Virus World

(Reuters) - AstraZeneca and Oxford University’s COVID-19 vaccine is more effective when its second dose is given three months after the first, instead of six weeks, a peer-reviewed study published in The Lancet medical journal showed on Friday. The study confirmed the Anglo-Swedish drugmaker’s findings from earlier this month that showed the vaccine had 76% efficacy against symptomatic coronavirus infection for three months after the first dose. Efficacy was found to be at 81% with the longer interval of 12 weeks between the first and second dose, compared with 55% efficacy up to the six-week gap, according to the Lancet study, which backs British and WHO recommendations for longer intervals. (bit.ly/3bmLX25) Faced with a resurgence in infections and new, highly transmissible variants of the virus, many countries are hoping to broaden immunization by giving some protection to as many people as possible with a first dose, while delaying subsequent shots.

Findings in The Lancet (Feb. 19, 2021):

http://www.thelancet-press.com/embargo/oxfordvaccineinterval.pdf 

LONDON (AP) — The U.K. on Monday became the first nation in the world to start using the COVID-19 vaccine developed by Oxford University and drugmaker AstraZeneca, ramping up a nationwide inoculation program as rising infection rates are putting an unprecedented strain on British hospitals. Brian Pinker, an 82-year-old dialysis patient, received the first shot at 7:30 a.m. at Oxford University Hospital. “The nurses, doctors and staff today have all been brilliant, and I can now really look forward to celebrating my 48th wedding anniversary with my wife, Shirley, later this year,” Pinker said in a statement released by the National Health Service.  The rollout of the new vaccine comes at a crucial moment for U.K. authorities, who are battling a surge in infections blamed on a new virus variant that authorities have said is much more contagious. Scotland imposed a lockdown until the end of January amid increasing pressure on officials to tighten restrictions throughout the U.K. Prime Minister Boris Johnson, who has said tougher measures are imminent, announced a nationwide address at 8 p.m. The UK Parliament will be recalled to sit on Wednesday.

“If you look at the numbers, there’s no question we will have to take tougher measures and we will be announcing those in due course,” Johnson said while visiting some of the people receiving the Oxford-AstraZeneca vaccine at Chase Farm Hospital in north London. The U.K. is in the midst of an acute outbreak, recording more than 50,000 new coronavirus infections a day over the past six days. On Sunday, it notched up another 54,990 cases and 454 more virus-related deaths to take its confirmed pandemic death toll total to over 75,000, one of the worst in Europe. Some areas northeast of London have infection rates of over 1,000 cases per 100,000 people. Scottish leader Nicola Sturgeon says that beginning Tuesday, people in Scotland will be legally required to stay at home except for essential reasons to help ease the pressure on hospitals and intensive care units. Under the new lockdown rules in Scotland, people can go out for exercise but can only meet one other person from another household. School closures are extended until February except for children of key workers and children under social care.  “I am more concerned about the situation we face now than I have been at any time since March last year,” she said Scotland, which has its own devolved government, has often imposed stricter coronavirus restrictions than those in England throughout the pandemic. U.K. regulators last week authorized emergency use of the Oxford-AstraZeneca shot, giving public health officials a second vaccine in their medical arsenal. Britain’s mass vaccination program began Dec. 8 with the shot developed by New York-based Pfizer and its German partner BioNTech.

Britain has secured the rights to 100 million doses of the Oxford-AstraZeneca vaccine, which is cheaper and easier to use than some of its rivals. In particular, it doesn’t require the super-cold storage needed for the Pfizer vaccine. The new vaccine will be administered at a small number of hospitals for the first few days so authorities can watch out for any adverse reactions. But the NHS said hundreds of new vaccination sites — including local doctors’ offices — will open later this week, joining the more than 700 vaccination sites already in operation. A “massive ramp-up operation” is now underway in the vaccination program, Johnson said. But aspects of Britain’s vaccination plans have spurred controversy. Both vaccines require two shots, and Pfizer had recommended that the second dose be given within 21 days of the first. But The U.K.’s Joint Committee on Vaccination and Immunization said authorities should give the first vaccine dose to as many people as possible, rather than setting aside shots to ensure others receive two doses. It has stretched out the time between the doses from 21 days to within 12 weeks. While two doses are required to fully protect against COVID-19, both provide high levels of protection after the first dose, the committee said. Making the first dose the priority will “maximize benefits from the vaccination program in the short term,” it said. Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said policymakers are being forced to balance the potential risks of this change against the benefits in the middle of a deadly pandemic....

Detailed data published in the Lancet show the vaccine may significantly reduce hospitalization from the disease. The Covid-19 vaccine being developed by the University of Oxford and AstraZeneca appears to have moderate efficacy in preventing symptomatic illness, and may significantly reduce hospitalization from the disease, data from four clinical trials of the vaccine reveal.  The highly anticipated publication of the data, released Tuesday in The Lancet, also point to some signals that deserve further exploration — the possibility of protection after a single dose and the suggestion that at least one dosing regimen may have led to a decrease the number of asymptomatic infections. “This warrants — it’s screaming for — more work in this area,” vaccine researcher Saad Omer, director of Yale University’s Institute of Global Health, said of the hint the vaccine may reduce asymptomatic infections. “You can’t ignore the results but you have to be judicious about moving forward.” The Lancet paper was released on a busy day for Covid-19 vaccine news: The United Kingdom began vaccinating with Pfizer’s vaccine and the Food and Drug Administration posted Pfizer’s data online in advance of an advisory committee meeting Thursday looking at whether that vaccine should be given emergency use authorization in the United States. “This is evolving science. You are seeing sausages being made — in front of the world’s eyes,” Omer said. Topline data on the AstraZeneca vaccine from a Phase 3 trial were released in November. Tuesday’s results — the first Phase 3 clinical data for a Covid vaccine to be published in a scientific journal — pool data from trials of various phases and includes safety data on more than 20,000 participants.

