Scientists, drugmakers and governments have moved with unprecedented speed to develop multiple vaccines for the new coronavirus.
The fastest of them have proven their vaccines can strongly protect against COVID-19. And a handful of shots from developers in the U.S., U.K., Germany, China and Russia have now been cleared by regulators around the world.
Estimates of vaccine efficacy from Phase 3 clinical trials
Their success is a scientific feat with few parallels. No vaccine has ever been developed so quickly before, never mind readied for widespread use.
With the health of their citizens at stake, governments invested enormous sums of money into vaccine research and development, and to prepare to manufacture and distribute what will likely need to be billions of doses necessary to keep the pandemic at bay.
The immunization campaigns that are now underway will help determine whether the virus becomes endemic, recurring year after year, or is ultimately checked. Yet initial doses of authorized vaccines are in short supply, and early access has largely been dictated by lucrative deals struck between drugmakers and governments.
Vaccine frontrunners have progressed quickly
Here's where things stand for 14 of the most advanced, most promising or best-funded vaccine candidates. Use the menu on the left to jump to a developer.
One of the advantages to messenger RNA technology — a drug-making approach that uses genetic instructions to teach cells to make proteins — is that it can be used to build a vaccine more easily than traditional methods. Moderna's coronavirus vaccine is proof.
The vaccine went from a computer design in January 2020 to human study in just three months, making Moderna the first U.S. company to reach that point.
Phase 1 results came in late May, as did the start of a mid-stage trial. A Phase 3 study began on July 27 and, four months later, delivered strongly positive results that indicated the vaccine was 94% effective in preventing COVID-19.
The finding was a dramatic achievement. Taken together with a similarly positive readout from Pfizer and BioNTech, which in November said their shot was 95% effective in preventing COVID-19, researchers could be sure that mRNA vaccines were protective.
Crucially, Moderna's vaccine also appeared safe, with no unexpected or serious side effects. The company asked the Food and Drug Administration for emergency approval on Nov. 30 and a panel of agency advisers endorsed the vaccine on Dec. 17. Just one day later, the FDA granted authorization for the shot, marking a milestone for both the U.S. public health response to the pandemic and for the decade-old biotech.
Initial supplies were limited to several tens of millions of doses, although the company and its manufacturing partners quickly ramped up production. On Feb. 12, the U.S. contracted to buy another 100 million doses from Moderna, bringing its total on order to 300 million.
Moderna has come under scrutiny, too, both for the price it charged the U.S. government as well as for the intellectual property it claims for its vaccine. Government scientists have supported Moderna's work and could hold rights to some of the underpinning technology. Moderna has said it will not enforce patent rights related to its vaccine technology for the duration of the pandemic.
One unknown as the pandemic goes on is whether the first generation of mRNA vaccines will be equally protective against virus variants first identified in the U.K. and South Africa.
Scientists working for NIH and Moderna have been able to establish in laboratory tests that mutations in the U.K. variant have little to no effect. But the variant from South Africa resulted in a weaker immune response. Still unclear, however, is whether the drop in potency will compromise protection.
Even so, Moderna has begun testing a booster shot specifically designed to counter the variant from South Africa. The first volunteer was dosed March 10.
CanSino had the distinction of being among the first to begin testing its vaccine in humans, report early data and start immunizations outside of a clinical study. But those milestones faded as the company struggled to complete a large Phase 3 trial and obtain the kind of proof regulators outside of China would need to authorize use.
Early and mid-stage trial results were sufficient to persuade the Chinese military to clear emergency use of CanSino's vaccine in soldiers last summer. Declining COVID-19 cases in China, however, pushed CanSino and other Chinese vaccine developers to seek study sites overseas.
CanSino, which has ties to Canada, had originally intended to study its shot in Canada, but an agreement there reportedly came undone.
A large late-stage study is recruited volunteers in South America, Mexico, Pakistan and Russia. On Feb. 24, 2021, Cansino reported its vaccine was 65% effective in preventing symptomatic cases and 90% efficacy in preventing severe disease 28 days after a single shot. One day later, China's drug regulatory issued a conditional market authorization.
Mexico and Pakistan approved the vaccine earlier in February as well.
