Treat reports about a COVID-19 vaccine with an appropriate level of informed caution

An experimental coronavirus vaccine developed by Moderna provoked an immune response without major side effects in an early-stage clinical trial, scientists reported Tuesday in the New England Journal of Medicine. Moderna coronavirus vaccine shows promising results in early clinical trial:

The Phase I trial, conducted in partnership with the National Institute of Allergy and Infectious Diseases, enrolled 45 people who were given two doses of the vaccine in March and April. More than half of participants developed mild side effects, including chills and body aches, and three did not receive the second vaccine dose.

The vaccine is the first developed by a U.S. company to publish clinical trial results. Moderna, which has received more than $500 million from the government to develop its shot, released partial results on 8 of the 45 trial participants in a press release in May.

What it means: Participants received either a low, medium or high dose of the vaccine. Those who in all three groups who received both shots eventually produced “high levels of neutralizing antibody activity” that may keep Covid-19 at bay, the scientists reported. The antibody levels were similar to those seen in people who recovered from coronavirus infections.

But wait: The development of the antibodies is not direct proof that the vaccine works. Determining that will require a final, Phase III clinical trial.

What’s next: Researchers began enrolling participants in a Phase II trial in late May to further study the vaccine’s safety and its ability to produce an immune response.

Moderna plans to start a Phase III trial on July 27 to determine whether the vaccine can prevent coronavirus infection. That trial — conducted with help from NIAID and the federal government’s Operation Warp Speed initiative — will eventually enroll 30,000 people.

Vanderbilt University Medical Center staff scientist and protein chemistry expert Sanjay Mishra explains what the results of the Phase 1 trial mean. An infectious disease expert explains the results from Moderna’s latest vaccine trials:

What was Moderna testing for?

They were testing for two things – the proof of concept, and whether there are any side effects.

What were the results?

The results that just came out in the New England Journal of Medicine are interim. We have to be really clear about it.

This particular batch of results is from 45 adults between the ages of 18 and 55 who were not screened for infection [for COVID-19]. So we would call them healthy adults, although no serology or PCR (polymerase chain reaction) tests were done before the trial began.

They were given one of the three doses – 25, 100 or 250 micrograms. More than half the participants had discomfort, like fatigue, chills, headaches, myalgia (muscle pain) and pain at the injection site. After 28 days, the exact same dose was given a second time. After the second dose, these events of discomfort were far more common. But in general, you can say there was nothing severe reported. And then on the 29th day, blood was drawn.

These blood samples were tested for their antibody response. They found that the antibody responses, as you would expect, were higher with the higher dose. They were slightly higher than what you would expect to see in patients who had been recovering from a coronavirus infection.

They tested these things in three different ways. One of these is where you are testing the quantity of antibodies made. Then they also tested the efficacy of these antibodies in the serum through two different methods. All in all, it does seem that there is binding and neutralization of the virus.

But the second batch of results, which is from the older patients, has still not been announced. So that would be coming farther down the line. After that, they hope to come up with the third batch of results, which will include the durability of immunity from both of these age groups in one batch.

What conclusions can we draw?

The results are promising. At least they proved the concept. The results show that when you give this vaccine, the body makes antibodies. But we don’t know whether those antibodies will lead to immunity in the body because all of the results that we have are observed outside the body [in blood samples].

And so that proof will come from a larger data set in the next stage. Then we would know whether the people who have received these vaccines are at least 50% less likely to become infected [to meet FDA guidelines for vaccine efficacy]. So they are good results, they are promising results, but they are pretty early in the game, so to speak.

How did you feel when you heard the news?

I feel cautiously optimistic. The study provides promising data on the safety and immunogenicity, or the ability to provoke an immune response. It is a good starting point for training the immunity of the body. But if I can paraphrase Robert Frost, we still have miles to go before we sleep.

Vaccine development is complex and there’s a lot more work that needs to be done before this can become an actual marketable candidate.