The results confirm that two standard doses of the vaccine were 62% effective in preventing symptomatic Covid-19 disease in some trials. But when efficacy data from the trials were combined — including trials in which volunteers received a low dose followed by a standard dose of vaccine — the vaccine was deemed to be 70% efficacious. Among only volunteers who received a low dose followed by a standard dose of vaccine, the vaccine had 90% efficacy. It’s still not clear why efficacy in this group — which did not include anyone over the age of 55 — was so high. Some experts even wonder if it is the result of the play of chance, and not a true difference. “I think there remain questions about whether the result in the low-dose standard dose is a real robust biological result,” said Natalie Dean, a biostatistician at the University of Florida. “Will it hold up?” Some scientists have suggested the seemingly incongruous result may be due to the initial lower dose actually priming the immune system in a more effective way than a standard dose would — which, if true, would allow more people to be vaccinated more quickly, if the vaccine is approved for use. Omer said the signal needs to be explored further, in consultation with regulatory agencies.  “I think you cannot ignore the 90% efficacy signal from a scientific perspective,” he said, suggesting a new Phase 3 trial or even a Phase 2b trial could answer the question of whether this vaccine regimen actually works better. Nahid Bhadelia, medical director of the special pathogens unit at Boston Medical Center, agreed. “There’s a marginal cost of waiting, but there is a marginal cost of vaccinating people with what turns out to be a less efficacious strategy. What if low-dose, standard-dose is the way to go?” she asked. AstraZeneca is still deliberating whether to conduct another trial to explore using this dosing regimen, Mene Pangalos, AstraZeneca’s executive vice president for biopharmaceuticals R & D, said Tuesday during a press briefing.

Some of the trials included in this pooled analysis collected weekly nasal swabs from participants to try to determine if the vaccine reduced asymptomatic infections, which would not come to light otherwise. This makes it unique among the Covid-19 vaccine trials. The early findings suggested the low dose, full dose regimen may have reduced the number of asymptomatic cases. Reducing the number of unknowingly infected people in a population could cut back on transmission of the SARS-CoV-2 virus, which causes Covid-19. But lead author Andrew Pollard, director of the Oxford vaccine group, suggested more data are needed to see if this effect is real.  “At the moment this isn’t strong enough to make definite claims. But it does certainly suggest there is the potential for something important in there,” Pollard said. Pangalos said AstraZeneca is submitting its data on a rolling basis to regulatory agencies in multiple countries around the world and expects that the data generated so far will be sufficient to win regulatory approval for the vaccine. The company expects, though, that the Food and Drug Administration will require AstraZeneca to complete its larger, ongoing U.S.-based trial before considering issuing an emergency use authorization for the vaccine in this country. The Lancet publication pooled data from Phase 1/2 and Phase 2/3 in the United Kingdom, a Phase 3 trial in Brazil and a Phase 1/2 trial in South Africa.  Most of the participants in all of the trials were adults aged 18 to 55, so the evidence for efficacy in older adults is limited. The paper did not attempt to estimate vaccine efficacy in this population at all, saying more work would be done to look at the question. But Pollard said immunogenicity data — generated by looking for antibody responses in blood samples from trial participants — suggest the vaccine may induce similar levels of protection across a variety of age groups “because there is no daylight between the levels of immune response even in the over 70s, when we compare with the younger adults.” There were three severe adverse events reported, two of which may have been related to receipt of the vaccine. (One was in the control arm.) One person developed transverse myelitis, a rare but potentially serious neurological condition. This person, whose case was previously reported, received the vaccine....

Findings Published in The Lancet (Dec. 8, 2020):

https://doi.org/10.1016/S0140-6736(20)32661-1

Experimental COVID-19 vaccine also triggers lower adverse responses among older people, British drug maker AstraZeneca said, raising hopes in the fight against the coronavirus pandemic. The vaccine, developed by the University of Oxford, also triggers lower adverse responses among the elderly, AstraZeneca, which is helping manufacture the vaccine, said on Monday. This could potentially be seen as a game-changer in the battle against the novel coronavirus, which has infected more than 43 million people worldwide, killed at least 1.15 million people, shuttered swathes of the global economy, and turned normal life upside down for billions of people. “It is encouraging to see immunogenicity responses were similar between older and younger adults and that reactogenicity was lower in older adults, where the COVID-19 disease severity is higher,” an AstraZeneca spokesman said. “The results further build the body of evidence for the safety and immunogenicity of AZD1222,” the spokesman said, referring to the technical name of the vaccine. 

AstraZeneca did not provide details of the data behind the statement or say when it would publish eagerly awaited late-stage phase-three trial data, which would show whether the vaccine works well enough in large-scale trials for it to be approved. The Oxford/AstraZeneca vaccine is expected to be one of the first from big pharma to secure regulatory approval, along with Pfizer and BioNTech’s candidate, as the world tries to plot a path out of the COVID-19 pandemic. The news that older people get an immune response from the vaccine is positive because the immune system weakens with age and older people are those most at risk of dying from the coronavirus. British Health Secretary Matt Hancock said a vaccine was not yet ready, but he was preparing logistics for a possible roll-out mostly in the first half of 2021.  Asked if some people could receive a vaccine this year, he told the BBC: “I don’t rule that out but that is not my central expectation. “The programme is progressing well [but] we’re not there yet,” Hancock said.

AstraZeneca’s vaccine study is being investigated further by the Food & Drug Administration (FDA) after a participant experience a suspected adverse reaction to the drug. This could put additional delays on the British drugmaker’s late-stage trial. Meanwhile, European regulators are set to announce the start of AstraZeneca’s review in Europe as soon as this week - the first vaccine to undergo EU approval. AstraZeneca’s CEO said on September 10 the vaccine would be ready by the end of the year or early next year, despite the COVID-19 trial halting due to the illness.

The US Food and Drug Administration (FDA) has broadened its investigation into the suspected adverse reaction of a participant in AstraZeneca's COVID-19 vaccine trial, whilst European regulators are set to announce its review as soon as this week. The FDA also wants to examine results from earlier studies of other vaccines produced by the same scientists of the AstraZeneca vaccine to see if similar side effects have emerged, three sources with knowledge of the trial told Reuters on Wednesday. But these checks don't mean the agency suspects safety concerns with any of the vaccines, the people said. "It just shows that the FDA is being thorough," one of the sources told Reuters. AstraZeneca's vaccine study, which is said to be one of the most advanced COVID-19 vaccines in the world, could be delayed even further due to the wider probe into safety issues carried out by the FDA. The drugmaker's phase three coronavirus vaccine trial was put on hold on September 6 following a serious illness of a participant in the UK who has reportedly come down with a rare spinal inflammatory disorder called transverse myelitis. Trials have now resumed in the UK, South Africa, India and Brazil, but US authorities are yet to give AstraZeneca the all-clear to restart trials. The US government has pledged up to $1.2 billion to support AstraZeneca's vaccine development and has secured 300 million doses for the whole country. AstraZeneca's CEO Pascal Soriot said an interview on September 10 it is normal for vaccine trials to be paused due to unexpected events, but that "the difference is with other vaccine trials is that the whole world is not watching them."