CanSino's choice of vaccine design may limit the shot's potential, though. Early studies showed pre-existing immunity to the adenovirus, or viral vector, that CanSino uses to deliver its vaccine appeared to compromise its effectiveness.
Inovio has fallen behind in its development of a coronavirus vaccine, having no big pharma partner and assembling only about $100 million in external funding.
A partial clinical hold imposed by the FDA in late September last year, meanwhile, kept the company from conducting further study of its vaccine candidate until mid-November, when the agency cleared a Phase 2 trial to begin.
Inovio's candidate uses DNA to coax cells to produce coronavirus proteins, thereby stimulating an immune response to protect against infection by the virus. To allow the DNA molecules to enter cells, Inovio uses a process called electroporation, a small electrical pulse that opens small pores in cells. The device used to do this was the subject of some of the FDA's concerns, which the company plans to address via the Phase 2 trial, now fully enrolled.
Should those questions be resolved, Inovio would then launch a Phase 3 trial that remains on partial clinical hold. In a March 1 regulatory filing, the company said it plans to respond to the FDA's questions in May, after which the agency would have 30 days to indicate whether the late-stage study could proceed.
Summary data from a small Phase 1 trial were disclosed by the company in June 2020, and published in a medical journal on Dec. 24. Vaccination was safe and spurred immune responses against the virus. Those responses appeared weaker than what was reported for Pfizer's and Moderna's shots, however.
Inovio's manufacturing capacity is also much less than that of Pfizer and Moderna, although the biotech has boosted its supply lines. Inovio recently signed Thermo Fisher to its manufacturing consortium, with the hope of producing 100 million doses in 2021. An initial round of manufacturing deals, with Ology Bioservices and Richter-Helm BioLogics, would have produced only 1 million.
In the U.S. and Europe, vaccine developers bet on newer technologies, such as messenger RNA or viral vectors, that, while less established, offer crucial advantages in speed. Sinovac, along with several other companies and institutions in China and India, however, have moved almost as quickly using the tried-and-true approach of inactivated virus vaccines.
Used for hepatitis A, influenza and rabies, these vaccines consist of viruses rendered uninfectious either through heat or harsh chemicals.
Sinovac wasn't the first to get going, but was able to obtain results from late-stage testing faster than several more closely tracked Western drugmakers. While initial reports of data from a study in Brazil suggested strong efficacy, later announcements put the shot's overall efficacy just over 50% — barely clearing a bar set by regulators around the world.
The higher figure, researchers in Brazil said, was from counting only COVID-19 cases that required medical assistance. Comparing protection against COVID-19 of any severity resulted in a lower number.
The incomplete disclosures added to confusion over Sinovac's vaccine, particularly as researchers running studies in Turkey and Indonesia also reported differing results.
The shot was reportedly approved in China in late August for emergency use in people at high risk of coronavirus infection. On Feb. 8, Sinovac said it had gained conditional marketing approval in the country. The vaccine also has been authorized for emergency use in Indonesia, Brazil, Turkey and Chile.
Sinovac is listed on the Nasdaq stock exchange, but trading in its stock has been halted since February 2019 — the result of a dispute with an activist investor over control of the company.
Moderna wasn't the only biotech to aggressively push forward with the promising, but until now unproven, messenger RNA technology.
Across the Atlantic, in Mainz, Germany, BioNTech started work on an mRNA vaccine for the coronavirus early on and agreed to partner with Pfizer in March 2020, joining forces with the larger drugmaker even before their legal teams had produced a contract.
The partnership turned out to be a historic one, with the two companies winning clearance from the U.K. drugs regulator for their shot just eight months later, followed quickly by authorization in Canada on Dec. 9 and an emergency clearance from the FDA on Dec. 11. Authorities in the EU granted conditional authorization on Dec. 21.
The U.K.'s decision was a world first for a coronavirus vaccine that had completed testing; earlier vaccine approvals in China and Russia were done before late-stage studies had begun.
Unlike Moderna and other frontrunners, Pfizer and BioNTech had initially advanced four prototypes, each with subtle differences, before choosing one to take into late-stage testing. A Phase 2/3 trial began on July 28 and enrolled some 44,000 volunteers over the course of three months.