This first batch of data is from the 18- to 55-year-old group. We do not know what the dosing would be for the older age group, which is the most vulnerable to COVID-19. As we age, we do not produce as many antibodies, which generally leads to poor vaccine response. So the question is: Will they have to go for a higher dose, which is usually the case in flu vaccines. The higher dosage, which is 250 micrograms, has led to somewhat more severe side effects in this study. So then how would that be balanced? It is still difficult to say.

What other vaccines are being developed?

There are 178 COVID-19 vaccines in various stages of development and 14 are leading to human trials, including from AstraZeneca and others. There are more potential candidates from Merck, Johnson & Johnson and others. There is a similar vaccine that is already being tested by Pfizer and BioNTech, and that has also shown positive results at the lower doses.

Since the beginning of research into COVID-19, there have been a number of anecdotal reports that those who have had the virus and recovered can be reinfected a second time, which causes concern about the length of time that any antibodies the body may produce may last and provide protection.

A new research paper released on the medical server medrxiv.org on Saturday, and not yet published in a peer-reviewed medical journal, suggests that antibody responses may start to decline 20 to 30 days after Covid-19 symptoms emerge. Covid-19 immunity from antibodies may last only months, UK study suggests:

After people are infected with the novel coronavirus, their natural immunity to the virus could decline within months, a new pre-print paper suggests.

“We show that IgM and IgA binding responses decline after 20-30 days,” the researchers from institutions in the United Kingdom wrote in the paper, which also found that the severity of Covid-19 symptoms can determine the magnitude of the antibody response.

The new study included samples collected from 65 patients with confirmed Covid-19 up to 94 days after they started showing symptoms and from 31 health care workers who had antibody tests every one to two weeks between March and June.

In general, it can take one to three weeks after infection for your body to make antibodies, according to the US Centers for Disease Control and Prevention.

Since early on in the pandemic, the World Health Organization has warned that people who have had Covid-19 are not necessarily immune from getting the virus again.

Yet the new study had some limitations, including that more research is needed to determine whether similar results would emerge among a larger group of patients and what data could show over longer periods of time when it comes to infection with the coronavirus, named SARS-CoV-2.

“This study has important implications when considering protection against re-infection with SARS-CoV-2 and the durability of vaccine protection,” the researchers wrote in the paper.

What this means for a Covid-19 vaccine

Even though it has yet to be peer reviewed, “the importance of this study is clear and the research has been rigorously undertaken,” Stephen Griffins, associate professor in the University of Leeds School of Medicine in the United Kingdom, who was not involved in the new study, said in a written statement distributed by the UK-based Science Media Centre on Monday.

“This work confirms that protective antibody responses in those infected with SARS-COV2, the coronavirus that causes COVID-19, appear to wane rapidly. Whilst longer lasting in those with more severe disease, this is still only a matter of months,” Griffins said.

“Similar short-lived responses are seen against other human coronaviruses that predominantly cause only mild illness, meaning that we can be re-infected as time goes by and outbreaks can adopt seasonality. With the more serious, sometimes fatal, outcomes of SARS-COV2, this is troubling indeed,” Griffins said. “Vaccines in development will either need to generate stronger and longer lasting protection compared to natural infection, or they may need to be given regularly.”

As of Monday, there were 23 Covid-19 candidate vaccines in clinical evaluation globally, according to WHO.

“[T]his study does reinforce the message that we can’t assume someone who has had COVID-19 can’t get it again just because they initially became antibody positive,” said Maini, who was not involved in the study. “It also means a negative antibody test now can’t exclude you having had COVID-19 a few months ago. And it suggests vaccines will need to be better at inducing high levels of longer lasting antibodies than the natural infection or that doses may need to be repeated to maintain immunity.”

‘Incomplete, transitory and then disappear’

The new paper adds to a growing body of evidence suggesting that natural immunity to Covid-19 with antibodies may not last as long as hoped — and that the level of severity of the initial coronavirus infection can be linked to the magnitude of antibody response.

In June, a small study found that people who have coronavirus infections but never develop symptoms could have weaker immune responses to the virus.

That study, published in the journal Nature Medicine, found that a group of about three dozen Covid-19 patients who were asymptomatic had levels of antibodies that were significantly lower than what was found among patients who had mild symptoms — a finding that suggests the asymptomatic patients had weaker immune responses.