Meanwhile, European regulators are set to announce a review of AstraZeneca's vaccine as soon as this week, according to a source familiar with the matter, per Bloomberg.  The head of the European Medicines Agency, Marco Cavaleri, said in July the agency would announce "rolling reviews" of potential coronavirus vaccines after the summer, adding that the EU could approve the first effective vaccine by the end of this year. A rolling review avoids delays, allowing a quick approval of a drug from the European Commission, which is necessary in emergencies like a pandemic. Shares in AstraZeneca rose 1% in early London trading on Wednesday.

The companies hope to earn the trust of the public and of scientists who have clamored for details of the studies.  Two drug companies that are leading the race to develop coronavirus vaccines bowed to public pressure on Thursday, abandoning their traditional secrecy and releasing comprehensive road maps of how they are evaluating their vaccines. The companies, Moderna and Pfizer, revealed details about how participants are being selected and monitored, the conditions under which the trials could be stopped early if there were problems, and the evidence researchers will use to determine whether people who got the vaccines were protected from Covid-1. Moderna’s study will involve 30,000 participants, and Pfizer’s 44,000.  Companies typically share these documents after their studies are complete. The disclosures while the trials are still underway, a rare move, are aimed at addressing growing suspicion among Americans that President Trump’s drive to produce a vaccine before the election on Nov. 3 could result in a product that was unsafe.  The plan released by Moderna on Thursday morning included a likely timetable that could reach into next year for determining whether its vaccine works. It does not jibe with the president’s optimistic predictions of a vaccine widely available to the public in October.

Pfizer’s plan does not appear to estimate when its results could be available. Its chief executive has said repeatedly that the company hopes to have an answer as early as October. Moderna has said only that it could have a result before the end of the year. Moderna’s 135-page plan, or protocol, indicated that the company’s first analysis of early trial data might not be conducted until late December, though company officials now say they expect the initial analysis in November. In any case, there may not be enough information then to determine whether the vaccine works, and the final analysis might not take place until months later, heading into the spring of next year. Moderna’s timeline meshes with the cautionary estimates from many researchers, including Dr. Robert R. Redfield, the director of the Centers for Disease Control and Prevention, who told senators on Wednesday that a vaccine would not be widely available until the middle of next year. Hours later, Mr. Trump sharply contradicted him, making unsubstantiated projections that a vaccine could become widely available weeks from now. On Wednesday, Joseph R. Biden Jr., the Democratic presidential nominee, said in Wilmington, Del., that the process used to evaluate and approve a vaccine would have to be “totally transparent” to win public confidence. He has said that Mr. Trump’s calls for companies and regulators to speed the process have shaken the public’s faith in vaccines and that politics has no place in vaccine development. Researchers in particular have been urging vaccine makers to share the detailed blueprints of their studies so that outside experts can evaluate them. At least one expert, after reading the plans, has already raised questions about the way the trials were designed. “I want to acknowledge a good deed done,” said Peter Doshi, who is on the faculty at the University of Maryland School of Pharmacy in Baltimore and an editor with The BMJ, a medical journal. He previously requested the plans from Moderna and Pfizer. “They have opened up, for the first time, the ability for researchers not involved in the trial to form their own independent judgment about the design of this study.”

Until now, none of the nine companies that are testing vaccines in large clinical trials had released this level of detail. Moderna, AstraZeneca and Pfizer, which is collaborating with the German company BioNTech, are among the front-runners in the global race to produce a vaccine to fight the pandemic. A spokeswoman for AstraZeneca said the company intended to publish its protocol shortly. Novavax, which is expected to start a large, advanced clinical trial later this year, also did not comment. Johnson & Johnson, which has said it plans to begin a large trial this month, said it would have “more information to share” when the trial starts.AstraZeneca’s trial was stopped temporarily because of serious illness in a participant. It has resumed in Britain and Brazil, but not in the United States. Earlier studies of both vaccines in small numbers of people found that after the second shot, they developed so-called neutralizing antibodies, which can inactivate the virus in lab tests. The vaccines also produced a favorable response involving T-cells, another part of the immune system...

AstraZeneca should still know by year-end whether its experimental vaccine protects people against coronavirus, as long as it is cleared to resume trials soon, its chief executive said on Thursday amid doubts over its rollout. Governments desperate to put an end to the COVID-19 pandemic which has caused more than 900,000 deaths and huge economic and social disruption during 2020 are pinning their hopes on a vaccine. However British drugmaker AstraZeneca suspended late-stage trials on its potential vaccine this week after an illness in a participant in Britain who was reported to be suffering from symptoms associated with transverse myelitis, a rare spinal inflammatory disorder. The World Health Organization (WHO) has flagged the AstraZeneca vaccine, which is being developed with the University of Oxford, as the most promising for coronavirus.

CEO Pascal Soriot said during an online event on Thursday that AstraZeneca (AZN.L) did not yet know the diagnosis of the participant who was ill, adding that it was not clear if the volunteer had transverse myelitis and more tests were needed. The diagnosis would be submitted to an independent safety committee and this would usually then say whether trials can be resumed, Soriot said, adding it was usual for such pauses. “It’s very common, actually, and many experts will tell you this,” Soriot said, adding: “The difference with other vaccine trials is, the whole world is not watching them, of course. They stop, they study, and they restart.” Shares in AstraZeneca fell on Wednesday after the trial halt raised doubts about the timeline for the vaccine’s rollout.

AstraZeneca would supply vaccines to countries at the same time to ensure a fair and equitable distribution, Soriot said, reiterating that the company was close to having capacity to produce 3 billion doses at sites set up around the world to prevent governments from restricting distribution. With up to 60,000 people set to participate in the study program, AstraZeneca’s CEO said the volume was typical of vaccine trials and large enough to spot rare side effects. “With this you are going to pick up very rare events.” he said, adding that a planned staggered launch, prioritizing at-risk groups, would provide further assurance for the masses that are set to be covered by government plans at a later stage. Serum Institute of India, one of AstraZeneca’s (AZN.L) development and production partners, said on Thursday it was joining the suspension, backtracking on remarks that it did not face any issues.