Data from the trial showed a better-than-expected 95% efficacy in preventing COVID-19. Side effects are primarily injection site pain and other common vaccine reactions like fatigue and fever.
In March, real-world use of the vaccine in Israel confirmed the shot's strong protection, with data showing 97% efficacy against symptomatic COVID-19. Results also suggested vaccination helped prevent asymptomatic infection.
As with Moderna’s vaccine, though, the spread of virus variants first identified in the U.K. and South Africa has raised questions about whether Pfizer and BioNTech vaccine will remain as strongly effective. So far, only laboratory test results are available, and these have found that mutations in the South African variant resulted in an immune response two-thirds lower than the original strain of the virus did. Whether that makes vaccinated people more likely to become sick isn't clear, but the partners are also looking at a second booster shot as well as a variant-specific vaccine.
Pfizer and BioNTech have contracted to supply the U.S. with 300 million doses, the most recent order coming Feb. 12. Unlike others, the drugmaker didn't relied on government funding for testing and manufacturing, claiming it's been able to move faster on its own.
BioNTech did receive nearly $450 million from the German government, however, to support vaccine development — money the biotech will use to cover its share of expenses in the partnership.
With supplies limited, and countries desperate to expand vaccination drives, Pfizer and BioNTech have secured help from Sanofi, Novartis and Merck KGaA to produce and fill vials of its shot.
When Chinese scientists made the new coronavirus' genetic sequence available in January 2020, researchers at the University of Oxford were more prepared than most.
A team there was already working on a vaccine for the virus that causes MERS, a close cousin of SARS-CoV-2. The Oxford researchers quickly adapted their work and, by last April, had started a large Phase 1 trial of their new vaccine in the U.K.
AstraZeneca signed on to help soon after, licensing the vaccine and beginning efforts to prepare for manufacturing hundreds of millions of doses.
Their speed — larger studies began in May, June and September — made AstraZeneca and Oxford's vaccine among the world's leading efforts and the subject of political tug-of-wars over who would get access.
But the program hit several setbacks, beginning in early September when AstraZeneca and Oxford halted testing worldwide after one participant in the U.K. study fell sick with an unexplained neurological illness.
While regulators in the U.K. and other countries quickly signed off on a trial restart, a review by the FDA took much longer, dragging on for more than six weeks before the agency gave AstraZeneca a green light on Oct. 23 to resume vaccinations.
In late November, AstraZeneca shared preliminary data from studies in the U.K. and Brazil showing its vaccine could protect against COVID-19. Yet the positive results were confusing, showing dramatically different protection rates between a larger group that received two full doses of the shot and a smaller group that was given a half dose and then a full dose. Moreover, the half dose was the result of a manufacturing error, AstraZeneca later acknowledged.
Despite the confusion, the U.K. drugs regulator authorized the shot about a month later, clearing the two full dose regimen given to the majority of participants in the U.K.- and Brazil-based studies. The European Medicines Agency followed in late January with a conditional authorization. The agency's decision was shadowed, however, by a conflict between the two parties over supply, after AstraZeneca told the EU it would deliver fewer doses than originally planned.
A large U.S. trial has completed recruitment and, if successful, could lead to an authorization by the FDA. Another study may also be launched to clear up the confusion over the mixed data from the U.K. and Brazil studies. In the meantime, AstraZeneca and Oxford have shared other results. One preliminary analysis indicated the shot may slow transmission of the virus, though it's unclear to what degree. Another found the shot to be protective — albeit slightly less effective — against a contagious variant circling in the U.K.
AstraZeneca and Oxford's vaccine is viewed as important for global immunization efforts as it can be more easily distributed and stored. AstraZeneca has also committed to sell doses more cheaply than others, and expects to produce a greater number of doses.
While the Western world has focused on leading candidates from large multinational drugmakers, China's state-owned Sinopharm has advanced two inactivated vaccines through late-stage trials and to approvals in the UAE and Bahrain.
Early-stage studies began last April for both of Sinopharm's candidates, data from which were published in JAMA in August and The Lancet in October, respectively. In each case, vaccination via two injections was generally well tolerated and triggered immune system responses against coronavirus proteins.
Like other Chinese vaccine developers, however, Sinopharm was forced to test the experimental shots outside of China once the virus' spread was brought under control in the country.
