As of Aug. 20, 30 vaccines were being tested in people and another 139 were under development in laboratories, according to the World Health Organization (WHO). Biotech and pharmaceutical companies have partnered with universities and governments to develop vaccines, an important tool for controlling the virus.
As journalists work to keep communities informed about COVID-19 vaccines, they need to consider questions about safety, distribution and adoption.
Below we address three specific questions, focusing on policies and processes in the U.S.:
1) How will the U.S. Food and Drug Administration decide COVID-19 vaccines are safe for distribution in this country?
2) What can state and federal government agencies do to plan for distributing COVID-19 vaccines to the public?
3) What will governments and public health organizations do to encourage widespread use of COVID-19 vaccines when they become available?
Worldwide, more than 789,000 people have died from COVID-19, also called SARS-CoV-2, as of Aug. 21, including more than 172,000 in the U.S., according to WHO estimates. Businesses around the globe have had to shut down or limit operations. The worldwide fallout from the pandemic is likely to result in “rising levels of poverty, lives upended, careers derailed, and increased social unrest,” according to an August report from the Congressional Research Service (CRS), titled ”Global Economic Effects of COVID-19.” (CRS provides in-depth reports for members of Congress to use in drafting legislation. Their reports are available to the public.)
“All of us are seeking any ray of hope we can find in this time of pandemic, which is why our ears perk up every time we hear about or read news reports that suggest a COVID-19 vaccine is right around the corner,” said Susan Bailey, the president of the American Medical Association, in an Aug. 10 video conversation with Steve Hahn, commissioner of the U.S. Food and Drug Administration.
But the reality remains that developing, testing, manufacturing and distributing vaccines involves complicated and time-consuming processes. Amid a rush to develop COVID-19 vaccines, safety has to remain the priority, Bailey told Hahn.
“We cannot sacrifice the trust and wellbeing of our patients in our eagerness to develop a cure for this virus,” she said. “We can’t seek to end one health crisis by inviting another.”
How will the U.S. Food and Drug Administration determine whether COVID-19 vaccines are safe for distribution?
The FDA is the gatekeeper that decides which medical treatments can be used and marketed in the U.S. The agency requires such products to undergo several rounds of testing and for a larger number of people to be enrolled in these trials as the trials advance through stages, known as Phase 1, Phase 2 and Phase 3. These phases can be combined in urgent situations, such as a pandemic.
Several vaccines have already reached the last stage of testing. Researchers are trying, for example, to recruit 30,000 people for a Phase 3 trial of a vaccine developed by the Cambridge, Mass.-based biotechnology company Moderna and the National Institutes of Health. (The NIH’s Clinicaltrials.gov site lets the public keep tabs on the progress of these trials as well as other medical studies.)
Earlier this month, Russian President Vladimir Putin announced that his nation had become the first in the world to approve a coronavirus vaccine for widespread use. But this approval was based only on preliminary research, National Institutes of Health Director Francis S. Collins told reporters during an Aug. 13 conference call. Collins said the Russian plan was to conduct a Phase 1 trial with roughly 100 people and then claim victory in developing a COVID-19 vaccine.
“If that was the standard, we would have declared success several months ago,” Collins said.
But clearing Phase 1 is only the start of the pathway toward a medical treatment, Collins said.
“If you really want people to believe in the vaccine as being safe and being effective, it needs to be tested in much larger groups, as we are now doing in the Phase 3 trials, which will be the way we really answer that question,” Collins explained to those gathered for the call, organized by the U.S. Department of Health and Human Services.
In almost all medical research, scientists have to make educated guesses about how well findings for the group of patients they have studied applied to larger populations. That’s also true of FDA’s approvals of new medical treatments.
The number of patients who receive experimental drugs and vaccines in testing usually represents a fraction of the larger group of people likely to get a treatment after FDA approval. The federal agency must consider the likelihood people will suffer serious side effects when a treatment is used more widely.
For example, GlaxoSmithKline, a pharmaceutical company headquartered in England, submitted an application for Shingrix, a shingles vaccine, to the FDA’s Center for Biologics Evaluation and Research (CBER) on Oct. 21, 2016. GlaxoSmithKline sought approval for use of Shingrix for adults in the U.S. age 50 and older. But a U.S.-based pharmaceutical company, Merck & Co., had already sold a similar vaccine, reducing the urgency for the FDA to act.