Transverse myelitis cases after a vaccination have been documented before, but concrete links between the condition and vaccinations have not been established, experts said. The U.S.-based Mayo Clinic concludes that the association so far is not strong enough to warrant limiting any vaccine. A 2009 review in the journal Lupus of nearly 40 years of English-language publications found 37 cases of transverse myelitis associated with hepatitis B vaccines, measles-mumps-rubella, diphtheria-tetanus-pertussis and others.  The vaccines remained on the market, Stephen Evans, a professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said. Linking such an autoimmune response to a single factor like a vaccine is problematic, he said, given the number of immunological, hormonal or environmental factors at play. “It’s terribly difficult to be sure,” Evans said. 

RBC Capital Markets analyst Bryan Abrahams cautioned the trial participant’s condition must be thoroughly investigated. “Even a single case could possibly imply a rate or association higher in the study than what is normally observed sporadically” he wrote to investors, adding a one in 10,000 risk, if confirmed, would likely be unacceptable. BioNTech (BNTX.O), among the frontrunners in the vaccine race with partner Pfizer (PFE.N), echoed remarks by Soriot that clinical halts are a common feature of immunization trials. 

“Safety is a top priority,” its CEO Ugur Sahin told Reuters.

Pharmaceutical company AstraZeneca said it was pausing late-stage global trials. The race to develop a coronavirus vaccine careened into a speed bump Tuesday when the U.K.-based pharmaceutical company AstraZeneca announced it was pausing late-stage global trials of its leading vaccine candidate after one of the trial’s volunteers experienced a serious suspected adverse reaction. The company signed a deal to manufacture and distribute a vaccine developed at Oxford University and had hoped that the vaccine would be ready and available by the end of the year. The company announced it was voluntarily pausing its vaccine to investigate whether or not the illness in the volunteer was linked to the vaccine. For the Trump administration, which has badly mishandled the U.S. response to the pandemic, the near-singular focus now rests on producing an effective vaccine as fast as possible that could potentially let the country resume some semblance of normal daily life. President Donald Trump has played fast and loose with COVID cures of all sorts over the last six months and, never being one to let reality get in the way of what serves him best, caused concern over the sanity and safety of the well-established trial process.

The Trump administration has been considering fast-tracking the AstraZeneca vaccine, bypassing normal regulatory standards so that the president could have some good news to announce before Americans go to the polls on Nov. 3. “To speed up the process, the drugmaker has begun manufacturing the jab before the trials are complete or the vaccine is approved,” the Financial Times reports. “The partnership—which has received more than $1 billion in funding from the U.S. Biomedical Advanced Research and Development Authority—has agreed to deliver more than 300 million doses to the U.S. government.” In a statement, AstraZeneca described the decision to halt the trial as a “routine action” that “has to happen whenever there is a potentially unexplained illness in one of the trials, while it is investigated, ensuring we maintain the integrity of the trials.” “A person familiar with the situation, who spoke on the condition of anonymity, said that the participant who experienced the suspected adverse reaction had been enrolled in a Phase 2/3 trial based in the United Kingdom,” according to the New York Times. “The individual also said that a volunteer in the U.K. trial had received a diagnosis of transverse myelitis, an inflammatory syndrome that affects the spinal cord and is often sparked by viral infections. However, the timing of this diagnosis, and whether it was directly linked to AstraZeneca’s vaccine, is still unknown.”

The vaccine generated an immune response in a study of roughly 1,000 patients, and all of the side effects were deemed mild or moderate. The data, published in the medical journal the Lancet, also show that the vaccine caused side effects, including fever, headaches, muscle aches, and injection site reactions, in about 60% of patients. All of the side effects were deemed mild or moderate, and all resolved themselves over the course of the study. While the Oxford-AstraZeneca vaccine, known as AZD1222, has moved most rapidly into larger-scale studies of any major contender — and AstraZeneca has said that billions of doses could be manufactured — the new data represent the first glimpse researchers have gotten at its efficacy. They show a relatively safe vaccine, though side effects were greater than for a meningitis vaccine, to which it was compared, that engages the immune system to fight the virus. The Lancet also published results of another vaccine, from the Chinese biotech CanSino, that had been previously released. The Phase 2 results showed that, as was seen in the Phase 1 data, the vaccine induced neutralizing antibody responses — which could be vital to preventing the disease’s dangerous symptoms — in most subject. But further study continues to show that this vaccine works better in some people than others. And among those it didn’t work as well in were people aged 55 and older, a key target for Covid-19 vaccination. “The results of both studies augur well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety,” wrote two vaccine researchers from Johns Hopkins University, Naor Bar-Zeev and William Moss, in an accompanying editorial.

The data on the Oxford-AstraZeneca vaccine do not provide enough information to predict whether it will be more effective than other vaccines that are also entering clinical trials. AZD1222 is one of 23 potential Covid-19 vaccines that are being tested in clinical trials, according to the World Health Organization. Studies in which thousands of volunteers are given either a vaccine or placebo are necessary to know for sure if any vaccine prevents infection with SARS-Cov-2, and how well that vaccine works. No such studies have been completed. AZD1222 is one of 23 potential Covid-19 vaccines that are being tested in clinical trials, according to the World Health Organization. Studies in which thousands of volunteers are given either a vaccine or placebo are necessary to know for sure if any vaccine prevents infection with SARS-Cov-2, and how well that vaccine works. No such studies have been completed. The vaccine also produced a response in T cells, a type of white blood cell that attacks cells infected with viruses, according to the paper. In a statement, Andrew Pollard of the University of Oxford, the study’s lead author, said that the vaccine is intended to induce both types of responses. “We hope this means the immune system will remember the virus, so that our vaccine will protect people for an extended period,” he said...

Original study for the Oxford vaccine published at the Lancet (July 2020):

 https://doi.org/10.1016/S0140-6736(20)31604-4

Original study of Cansino's vaccine published at the Lancet (July 2020):

https://doi.org/10.1016/S0140-6736(20)31605-6

See also Editorial comment (July 2020):

https://doi.org/10.1016/S0140-6736(20)31611-1

An experimental coronavirus vaccine developed by Oxford University has protected six monkeys from “heavy quantities” of the pathogen — a promising breakthrough in the worldwide race for a cure. Researchers at the National Institute of Health Rocky Mountain Laboratory injected the six rhesus macaque monkeys with the Oxford concoction, then exposed them to “heavy quantities” of COVID-19 — exposure that had consistently sickened other monkeys in the lab, the New York Times reported Monday. But 28 days later, all the chimps were still healthy.