The company, a sprawling conglomerate and vaccine maker, turned to the Middle East and to South American for launching Phase 3 trials, the first of which began in July 2020.
A late-stage study in the UAE of one candidate, created by the Sinopharm subsidiary Beijing Institute of Biological Products, quickly enrolled and was expanded into Bahrain, Egypt and Jordan, with a target recruitment of 45,000 volunteers.
The UAE granted emergency authorization for the Beijing Institute shot in mid-September, followed by a full approval in December. A short announcement from the UAE health ministry indicated an interim analysis of Sinopharm's trial found vaccination was 86% effective, although no details were given to support that claim.
On Dec. 31, the Chinese government said it had conditionally approved the vaccine, citing new data from the Beijing Institute that put the shot's efficacy at 79%. "Millions" of doses have already been used to vaccinate healthcare workers and people who work overseas under an emergency use program, China's health ministry said.
The vaccine is also approved in Bahrain, Egypt, Jordan, Pakistan and Hungary./p>
Sinopharm's other shot was developed by another unit of the company, the Wuhan Institute of Biological Products, and is being studied in Phase 3 trials in the UAE, Morocco, Argentina and Peru.
Novavax, which has spent more than 30 years trying unsuccessfully to develop vaccines, is now within sight of getting its first authorized.
In January, the Maryland-based biotech reported results from a 15,000-volunteer U.K. trial indicating its coronavirus vaccine was about 90% effective in preventing symptomatic COVID-19 when compared to placebo. Follow-up study data in March indicated 96% efficacy against the original COVID-19 strain, and 86% efficacy against a variant first identified in the U.K.
Protection appeared much weaker, however, against a coronavirus variant originally detected in South Africa. Overall efficacy was about 49%, although that figure rose to 55% when people positive for HIV were excluded.
Novavax's work has gained broad financial support since it began development of its shot. By the end of last May, the company had won a large grant from the nonprofit Coalition for Economic Preparedness Innovations and started an initial clinical trial, boosting its shares nearly 9-fold in the process. In July 2020, the biotech secured support from the U.S. government, which committed $1.6 billion to fund late-stage testing of Novavax's vaccine and to buy 100 million doses.
Results from Novavax's Phase 1 study showed its vaccine spurred encouraging immune responses. Like other experimental shots, vaccination was associated with mostly mild side effects in most trial participants. The late-stage study in the U.K. began in late September, and completed enrollment in a little over two months.
Progress slowed in the U.S., with at least two delays to a Phase 3 trial that finally got underway on Dec. 28. Novavax completed enrollment of 30,000 volunteers in late February.
The company expects data sometime in the second quarter, after which it's planning to file for authorization in the U.S. and U.K.
Success could turn around Novavax, which prior to COVID-19 was struggling to stay afloat, and might reshape perception of a company that started but never finished work on vaccines for SARS and MERS.
Gamaleya Research Institute
Russia approved Gamaleya's vaccine on Aug. 11, less than two months after the first studies in humans began and, critically, before large-scale trials had proved whether it could protect against COVID-19.
The approval, which was announced by President Vladimir Putin, was the most significant example to date of how the race to develop a coronavirus vaccine has been cast in geopolitical terms.
Like the U.S., China and Europe, Russia pushed for fast development, spurring concerns that safety risks might go overlooked or crucial steps bypassed.
In the case of Gamaleya's vaccine, the government's urgency led to an approval following two small trials in just 76 volunteers. Such studies are designed to get an early sense of a vaccine's safety, as well as whether the shot spurs an immune response.
That data was published on Sept. 4 in The Lancet, showing Gamaleya's vaccine stimulated an immune response equal to that of patients who have recovered from coronavirus infections.
Proving protection from either coronavirus infection or disease requires larger, placebo-controlled tests involving thousands of participants. Gamaleya, with help from Russia's government and sovereign wealth fund, got started on a late-stage trial of its vaccine in late August, as the government was already beginning to distribute the shot.
On Dec. 14, Gamaleya released detailed data from that study, which gave 22,714 volunteers either the shot or a placebo. There were 62 cases of COVID-19 in patients who received the sham injection and 16 in the those who got the vaccine.
