaccine! Oust Doria.”
“Many people were really taken aback because of that post,” says Esper Kallas, who heads the vaccine trial site at the University of São Paulo that the participant had joined. “He was celebrating the failure of a vaccine.” For Bolsonaro, it was a PR victory over his arch political rival, the governor of São Paulo, who backed the CoronaVac trial. The president was also delighting in a setback for China, which Bolsonaro, like his ally, U.S. President Donald Trump, has criticized relentlessly.
It turned out the participant died from a drug overdose. His death had nothing to do with CoronaVac, and the trial quickly resumed.
China chose to navigate Brazil’s daunting politics because with an out-of-control pandemic—it is third in the world in total infections, with more than 100,000 new cases every week—the country is a magnet for vaccine testing and is desperate for vaccines. São Paulo state in September committed $90 million to Sinovac for 46 million doses. (This, notably, is 10 times cheaper than what the U.S. government is paying for the Pfizer/BioNTech and Moderna mRNA vaccines.) And Brazil could augment the supply by making vaccine itself. Sinovac says it may transfer its technology to the Butantan Institute, a major vaccine manufacturer in São Paulo, a collaboration Meng describes as a “win-win.”
China has had warmer receptions in other countries. Turkey in September launched a 13,000-person efficacy trial of Sinovac’s vaccine. Serhat Ünal, who heads the Hacettepe University Vaccine Institute—which is similar to Butantan in Brazil—and is on the scientific board of the Ministry of Health, says Turkey has “a good infrastructure for the phase III studies” and, unlike the United States and much of Europe, welcomed a Chinese vaccinemaker.
The three Chinese manufacturers also have large efficacy trials planned or underway in Indonesia, Pakistan, Saudi Arabia, Mexico, and Chile (see map, above). It’s a good strategy, Ünal says. “When you do the phase III in different countries, it’s more transparent, it’s more trustworthy,” he says.
As much as vaccine diplomacy and the “soft power game” influence where the Chinese vaccinemakers cut deals for efficacy trials, they are also driven by capitalism, says Yip, who for 4 years headed the China office of the U.S. Centers for Disease Control and Prevention. “Everybody’s clamoring for some COVID vaccine,” he says. “They all want to tell their people we have secured some vaccine for you.” And Chinese companies aim to profit by supplying it.
It’s a safe bet that one or more of China’s overseas trials will announce efficacy data any day now. The results so far for other vaccines have fed a growing sense that many vaccines will wallop what is, from a vaccine’s point of view, a somewhat wimpy virus. But China is not waiting for the phase III results before widely using the vaccines at home. Its regulators appear to be satisfied with animal studies combined with the minimal safety and immune response data from phase I and II trials. In June, CanSino received an emergency use authorization to vaccinate the military, and since then both Sinovac and CNBG have received green lights to vaccinate large populations outside of clinical trials.
A batch of 120,000 doses of Sinovac’s COVID-19 vaccine arrived in São Paulo’s international airport on 19 November. The vaccine will be used if ongoing efficacy trials show it is safe and effective.
With the pandemic vanquished at home, China is vaccinating its people as insurance—often, against a dangerously infected world. CanSino’s Yu says “thousands” of troops on peacekeeping missions have received his company’s vaccine before traveling to places that have a high burden of COVID-19. CNBG says “hundreds of thousands” of people in China have received its vaccines. “By doing this, we are able to build an immune barrier among specific groups of people like healthcare workers, pandemic prevention personnel, and border inspection personnel,” the company explained in its written replies to Science. Vaccination is “completely voluntary with informed consent,” CNBG stresses. What’s more, “We did not receive a single case report of severe adverse reaction, and no infections reported for vaccinees working in high risk areas.”
Sinovac’s Meng says “more than 90%” of the company’s employees have received its vaccine because they are considered a high-risk group; he received it because he travels overseas. (According to China’s Ministry of Culture and Tourism, 155 million Chinese people traveled overseas in 2019, and 145 million tourists visited the country.) In October, the company began to sell its vaccine—$60 for two doses—in Yiwu, a city in Zhejiang province. And Yip says the government was even considering vaccinating all of Beijing after a COVID-19 outbreak there in June. Yip says officials “already had written the guidelines”; if more than 500 cases had surfaced, “they would shoot up everybody in Beijing with the vaccine.” In the end, contact tracing, testing, and isolation of infected people limited the outbreak to 335 cases.
Morrison says the Chinese government has clearly “decided at the highest levels” that it’s worth the gamble to create “facts on the ground” and gain a global marketing advantage by having the first COVID-19 vaccines in wide use. “It’s high risk and it’s potentially high gain,” he says.
But what if harm does occur? “You shouldn’t apply the rules of peacetime during the war. Our lives are turned upside down,” says Yip, who lives part-time in Beijing.
If its vaccine gamble succeeds, China’s image will gain a boost both at home and abroad. “They have reputational problems, internal and external,” Morrison says.
In May, China’s President Xi Jinping told the World Health Assembly, which governs the World Health Organization (WHO), that the country would make its COVID-19 vaccines “a global public good,” a somewhat vague declaration that had many China watchers scratching their heads. But then China followed up on this commitment in October by joining the COVID-19 Vaccines Global Access (COVAX) Facility, an effort led in part by WHO and CEPI to make sure that any products proved safe and effective quickly reach rich and poor countries alike.
Although joining COVAX arguably gives China an insurance policy to obtain vaccines if its own candidates fail, Morrison says it’s primarily a diplomatic move. COVAX hasn’t received support from the United States or Russia, and China sees that it “could have a controlling influence over a major international mechanism.” In addition, says Alexandra Phelan, a lawyer at Georgetown University’s Center for Global Health Science and Security who specializes in China, “It is a good act of a global citizen to support this effort.”
If a China-made vaccine proves safe and effective, it could help people forget the pandemic started there and how badly the government responded at first, Morrison says. And at home, it could brighten the image of China’s vaccinemakers. Chinese citizens have reeled from a series of scandals over the past decade that include use of ineffective diphtheria, pertussis, and tetanus vaccines; improper records for a rabies vaccine; and sales of an expired polio vaccine.
In something of a twist, Yip says China’s middle class may prefer to receive a vaccine from a reputable foreign company. “Their level of confidence in Chinese-made vaccines is quite low because of all the repeated scandals,” he says. AstraZeneca and Pfizer have agreements to produce their products with Chinese manufacturers. “They will outsell the CNBG, Sinovac, and CanSinos by 10 to one—and they will charge 10 times more,” Yip predicts.
A successful China-made COVID-19 vaccine that has been scrutinized by outside regulators would reassure the domestic market, Phelan says. “There’s a lot of domestic ground to make up.”
In Brazil, Kallas says a similar dilemma could play out if Butantan, as hoped, starts to make Sinovac’s CoronaVac. “There is a saying here that the neighbor’s chicken is always the most tasty,” Kallas says. “We have this perception that everything we do is not as good as the imported thing.”
But for now, Brazil is embracing the Chinese vaccine. With cases surging, the arrival of a mere 120,000 doses of CoronaVac on 19 November became a big news story. The bias against China is little more than a far-right political “contamination,” Kallas says, and most Brazilians see CoronaVac as “a viable option.”
“I’d take it, no questions asked—this is a no-brainer,” he adds. “The Pfizer and Moderna news were taken as a relief, but the problem is that both these vaccines are not in Brazil’s grasp.”
In Brazil, as in much of the world, China’s warp speed vaccines may still, in the most meaningful way, come in first.
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With global push for COVID-19 vaccines, China aims to win friends and cut deals - Science Magazine
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