“The rhesus macaque is pretty much the closest thing we have to humans,” Dr. Vincent Munster, who conducted the Oxford tests, told the Times. The vaccine is now set to undergo human trials, with tests scheduled for more than 6,000 people by the end of next month. If the trial proves safe and effective, the scientists are optimistic that with emergency approval from regulators, the first few million doses could be available by September, the outlet said.

The British university has had a head start in trying to develop a coronavirus vaccine — the university’s Jenner Institute ran trials on an earlier strain of the virus last year which proved harmless to humans, according to the Times. Another research company, Chinese-based SinoVac, is also making progress, however. The company said its tests on rhesus macaques also showed promise — and the company has recently started a clinical trial with 144 patients.

A new study by researchers at the University of Oxford underscores the importance of mass inoculation as a path out of the pandemic.  The vaccine developed by the University of Oxford and AstraZeneca not only protects people from serious illness and death but also substantially slows the transmission of the virus, according to a new study — a finding that underscores the importance of mass vaccination as a path out of the pandemic. Researchers at the University of Oxford measured the impact on transmission by swabbing participants every week seeking to detect signs of the virus. If there is no virus present, even if someone is infected, it cannot be spread. And they found a 67 percent reduction in positive swabs among those vaccinated. The results, detailed by Oxford and AstraZeneca researchers in a manuscript that has not been peer-reviewed, found that the vaccine could cut transmission by nearly two-thirds.  Matt Hancock, the British health secretary, hailed the results on Wednesday as “absolutely superb.” “We now know that the Oxford vaccine also reduces transmission and that will help us all get out of this pandemic,” Mr. Hancock said in an interview Wednesday morning with the BBC.  The results, he said, “should give everyone confidence that this jab works not only to keep you safe but to keep you from passing on the virus to others.”

Some scientists looking at the limited information released cautioned that more analysis of the data was needed before such broad conclusions could be firmly stated. “While this would be extremely welcome news, we do need more data before this can be confirmed and so it’s important that we all still continue to follow social distancing guidance after we have been vaccinated,” said Dr. Doug Brown, chief executive of the British Society for Immunology. The Oxford and AstraZeneca researchers also found that a single dose of the vaccine was 76 percent effective at preventing Covid-19. The data measured the three months after the first shot was given, not including an initial three-week period needed for protection to take effect.  The encouraging results, lend support to the strategy deployed by Britain and other countries to prioritize providing as many first doses of vaccines as possible, setting aside concerns that people will get their second doses later than initially planned. The latest data do not have bearing on the debate over whether to further space out the doses of the two vaccines authorized in the United States, those from Pfizer-BioNTech and Moderna, since the data on AstraZeneca’s candidate cannot be generalized to other vaccines. Some scientists have called on the United States to follow the lead of Britain and other countries that have opted to delay the second doses of vaccines by up to 12 weeks. But U.S. federal officials have resisted, saying such a move would not be supported by the data from clinical trials of the two vaccines currently available across the nation. Tuesday’s results could amplify pressure on U.S. health officials to delay second doses of AstraZeneca’s vaccine, though it has not yet been authorized by the country.

The vaccine appeared more effective when the interval between the two shots was longer than the originally intended four-week gap, the Oxford and AstraZeneca researchers found. Among clinical trial participants who got two standard-strength doses at least three months apart, the vaccine was 82 percent effective, compared to 55 percent effective when the doses were given less than six weeks apart.  A vaccination strategy that spaces out doses by three months “may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term,” the researchers wrote. The newly released study builds on data issued late last year, which found that the vaccine was 62 percent effective when given as two standard-strength doses. In those initial findings, the vaccine’s efficacy was much higher, at 90 percent, when the first dose of the vaccine was given at half-strength. Oxford and AstraZeneca researchers initially attributed the different levels of effectiveness to the lower strength of the initial dose. But they gradually reached a different conclusion: the amount of time between doses was the more likely explanation.  In the United States, the Food and Drug Administration is waiting on data from a clinical trial that enrolled about 30,000 participants, mostly Americans. Results from that study are expected later this month. The study is expected to arm AstraZeneca with enough safety data to allow it by around early March to seek authorization to provide the vaccine for emergency use. The United States has agreed to buy 300 million doses of AstraZeneca’s vaccine, but neither the company nor the federal government has said when and in what quantities those doses will be available after the vaccine is approved.

Preprint available (Feb. 1, 2021): 

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268

Univ. Oxford Press Release:

https://www.ox.ac.uk/news/2021-02-02-oxford-coronavirus-vaccine-shows-sustained-protection-76-during-3-month-interval# 

It aims to inoculate some 300m people this year in one of the world's largest vaccination campaigns. The drugs regulatory authority gave the green light to the jabs developed by AstraZeneca with Oxford University and by local firm Bharat Biotech. Prime Minister Narendra Modi called it "a decisive turning point". India plans to inoculate some 300 million people on a priority list this year. It has recorded the second-highest number of infections in the world, with more than 10.3 million confirmed cases to date. Nearly 150,000 people have died. On Saturday India held nationwide drills to prepare more than 90,000 health care workers to administer vaccines across the country, which has a population of 1.3 billion people.  The Drugs Controller General of India said both manufacturers had submitted data showing their vaccines were safe to use. However, opposition politicians and some doctors have criticised a lack of transparency in the approval process.

A phase 2 clinical trial has found AstraZeneca’s COVID-19 vaccine delivers similar immune responses in people aged over and under 70 years. The update, which suggests the vaccine is better tolerated by seniors, provides further evidence that prophylactics may work in the people most vulnerable to the coronavirus.  This week, Pfizer has reported 94% efficacy in people aged over 65 years, and Moderna has said the effectiveness of its vaccine is consistent across subgroups. The updates go some way toward quelling fears that vaccines will fail the population that most needs protecting from SARS-CoV-2. AstraZeneca, which could be the next company to drop phase 3 data, added to the evidence on the use of COVID-19 vaccines in older adults in a paper published in The Lancet. The paper reported data on 560 people enrolled in the phase 2 portion of the phase 2/3 clinical trial of the ChAdOx1 nCoV-19 vaccine AstraZeneca is developing with the University of Oxford. 