The FDA required three stages of testing for the Shingrix application. Shingrix’s Phase 3 testing program involved more than 38,000 people, GlaxoSmithKline said. An analysis pooling Phase 3 results indicates Shingrix was effective against shingles in about 90% of cases across all age groups, GSK said.
The FDA brought the Shingrix application before a panel of its advisers, the Vaccines and Related Biological Products Committee (VRPBPC), on Sept. 13, 2017. Committee members voted unanimously in favor of the application. On Oct. 20, 2017, the FDA approved it, a day ahead of the agency’s target date.
The Shingrix application was not hurried. Even though shingles can be serious for people with compromised immune systems, this painful condition subsides within three to five weeks for most healthy people who receive treatment soon after an outbreak, according to the NIH.
The FDA started the clock on the Ebola vaccine review in July 2019 and set an initial target date of March 2020 to complete it. But the FDA completed the review well ahead of schedule — it announced its first-ever approval of an Ebola vaccine on Dec. 19, 2019. The approval was largely based on a study of 3,537 people who had either contracted Ebola or been in contact with those who had.
A Merck COVID-19 vaccine candidate, being developed with the International AIDS and Vaccine Initiative (IAVI), uses the same approach taken with the Ebola vaccine, Julie Gerberding, the company’s chief patient officer and executive vice president at Merck, said at a House hearing in July. This vaccine uses a modified form of a common animal virus, vesicular stomatitis virus, that is modified to express proteins that stimulate an immune response, IAVI says.
Johnson & Johnson also is working on a COVID-19 vaccine that borrows from an approach used in an Ebola vaccine. Johnson & Johnson’s Ebola vaccine was approved in Europe this year. Its vaccine is built upon an inactivated version of a common kind of virus, adenovirus.
But the Merck and Johnson & Johnson vaccines are not as advanced in testing as are ones employing experimental technologies that have yet to result in approved drugs for people.
One of the most advanced candidates is Moderna’s mRNA-1273. In developing this vaccine, Moderna scientists intend to use messenger RNA, which carries genetic instructions to try to make human cells produce specific proteins. These are intended to spur the immune system into action. Moderna spells out the speculative nature of its approach in its routine filings with the Securities and Exchange Commission (SEC), as biotech companies usually do. (SEC filings should be a go-to source for journalists reporting on biotechnology. In these forms, companies often provide clear descriptions of their technologies in language intended for a broad audience. The companies also outline possible pitfalls with their experimental medicines.The SEC offers an introduction to its forms here.)
“As a potential new class of medicines, no mRNA medicines have been approved to date by the FDA or other regulatory agency,” Moderna said in an August filing with the SEC.
Other organizations are looking to already proven methods for vaccine development.
Lawmakers and scientists have raised concerns about the pressure FDA officials will face to speed their decision on approving a COVID-19 application.
There are urgent medical and economic reasons for the agency to act fast to review the data accompanying applications for COVID-19 vaccines. The stated goal of President Donald Trump’s so-called Operation Warp Speed is to deliver 300 million doses of a safe and effective COVID-19 vaccine by January 2021.
Trump is seeking re-election on Nov. 3, prompting questions about whether he will pressure the FDA to clear a vaccine sooner.
At a July hearing, the chairman of the U.S. House Energy and Commerce Committee, Rep. Frank Pallone Jr., said he feared the Trump administration might force the FDA to approve an ineffective vaccine. “We all want a COVID-19 vaccine to be developed as soon as possible, but before a vaccine is distributed, public health experts must ensure that it is safe, effective, and available to all who need it,” said Pallone, a Democrat from New Jersey.
In this document, the FDA officials outlined their expected requirements for clearing a COVID-19 vaccine. They expect that a COVID-19 vaccine worthy of approval would appear to prevent infections or decrease their severity in at least 50% of people who get the shot. That 50% benchmark is part of the main goal — known as a primary endpoint — of vaccine studies conducted to meet the FDA’s approval. Those seeking approval must be able to answer the question of whether the shot reduces people’s chances for developing a COVID-19 infection.
Hahn, the FDA commissioner, addresses these concerns in an Aug. 7 viewpoint article in JAMA, “Unwavering Regulatory Safeguards for COVID-19 Vaccines.” Hahn and his co-authors explain why the agency took the unusual step of setting a target rate for effectiveness for COVID-19 vaccine applicants.