Because three times as many trial participants received the vaccine as did placebo, Gamaleya calculated efficacy against COVID-19 as more than 91%. The institute said it will submit the data to a peer-reviewed medical journal for publication.
In the meantime, Gamaleya has begun working together with AstraZeneca, pairing the special virus it uses to deliver its shot with one used by the British drugmaker, a move aimed at improving the efficacy of AstraZeneca's vaccine. The two partners announced Feb. 9 that the trial, which will take place in Azerbaijan, will begin at the end of February.
Nearly 50 countries have authorized GRI's shot, and vaccinations have begun in Belarus, according to the state-owned Russian Direct Investment Fund.
In early March last year, the American CEO of CureVac, Daniel Menichella, joined the heads of other coronavirus vaccine developers in a meeting with President Donald Trump at the White House.
A little more than a week later, Menichella was out as CureVac's CEO and the German biotech was at the center of swirling rumors that the U.S. had sought to buy the company, or its research.
CureVac denied any offer was ever extended. But the incident set off alarm bells in Berlin and made clear early on the potential for conflict between governments over vaccines.
Seemingly in response, the German government invested 300 million euros in CureVac for a 23% stake. CureVac added another $500 million through private investments, an alliance with GlaxoSmithKline and an initial public offering in the U.S. Much of the proceeds are being used to develop its coronavirus shot.
CureVac's vaccine, which has also been funded by CEPI, uses messenger RNA to encode the coronavirus' spike protein, much like BioNTech's and Moderna's. Early tests showed the shot spurred an immune response against the SARS-CoV-2 virus.
Months passed before, on Dec. 14, CureVac said it was beginning a Phase 2b/3 trial that is set to enroll 36,500 volunteers in Europe and South America. The trial will test a two-dose regimen, spaced four weeks apart. Trial monitors will take early looks at the shot's efficacy after 56 and 111 COVID-19 cases, CureVac said. A final analysis will occur after 185 cases.
How quickly those cases occur will depend on the level of virus spread where the trial is enrolling volunteers. Based on the current situation, CureVac anticipates it could have early data by the end of the first quarter, company CFO Pierre Kemula told BioPharma Dive.
CureVac's program has gotten support from two large drugmakers. First, the biotech partnered with Bayer on further development and, should trials succeed, supply of its vaccine. Then GlaxoSmithKline agreed to help make 100 million more doses of the shot in 2021, as well as co-develop second-generation versions to combat future coronavirus variants.
The U.K. government is backing that effort, too, promising to help speed testing and production of vaccines targeted against new variants.
Clover's candidate was the second protein-based vaccine to begin human testing for the new coronavirus, trailing only Maryland-based Novavax when its Phase 1 study began in mid-June.
Like the name suggests, protein-based vaccines are designed to expose the body's immune system to viral proteins. In the case of SARS-CoV-2, that's the spike protein which the virus uses to enter cells.
Protein-based vaccines are often paired with adjuvants, compounds that help boost the immune response to vaccination. Clover chose to test its candidate together with adjuvants developed by GlaxoSmithKline and Dynavax, and planned to study both in mid- to late-stage studies.
On Feb. 1, however, Clover announced it would only proceed with a trial of its vaccine and Dynavax's adjuvant, which the companies expect to begin in the first half of this year. The partnership with GSK, Clover said, was discontinued and the planned study dropped.
The decision was unexpected, particularly as Clover had said early testing results showed both adjuvants to be safe and capable of raising an immune response.
CEPI has provided Clover with financial muscle, pledging nearly $70 million in July to fund the Phase 1 study and prepare manufacturing capacity should the candidate succeed. The group will fund the Phase 2/3 trial and, on Feb. 1, extended a roughly $100 million forgivable loan to begin “at-risk” manufacture of the vaccine.
J&J was first among larger drugmakers to pursue a coronavirus vaccine, announcing in January 2020 plans to develop one using the same technology that underpins several other of the pharma's experimental vaccines.
Initially, J&J didn't expect to begin clinical study until September, a timeline that would have previously marked record speed but in the COVID-19 age appeared more deliberate.
The pharma sped up its plans, however, securing help from the U.S. government through Operation Warp Speed. An initial study began in late July and two months later, on Sept. 23, J&J kicked off a global Phase 3 study.