Investigators gave the vaccine, also known as AZD1222, to 200 people aged 70 years and older. A further 40 people in that age group received the control vaccine, MenACWY. The clinical trial also randomized 160 people aged 18 to 55 years and 160 people aged 56 to 69 years to receive either the COVID-19 or control vaccines. Immunogenicity was similar in all three groups. People of all ages experienced a specific antibody response to the SARS-CoV-2 spike protein and receptor-binding domain 28 days after getting the first vaccine dose. Antibody titers rose in all three cohorts after the booster shot. Neutralizing antibody responses were similar across age groups, as were spike-specific T-cell responses. The immune responses in older adults are encouraging given the body of evidence that vaccines can trigger relatively weak responses in seniors. However, there are limitations to what can be concluded from the data. The paper lacks data on whether the immune responses confer protection against the coronavirus, and the older cohort may not be representative of the broader population of seniors. With a median age of 73 to 74 years, the people in the older cohort are younger than many of the individuals likely to be first to receive COVID-19 vaccines. The U.K. vaccination schedule, for example, calls for people in care homes to be vaccinated first, followed by the over-80s and then the over-75s. People in the study cohort are also likely healthier than the average senior. As the trial took place amid a national lockdown, the protocol excluded individuals with substantial comorbidities or clinical frailty. The phase 3 trial, which an Oxford professor said will “definitely” read out by Christmas, has a more diverse population and will show whether the immune responses translate into fewer cases of symptomatic COVID-19.

For now, the signs in seniors are encouraging. As well as seeing similar immunogenicity across age groups, the phase 2 found the vaccine has a lower reactogenicity profile in older adults. In the 18-to-55 cohort, 8% of people reported severe fatigue after the first dose. Six percent of participants reported severe chills and “feverish” symptoms. There were no severe cases of those reactions in the over-70 group after the first dose and only one severe reaction of any kind, malaise. Nobody over 70 experienced a severe reaction after the boost dose. The only reaction to affect most older people after either dose was tenderness. That is in contrast to people in the younger cohort, most of whom reported some degree of tenderness, pain, muscle ache, fatigue or headache after the first dose.  No participants in the trial had suspected unexpected serious adverse reactions. As the authors of The Lancet paper note, suspected unexpected serious adverse reactions have been seen in the phase 3 trial, leading to a delay to that study. The reactions will be reported in detail in a future paper.

Study cited published in the Lancet (Nov. 18, 2020):

https://doi.org/10.1016/S0140-6736(20)32466-1

AstraZeneca Plc's COVID-19 vaccine trial in the United States is expected to resume as early as this week after the U.S. Food and Drug Administration completed its review of a serious illness in a study participant, four sources told Reuters. AstraZeneca’s large, late-stage U.S. trial has been on hold since Sept. 6, after a participant in the company’s UK trial fell ill with what was suspected to be a rare spinal inflammatory disorder called transverse myelitis. The sources, who were briefed on the matter but asked to remain anonymous, said they have been told the trial could resume later this week. It was unclear how the FDA would characterize the illness, they said. An FDA spokeswoman declined to comment.

The agency is requiring researchers conducting the trial to add information about the incident to consent forms signed by study participants, according to one of the sources.  The agency is requiring researchers conducting the trial to add information about the incident to consent forms signed by study participants, according to one of the sources. “In this case, after considering the information, the independent reviewers and MHRA (Medicines and Healthcare products Regulatory Agency) recommended that vaccinations should continue,” the draft consent form stated. “Close monitoring of the affected individual and other participants will be continued.” Regulators in Brazil, India and South Africa also previously allowed AstraZeneca to resume its vaccine trials there.

AstraZeneca, which is developing the vaccine with Oxford University researchers, had been seen as a frontrunner in the race to produce a vaccine for COVID-19 until its trials were put on hold to investigate the illness. Early data from large-scale trials in the United States of vaccines from Pfizer Inc PFE.N and Moderna Inc MRNA.O are expected some time next month. Johnson & Johnson JNJ.N last week paused its Phase III COVID-19 vaccine trial to investigate an unexplained illness in a study participant. At the time of the announcement, the company did not know whether the volunteer had been given its vaccine or a placebo. A J&J spokesman on Tuesday said the study remains on pause as the company continues its review of medical information before deciding to restart the trial. J&J noted last week that its “study pause” was voluntary. By contrast, AstraZeneca’s trial is on “regulatory hold,” which is imposed by health authorities...

Experts are concerned that the company has not been more forthcoming about two participants who became seriously ill after getting its experimental vaccine. AstraZeneca revealed details of its large coronavirus vaccine trials on Saturday, the third in a wave of rare disclosures by drug companies under pressure to be more transparent about how they are testing products that are the world’s best hope for ending the pandemic. Polls are finding Americans increasingly wary of accepting a coronavirus vaccine. And scientists inside and outside the government are worried that regulators, pressured by the president for results before Election Day on Nov. 3, might release an unproven or unsafe vaccine. “The release of these protocols seems to reflect some public pressure to do so,” said Natalie Dean, a biostatistician and expert in clinical trial design for vaccines at the University of Florida. “This is an unprecedented situation, and public confidence is such a huge part of the success of this endeavor.” Experts have been particularly concerned about AstraZeneca’s vaccine trials, which began in April in Britain, because of the company’s refusal to provide details about serious neurological illnesses in two participants, both women, who received its experimental vaccine in Britain. Those cases spurred the company to halt its trials twice, the second time earlier this month. The studies have resumed in Britain, Brazil, India and South Africa, but are still on pause in the U.S. About 18,000 people worldwide have received AstraZeneca’s vaccine so far.

AstraZeneca’s 111-page trial blueprint, known as a protocol, states that its goal is a vaccine with 50 percent effectiveness — the same threshold that the Food and Drug Administration has set in its guidance for coronavirus vaccines. To determine with statistical confidence whether the company has met that target, there will have to be 150 people ill with confirmed coronavirus among participants who were vaccinated or received placebo shots. However, the plan anticipates that a safety board will perform an early analysis after there have been just 75 cases. If the vaccine is 50 percent effective at that point, it might be possible for the company to stop the trial early and apply for authorization from the government to release the vaccine for emergency use. In allowing only one such interim analysis, AstraZeneca’s plan is more rigorous than the others that have been released, from Moderna and Pfizer, Dr. Eric Topol, a clinical trials expert at Scripps Research in San Diego, said in an interview. Moderna allows two such analyses, and Pfizer four. He said the problem with looking at the data too many times, after a relatively small number of cases, is that it increases the odds of finding an appearance of safety and efficacy that might not hold up. Stopping trials early can also increase the risk of missing rare side effects that could be significant once the vaccine is given to millions of people. Dr. Topol said AstraZeneca’s plan, like those of Moderna and Pfizer, had a problematic feature: All count relatively mild cases of Covid-19 when measuring efficacy, which may hamper efforts to determine whether the vaccine prevents moderate or severe illness.