The speed at which experimental COVID-19 vaccines are being developed and tested “has provoked public anxiety about the safety and effectiveness of vaccines developed on expedited timelines,” Hahn and his co-authors write.
They cite a May poll of 1,056 U.S. adults, in which 31% indicated they were uncertain whether they would receive a potential COVID-19 vaccine and 20% indicated they would not take it.
“Given the widespread potential use of a COVID-19 vaccine, transparent discussion at FDA’s Vaccines and Related Biological Products Advisory Committee will be needed prior to vaccine authorization or licensure to ensure clear public understanding of the evidence supporting vaccine safety and efficacy,” Hahn and his co-authors write.
Calculating confidence intervals
Scientists usually must do educated guesswork to estimate the likelihood that their study findings reflect what patients will experience in the real world. A calculation known as the confidence interval estimate provides a range of numbers within which the true value likely exists. Confidence intervals, abbreviated as CI, can be set to 90% and 99%, but the 95% mark is most common in medicine.
A National Institutes of Health backgrounder explains the 95% confidence interval with the following hypothetical example: “If a study is 95% reliable, with a confidence interval of 47-53, that means if researchers did the same study over and over and over again with samples of the whole population, they would get results between 47 and 53 exactly 95% of the time.”
Hahn and his co-authors note in JAMA that the FDA will ask vaccine developers to provide evidence their vaccines have an effectiveness rate of at least 30%. The FDA also likely will require drug makers to report on how people fare after taking their vaccines following their initial approval. The agency often mandates post-marketing studies to keep tabs on the risks for complications, including serious health threats, from approved products.
The FDA tells companies what kinds of studies they need to fund for their approved products, seeking to learn more about their safety and effectiveness, the NIH’s Collins explained during a U.S. Senate hearing on July 2. Regulators may want to know information such as how long a COVID-19 vaccine will provide protection.
“You don’t stop looking once FDA has given an approval,” Collins said. “You carry out long-term studies to make sure that there’s not some unexpected results or that the drug stops working.”
It’s important to note that side effects sometimes are not detected until a medical treatment has been on the market for a while.
“The vaccine is safe, well-tolerated” and appears to spark a reaction in the immune system, Horton tweeted on July 20.
Califf responded, tweeting: “I know @richardhorton1 knows this, but for lay people viewing this, ‘safe’ in this context just means nothing bad happened that should pause larger trials. Safety of vaccines can only be determined by very large, controlled trials followed by serious post-market surveillance.”
I know @richardhorton1 knows this, but for lay people viewing this, “safe” in this context just means nothing bad happened that should pause larger trials. Safety of vaccines can only be determined by very large, controlled trials followed by serious post-market surveillance. https://t.co/T6ZD8TgkzK
Longtime health care journalist Gary Schwitzer highlights this exchange in his blog on HealthNewsReview.org, where he also offers tips and resources for journalists on avoiding hype in covering medical studies.
In a July commentary in JAMA, “Communicating Science in the Time of a Pandemic,” Schwitzer and Richard Saitz, a professor at the Boston University Schools of Medicine and Public Health, say the COVID-19 pandemic has triggered “perhaps the most challenging time for science communication in decades.”
“Races are underway in parallel: to find answers to perplexing coronavirus questions, to announce research findings to clinical and scientific colleagues, and to report those findings to a confused and concerned global audience,” write Schwitzer and Saitz.
“There are no winners in these races if harm — even though unintentional — is wrought by the dissemination of hurried, incomplete, biased misinformation,” they write.
2) What can state and federal government agencies do to plan for distributing COVID-19 vaccines?
In discussing vaccines, Trump has given far more optimistic estimates for COVID-19 vaccines than many scientists do.
“We’re balancing speed and safety, and we’re on pace to have a vaccine available this year, maybe far in advance of the end of the year,” Trump said during an Aug. 3 press conference.
“The rapid identification of immunogenic targets of a novel coronavirus, the leveraging of experimental vaccine platforms, and the tragic nature of an ongoing pandemic have created a fertile breeding ground for innovation,” they write. “Although the ultimate success of a vaccine candidate, or candidates, remains unknown, the changes in the field of vaccinology that these exigent circumstances have brought are likely here to stay.”