Then last week, a Spanish government study found that just 5% of people in Spain have coronavirus antibodies and in a potentially worrying development, the study also indicated that people’s immunity to coronavirus wanes after just a few weeks. The findings show that 95% of Spain’s population remains susceptible to the virus.

This means that any perceived immunity “can be incomplete, transitory and then disappear,” Dr. Raquel Yotti, head of the Carlos III Health Institute, a key government agency leading the study, said in a news conference at the time.

The study “reflects the difficulty of obtaining herd immunity in the short term,” the Health Ministry said in a statement. Herd immunity is achieved when enough of a population has become infected with a virus or bacteria — or vaccinated against it — to stop its circulation.

Spain’s study from April to June involved more than 61,000 participants — which the European Center for Disease Prevention and Control told CNN appears to be the largest to date in Europe.

I have noticed a troubling tendency of the pharmaceutical companies working on a COVID-19 vaccine to release press releases, breathlessly reported by the media, of small studies that have produced some early positive results. It is often not a peer-reviewed study.

The real test of a vaccine comes in the Phase III study, where patients are tracked for several years to determine the efficacy and safety of the vaccine. Researchers have been given the approval to skip this lengthy tracking requirement because of the emergency that COVID-19 presents to the world. Which means that a vaccine rushed to approval for public use may not prove effective over time, or may produce side effects that are unknown at the time of approval because there has not been adquate tracking of patients over time.

Merck CEO Ken Frazier says Big Pharma Exec Says Lawmakers Touting Vaccine By Year’s End Doing ‘Grave Disservice’:

The CEO of one of America’s largest pharmaceutical companies issued a bleak warning about the prospect of a vaccine for the novel coronavirus by the end of the year, saying lawmakers touting the possibility were doing a “grave disservice to the public.”

Ken Frazier, the CEO of Merck, made the comments in an interview with Harvard Business School last week. He directly targeted politicians who have asserted that a vaccine is around the corner, without naming President Donald Trump, saying such statements were premature and “actually tell the public not to do the things that the public needs to do.”

“What worries me the most is that the public is so hungry, so desperate to go back to normalcy, that they are pushing us to move things faster and faster,” Frazier said during an interview last week with Harvard professor Tsedal Neeley. “But ultimately, if you’re going to use a vaccine in billions of people, you better know what that vaccine does.”

He said that Merck’s most recent vaccine against Ebola took more than five years to produce, saying such research “requires a rigorous scientific assessment.”

“And here we didn’t even understand the virus itself or how the virus affects the immune system,” he continued.

Merck is one of the largest pharmaceutical companies in the world and has been working alongside dozens of other major research groups to develop a vaccine to the coronavirus. Medical officials have stressed that even with social distancing measures, society will only be able to return to a pre-pandemic normal with an appropriate vaccine of therapeutic treatment for those that contract COVID-19.

Trump has repeatedly stressed that a vaccine is not far off, saying this month three efforts “are really, really looking good” and “we think we’re going to have it soon.” The White House has funneled resources into an effort called “Operation Warp Speed” to do so, and while some trials have shown promise, there are still many unanswered questions.

“I think when people tell the public that there’s going to be a vaccine by the end of 2020, for example, I think they do a grave disservice to the public,” Frazier said last week. “I think at the end of the day, we don’t want to rush the vaccine before we’ve done rigorous science. We’ve seen in the past, for example, with the swine flu, that that vaccine did more harm than good.”

“We don’t have a great history of introducing vaccines quickly in the middle of a pandemic,” he added.

You should treat the over-excited hype from media types in reporting on these vaccine studies with an appropriate level of informed caution that reporters frequently fail to exhibit. It may be a long time before there is a safe and effective vaccine for COVID-19, if ever. Don’t be fooled by the hype over early studies.

UPDATE 7/20/20: A coronavirus vaccine from Oxford University and AstraZeneca, perhaps the most promising candidate currently in development, appears to be safe and produces an immune response, according to preliminary findings published in The Lancet.

The Oxford vaccine is in phase three trials, the last step before possible approval. According to the Economist, it could be cleared for emergency use as early as October.