Such plans are not usually shared with the public “due to the importance of maintaining confidentiality and integrity of trials,” Michele Meixell, a spokeswoman for AstraZeneca, said in a statement. The company has released few details about the two cases of serious illness in its trial. The first participant received one dose of the vaccine before developing inflammation of the spinal cord, known as transverse myelitis, according to a participant information sheet for AstraZeneca’s vaccine from July. The condition can cause weakness in the arms and legs, paralysis, pain and bowel and bladder problems. The case prompted a pause in AstraZeneca’s vaccine trials to allow for a safety review by independent experts. A company spokeswoman told the Times last week that the volunteer was later determined to have a previously undiagnosed case of multiple sclerosis, unrelated to the vaccine, and that the trial resumed shortly thereafter. Transverse myelitis can sometimes be the first sign of multiple sclerosis, which involves more complex symptoms. But the myelitis alone can also occur after the body encounters an infectious agent like a virus. The company said it had not confirmed a diagnosis in the second case, a participant who got sick after the second dose of the vaccine. A person familiar with the situation who spoke with The Times on the condition of anonymity said the participant’s illness had been pinpointed as transverse myelitis. The trial was paused again on Sept. 6 after she fell ill. The condition is rare, but serious, and experts said that finding even one case among thousands of trial participants could be a red flag. Multiple confirmed cases, they said, could be enough to halt AstraZeneca’s vaccine bid entirely...

A large, United Kingdom-based Phase 2/3 study testing a Covid-19 vaccine being developed by AstraZeneca has been restarted, according to a statement from the company. News that the trial is resuming comes four days after the disclosure that it had been paused because of a suspected serious adverse reaction in a participant.  A spokesperson for AstraZeneca told STAT that at this point, only the trial in the U.K. has been resumed. The company is also conducting Phase 2/3 or Phase 3 trials in the U.S., Brazil, and South Africa.  “The Company will continue to work with health authorities across the world and be guided as to when other clinical trials can resume to provide the vaccine broadly, equitably and at no profit during this pandemic,” the spokesperson, Michele Meixell, wrote in an email.

Saturday’s statement from AstraZeneca said the independent U.K. investigation into the event has concluded and it advised the Medicines Health Regulatory Authority, Britain’s equivalent of the Food and Drug Administration, that it was safe to resume the trial. The MHRA concurred and gave the green light for the trial to restart. The illness that triggered the international pause, which occurred in a woman who was in the vaccine arm of the U.K. trial, has not been officially disclosed, though AstraZeneca CEO Pascal Soriot told a group of investors on Wednesday that her symptoms were consistent with transverse myelitis, a serious condition involving inflammation of the spinal cord that can cause muscle weakness, paralysis, pain and bladder problems. The AstraZeneca statement said information about the illness the woman suffered cannot be disclosed. Oxford University, where the vaccine was developed, said in a separate statement that the nature of the illness cannot be revealed “for reasons of participant confidentiality.” As part of the review process, independent boards overseeing trials of a number of other Covid-19 vaccines were analyzing their own data, looking for cases. There are at least 35 vaccines in clinical trials around the world, nine of which are in Phase 3, the final stage of testing.

It’s not uncommon for clinical trials to be paused. This is the second known hold of studies of the AstraZeneca vaccine. A woman in the U.K. trial was diagnosed with multiple sclerosis in July, but that event, which triggered the first pause, was deemed not to be related to the vaccine. An AstraZeneca spokesperson previously described the decision as a “routine action which has to happen whenever there is a potentially unexplained illness” in a trial. Still, the pause drew extraordinary attention because of the urgent need for progress on Covid-19 vaccines in the midst of the pandemic.

Adenovirus vectors deliver the genetic instructions for SARS-CoV-2 antigens directly into patients' cells, provoking a robust immune response. But will pre-existing immunity from common colds take them down?  Six vaccine candidates in clinical trials for COVID-19 employ viruses to deliver genetic cargo that, once inside our cells, instructs them to make SARS-CoV-2 protein. This stimulates an immune response that ideally would protect recipients from future encounters with the actual virus. Three candidates rely on weakened human adenoviruses to deliver the recipe for the spike protein of the pandemic coronavirus, while two use primate adenoviruses and one uses measles virus. Most viral vaccines are based on attenuated or inactivated viruses. An upside of using vectored vaccines is that they are easy and relatively cheap to make. The adenovirus vector, for example, can be grown up in cells and used for various vaccines. Once you make a viral vector, it is the same for all vaccines, says Florian Krammer, a vaccinologist at the Icahn School of Medicine at Mount Sinai. “It is just the genetic information in it that is different,” he explains. Once inside a cell, viral vectors hack into the same molecular system as SARS-CoV-2 and faithfully produce the spike protein in its three dimensions. This resembles a natural infection, which provokes a robust innate immune response, triggering inflammation and mustering B and T cells. But the major downside to the human adenoviruses is that they circulate widely, causing the common cold, and some people harbor antibodies that will target the vaccine, making it ineffective.

CanSino reported on its Phase II trial this summer of its COVID-19 vaccine that uses adenovirus serotype 5 (Ad5). The company noted that 266 of the 508 participants given the shot had high pre-existing immunity to the Ad5 vector, and that older participants had a significantly lower immune response to the vaccine, suggesting that the vaccine will not work so well in them. “The problem with adenovirus vectors is that different populations will have different levels of immunity, and different age groups will have different levels of immunity,” says Nikolai Petrovsky, a vaccine researcher at Flinders University in Australia. Also, with age, a person accumulates immunity to more serotypes. “Being older is associated with more chance to acquire Ad5 immunity, so those vaccines will be an issue [with elderly people],” Krammer explains. Moreover, immunity against adenoviruses lasts for many years. “A lot of people have immunity to Ad5 and that impacts on how well the vaccine works,” says Krammer. In the US, around 40 percent of people have neutralizing antibodies to Ad5. As part of her work on an HIV vaccine, Hildegund Ertl of the Wistar Institute in Philadelphia previously collected serum in Africa to gauge resistance levels to this and other serotypes. She found a high prevalence of Ad5 antibodies in sub-Saharan Africa and some West African countries—80 to 90 percent. A different group in 2012 reported that for children in northeast China, around one-quarter had moderate levels and 9 percent had high levels of Ad5 antibodies.  “I don’t think anyone has done an extensive enough study to do a world map [of seroprevalence],” notes Ertl. 