Already, many advocacy groups and academic researchers are wrestling with thorny questions about distributing vaccines, including the inevitable decisions about which groups of people should get COVID-19 vaccines first.
The National Governors Association on Aug. 3 issued a memorandum about preparing for an eventual mass distribution of these vaccines. Immunizing the U.S. population against COVID-19 “will likely require the single largest vaccination campaign ever undertaken” in the nation, the NGA said in the memo. “Although a vaccine is not yet available, lessons learned from the acquisition and distribution of COVID-19 diagnostics and therapeutics suggest that governors may want to begin addressing the challenges of mass distribution before its arrival,” the association wrote.
State leaders will rely on guidance from the national Centers for Disease Control and Prevention in making “difficult decisions” about prioritizing who should get the COVID-19 vaccine first, the NGA said in its memo.
3) What will governments and medical groups do to encourage widespread use of COVID-19 vaccines when they become available?
At the July 24 NAM meeting, Redfield spoke of a need to begin building public confidence in COVID-19 vaccines.
“I’m sure there will be many people who have different points of views,” with some unwilling to take them, as has happened with other vaccines, Redfield said. “We’re knee-deep in resistance.”
Researchers have begun to propose ideas for increasing uptake of future U.S.-approved COVID-19 vaccines. A July report from researchers at Johns Hopkins University and Texas State University offers many recommendations, including that each state establish a public oversight committee to review systems that influence understanding of COVID-19 vaccines. The report is the product of an initiative called the Working Group on Readying Populations for COVID-19 Vaccine, comprising more than 20 scientists and communications experts.
Michelle M. Mello, a professor of law and medicine at Stanford University, and her co-authors suggest in a June perspective article in the New England Journal of Medicine that state officials begin now to consider what options they might have in terms of possible mandates for vaccines for COVID-19.
“As with social distancing orders, we can expect that the advent of SARS-CoV-2 vaccines will spark intense clashes of feeling about what people owe to one another in the fight against the pandemic,” Mello and co-authors write in the article, “Ensuring Uptake of Vaccines against SARS-CoV-2.”
“Careful deliberation now about state vaccination policy can help ensure that we have a strategy when the breakthrough comes,” they write.
A resurgence of measles in recent years in the U.S. has been linked to parents opting not to have their children vaccinated. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, and his co-authors looked at some of the reasons children were not getting their measles shots in a perspective article published last year in the New England Journal of Medicine, “Measles in 2019 — Going Backward.”
“Although there are valid reasons why some people might not be vaccinated, such as a medical contraindication due to marked immunosuppression, the failure to vaccinate too often stems from misconceptions about vaccine safety, especially those resulting from a now-debunked claim that posited a connection between the vaccine and autism,” write coauthors Catharine I. Paules, Hilary D. Marston and Fauci.
Public officials were concerned about vaccine hesitancy long before COVID-19 emerged.
In a 2019 report, Sara M. Tharakan, a global health analyst at the Congressional Research Service, suggests U.S. lawmakers look into the effectiveness of global vaccination campaigns as “a tool of domestic pandemic preparedness” amid these outbreaks. Congress could look at ways in which the federal government could help raise vaccination rates, possibly through campaigns to battle misinformation, Tharakan writes.
The WHO last year included vaccine hesitancy on its list of top-10 global health threats, along with Ebola, the prospect of a global influenza pandemic and climate change.
In a March 2019 editorial in The Washington Post, a group of public health experts, including Barry R. Bloom of Harvard, Lawrence O. Gostin of Georgetown and Jonathan Fielding of the University of California, Los Angeles, noted how social media “is infected with viral messaging from bots and trolls that masquerade as legitimate information outlets but instead stoke illegitimate fear of vaccines.”
“The medical and public-health community has overwhelming scientific evidence that demonstrates the safety and effectiveness of vaccines,” they write. “Yet parents today can easily go to Google to find discredited anti-vaxxer pediatricians or find solace among anti-vaxxer ‘friends’ in Facebook groups full of misinformation.”
At an Aug. 6 press conference about the COVID-19 pandemic, Bloom, who is currently a research professor at the Harvard T.H. Chan School of Public Health, raised concern about the public’s unwillingness to receive a future vaccine to fight this coronavirus.
“My biggest concern right now is not that the vaccines won’t have sufficient efficacy to make it worthwhile distributing them, some of them, at least,” Bloom said. “It’s that people won’t take them.”