J&J had planned to recruit 60,000 volunteers, but reduced its enrollment target after cases of COVID-19 began to accelerate rapidly in the U.S. during the late fall. On Dec. 17, the drugmaker announced the study had been fully enrolled with approximately 45,000 participants.
In January 2021, data from that study showed a single dose of J&J's vaccine was 66% effective in preventing moderate or severe COVID-19. Efficacy was higher among participants recruited in the U.S., but lower in volunteers in Latin American and South Africa, where new, more virulent variants of SARS-CoV-2 are prevalent.
Still, the company's shot could play a critical role in the response to the pandemic, as it can be given via one injection and shipped at normal refrigerator temperatures. On Feb. 27, the U.S. FDA granted it emergency authorization, making J&J;'s vaccine the third available in the country. European regulators followed with a conditional authorization on March 11.
J&J expects to be able to supply 1 billion doses of its vaccine, with 200 million set to go to the U.S. J&J; said it will deliver 20 million doses to the U.S. by the end of March and the rest by the end of June.
In the U.S., the Bided administration helped to broker a deal involving Merck & Co., which agreed to help J&J; make its vaccine and fill vials for shipping. Officials expect the collaboration could expand the number of doses produced.
Sanofi and GlaxoSmithKline agreed to join forces last April, the former contributing its protein-based vaccine technology and the latter its immune-boosting adjuvants, both of which have previously been used against influenza.
From the outset, it was clear that Sanofi and GSK wouldn't be among the first to complete testing. Their initial development timeline was months behind that of Moderna, Pfizer and even Novavax, which uses a similar technology.
The two companies hoped to make up for slower speed with a more potent vaccine than others, a view they attributed to their adjuvanted approach, which is meant to strengthen the body's immune response to vaccination.
In July, they locked in $2.1 billion in support from the U.S. government to back the effort.
But events have moved quickly since then. Pfizer and BioNTech, as well as Moderna, showed their vaccines to be about 95% effective against COVID-19, far better results than anticipated.
Sanofi and GSK's shot, by comparison, fell well short of expectations. Initial results from a Phase 1 study in December were so disappointing the two companies decided to advance an upgraded formulation of the vaccine, a major setback that could delay the program by as much as nine months.
A Phase 2b study of the new vaccine began in February, with a late-stage trial expected to follow in the second quarter. Should those go well, initial availability could come by the end of the year.
Despite the delay, however, the companies' efforts could still be important, given the relative ease with which their vaccine can be shipped and stored and the number of countries depending on their progress. The U.S., U.K., Europe and Canada have pre-ordered hundreds of millions of doses. So has COVAX, an international alliance aiming to equitably distribute shots to poorer nations and economies.
In March, Sanofi began testing a mRNA vaccine it has been developing with Translate Bio, starting a Phase 1/2 trial that the companies expect to deliver results by the third quarter this year.
Merck came late to the coronavirus vaccine race, publicly announcing its efforts near the end of May. Rather than bet on newer messenger RNA technologies, Merck homed in on approaches it believed would produce immunity quickly with one shot.
But Merck's delay, surprising for one of the world's top vaccine makers, wasn't entirely due to initial caution. The pharma initially sought to partner with the University of Oxford, developer of the vaccine candidate now licensed by AstraZeneca, but was turned down, The Wall Street Journal reported in October.
Left searching for partners, Merck instead opted to buy the privately held Austrian company Themis and its vaccine candidate, as well as license another from the nonprofit group IAVI. A Phase 1/2 study of the Themis vaccine began in Belgium in early September, while a trial of the IAVI-developed shot got underway in November.
The company had argued it could make up ground on its rivals, but weaker-than-expected results from early tests led Merck to scrap development of both candidates in late January — a surprising and significant setback. Immune responses generated by both vaccines were comparatively less than what's been observed following natural infections as well as in testing of other experimental shots.
Instead, Merck said it will focus its resources on developing two COVID-19 treatments, including an antiviral drug now in mid-stage testing. In February, the company agreed to help make J&J;'s vaccine and fill vials for shipping, an unusual collaboration between large drugmakers that was brokered by the Biden administration.
https://www.biopharmadive.com/news/coronavirus-vaccine-pipeline-types/579122/