J&J’s Janssen is using a rarer adenovirus subtype, Ad26, in its COVID-19 vaccine, reporting in July that it protects macaques against SARS-CoV-2 and in September that it protects against severe clinical disease in hamsters. Ad26 neutralizing antibodies are uncommon in Europe and the US, with perhaps 10–20 percent of people harboring antibodies. They are more common elsewhere. “In sub-Saharan Africa, the rates are ranging from eighty to ninety percent,” says Ertl. Also critical is the level of antibodies in individuals, notes Dan Barouch, a vaccinologist at Beth Israel Deaconess Medical Center and Harvard Medical School. For instance, there was no neutralizing of Ad26-based HIV and Ebola vaccines in more than 80,000 people in sub-Saharan Africa, he says. “Ad26 vaccine responses do not appear to be suppressed by the baseline Ad26 antibodies found in these populations,” because the titres are low, Barouch writes in an email to The Scientist. Barouch has long experience with Ad26-based vaccines and collaborates with J&J on their COVID-19 vaccine. The Russian Sputnik V vaccine, approved despite no published data or Phase 3 trial results, starts with a shot of Ad26 vector followed by a booster with Ad5, both of which carry the gene for the spike protein of SARS-CoV-2. This circumvents a downside of viral vector vaccines, specifically, once you give the first shot, subsequent injections will be less efficacious because of antibodies against the vector. Ertl says she has no idea of the proportion of the Russian population with Ad26 or Ad5 antibodies, and there seems to be little or no published data from countries that have expressed interested in this virus, such as Venezuela and the Philippines...

British drugmaker AstraZeneca says it has started Phase 3 trials of its coronavirus vaccine candidate in the United States. The vaccine, AZD 1222, is the third to enter large-scale trials in the United States, after vaccines made by Moderna and Pfizer/BioNTech. The vaccine, developed in partnership with Oxford University, has the backing of the US federal government. Rivals Moderna and Pfizer/BioNTec already have Phase 3 trials under way, also with federal government funding. AstraZeneca said it is "recruiting up to 30,000 adults aged 18 years or over from diverse racial, ethnic and geographic groups who are healthy or have stable underlying medical conditions, including those living with HIV, and who are at increased risk of infection from the SARS-CoV-2 virus."  Participants will receive two active or placebo doses, spaced four weeks apart. Currently, Phase 3 trials of AstraZeneca's vaccine are going on in Britain, Brazil and South Africa. Trials are also planned for Japan and Russia.

The day after data appeared from the vaccine maker Sinovac showed complete protection of rhesus monkeys by their vaccine candidate (whole inactivated SARS-CoV-2 virus particles), scientists from the Jenner Institute in Oxford issued a press release announcing that their vaccine (an adenovirus vector based vaccine that carried the SARS-CoV-2 spike protein) worked to protect rhesus monkeys and that they were moving forward with large scale human safety trials. At the time, the substantiating data was not available. Now it is, in the form of a May 13 BioRxiv preprint. Does the data support the claim?

Not really. All of the vaccinated monkeys treated with the Oxford vaccine became infected when challenged, as judged by recovery of virus genomic RNA from nasal secretions. There was no difference in the amount of viral RNA detected from this site in the vaccinated monkeys as compared to the unvaccinated animals. Which is to say, all vaccinated animals were infected. This observation is in marked contrast to the results reported from Sinovac trial. At the highest dose studied, no virus was recovered from vaccinated monkeys from the throat, lung, or rectum of the vaccinated animals. 

There is a second troubling result of the Oxford paper. The titer of neutralizing antibody, as judged by inhibition of virus replication by successive serum dilutions as reported is extremely low. Typically, neutralizing antibodies in effective vaccines can be diluted by more than a thousand fold and retain activity. In these experiments the serum could be diluted only by 4 to 40 fold before neutralizing activity was lost. Again, by contrast the titer of neutralizing antibodies in the serum of those vaccinated with whole inactivated SARS-CoV-2 was high. What then is the argument for pressing forward with the adenovirus vector SARS-CoV-2 spike protein vaccine? The authors present evidence to the effect that, although the vaccine did not protect the animals from infection, it did moderate the disease....

Preprint of the Study Discussed Available at bioRxiv:

https://doi.org/10.1101/2020.05.13.093195

The first human trials of a coronavirus vaccine developed by researchers at the University of Oxford will start today in the U.K. Making the announcement at a recent press briefing, U.K. government Health Secretary Matt Hancock pledged £20 million in government funding to support Oxford University’s ChAdOx1 nCoV-19 coronavirus vaccine program, and another £22.5 million to fund Phase II testing of a coronavirus vaccine in development by Imperial College London, which is projected to start human testing in June. The Imperial College London funding will also be used to help prepare for Phase III studies. “We will throw everything we’ve got at developing a vaccine,” Hancock added. “The U.K. is at the forefront of the global effort … and for all of the efforts around the world, two of the leading vaccine developments are taking place here at home, at Oxford and Imperial.”

The start of human testing in the U.K. coincides with Germany’s regulator, the Paul-Ehrlich-Institut, giving German biotech BioNTech and partner Pfizer the green light to start the first coronavirus vaccine clinical trial in the country. “This is the fifth authorized clinical trial worldwide in which a preventive specific COVID-19 vaccine candidate is tested in humans,” the Federal Institute for Vaccines and Biomedicines said. The Phase I/II study will evaluate the BNT162 vaccine program. Clinical trials are also expected to start in the United States upon regulatory approval, which is anticipated shortly, Pfizer said. The first part of the clinical study in Germany will test variants of the vaccine in 200 healthy volunteers aged 18–55 years. The second part of the study will be expanded to include volunteers who are at an increased risk of infection or increased risk of serious COVID-19 disease.