In keynote addresses at UAB’s COVID-19 Research Symposium, Anthony Fauci, M.D., and Kathleen Neuzil, M.D., shared the latest science on how COVID-19 spreads and the safety and efficacy of vaccines in late-stage trials.The fall COVID-19 Research Symposium at UAB, held Oct. 28, shined new light on the astounding progress that scientists have made toward understanding and stopping the deadliest pandemic to sweep the globe in more than a century.
The heart of that discussion was a series of presentations by UAB investigators on their clinical and basic science studies directed against crucial immunological questions, the development of cutting-edge diagnostic tests and the search for effective treatments for patients. UAB experts in health disparities shared the unique efforts that have been developed to bring testing and care to the communities hardest hit by the virus, and to find new solutions to address the disparities themselves in the long term. (Read a summary of these UAB presentations here.)
Bookending these presentations were keynote addresses by two of the foremost protagonists in the fight against COVID-19 worldwide.
Anthony Fauci, M.D., director of the NIH’s National Institute on Allergy and Infectious Diseases and a lead member of the White House Coronavirus Task Force, began the proceedings. In his talk, Fauci offered a fascinating summary of what researchers have learned about the origins of SARS-CoV-2, the virus that causes COVID-19, and how it spreads.
The symposium concluded with a keynote address from Kathleen Neuzil, M.D., director of the Center for Vaccine Development at the University of Maryland School of Medicine, who plays a leading role in vaccine development efforts against COVID-19 and is the only American member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization. In her talk, Neuzil gave an up-to-the-minute report on the status of the six COVID-19 vaccines being developed in the United States as part of the federal Operation Warp Speed project. She also explained the factors that are allowing vaccine development to be dramatically accelerated for COVID-19 while maintaining safety.
Answers to pressing questions
In their talks, Fauci and Neuzil provided answers — or, at least, intriguing evidence — for some of the most pressing questions on the planet, including:
- Where are you at highest risk for COVID-19 infection?
- Who is spreading COVID-19?
- What are the most common COVID-19 symptoms?
- Who is at highest risk for poor outcomes from COVID-19?
- Why do vaccine experts believe a COVID-19 vaccine developed so much faster than any previous vaccine can be safe?
- When can we expect a COVID-19 vaccine?
- What do the current data show about the safety and effectiveness of these vaccines in clinical trials?
Here are some highlights of these fascinating presentations.
Watch Dr. Fauci's presentation starting at 11:04 in the video above.
Fauci: Where are you at highest risk for COVID-19 infection?
“The risk of transmission varies by the type and duration of exposure, as well as other factors such as the viral load in the upper respiratory tract,” Fauci said. The prevention methods used by an infected person and people exposed to that person also play a role.
Transmissions are most common, Fauci said:
- among household contacts
- in gatherings or health care settings when PPE is not used
- in closed settings such as cruise ships, nursing homes and prisons
No sneeze or cough? COVID could still be spreading.
“It is important to point out that you do not need to sneeze or cough to transmit” the virus, Fauci noted. “It is transmitted by singing, by speaking loudly or even by breathing heavily.”
Restaurants, bars seem to be sources of spread
Fauci displayed data from a Centers for Disease Control and Prevention study of more than 300 people who had developed symptoms and were tested for COVID-19 at one of 11 health care facilities around the country in the month of July. Roughly half tested positive for COVID-19, and the other half, used as a control group, tested negative.
Researchers asked both groups a series of questions about their activities and possible exposures in the two weeks before their symptoms began.
- 42% of people with a positive test had known exposure to someone positive with COVID-19 in the past two weeks.
- People who tested positive for COVID-19 were more than twice as likely to have eaten at a restaurant as those who tested negative.
When the researchers focused on those people who tested positive but did not have exposure to someone known to have COVID-19, the odds of their having been to a bar or coffee shop were four times higher than for those who tested negative, and odds of their having been to a restaurant were three times higher.
Fauci: Who is spreading COVID-19?
|
“It is important to point out that you do not need to sneeze or cough to transmit” the virus, Fauci noted. “It is transmitted by singing, by speaking loudly or even by breathing heavily.” |
“A very important component of this infection is that about 40-45% of the people who are infected are in fact asymptomatic,” Fauci said, based on a review of data from more than 45,000 cases in 16 cohort studies. Fauci also pointed to a modeling study published in July that estimated that more than 50% of COVID transmissions were from individuals without symptoms.
These data lead to “the very strong recommendation that I and my colleagues have been putting forth for some time now” on the fundamentals of avoiding COVID-19 and reducing transmission, Fauci said:
- universal wearing of masks or cloth coverings
- maintaining physical distance
- avoiding crowds and congregate settings (“This is particularly important, and even more important when you are talking about indoors,” Fauci said. “In that regard, try to do things outdoors much more favorably than indoors.”)
- frequent handwashing
Fauci: What are the most common symptoms?
The clinical manifestations of COVID-19 are “protean,” Fauci said, meaning they can vary widely from person to person. But there are certain symptoms that occur frequently. “Early clinical manifestations are very similar to what we call a flu-like syndrome,” he said.
Fever – 83-99%
Cough – 59-82%
Fatigue – 44-70%
Loss of appetite – 40-84%
Shortness of breath – 31-40%
Muscle aches – 11-35%
(Source: World Health Organization)
“For those who do develop symptoms, they are mild to moderate in about 80% of individuals,” Fauci said. “But 15-20% of people have severe to critical manifestations.”
Fauci: Who is at highest risk for poor outcomes from COVID-19?
Older adults: “The people who are at increased risk for severe COVID-19 illness are, first, older adults,” Fauci said. A chart of the cumulative rates of hospitalization per 100,000 population across age groups “is very telling,” Fauci said.
Ages 85+ – 915
Ages 75-84 – 608
Ages 65-74 – 382
Ages 50-64 – 281
Ages 40-49 – 186
Ages 30-39 – 128
Ages 18-29 – 83
Ages 5-17 – 11
Ages 0-4 – 19
People of any age with certain underlying medical conditions: “Paramount among these are obesity, heart conditions and chronic obstructive lung disease,” Fauci said.
Minority populations are at far higher risk
“Very important are the racial and ethnic disparities that we see in the United States where African American and Latinx have a higher incidence of infection in the first place, usually on the basis of the jobs they generally have, putting them out in society in contact with people, and the increased prevalence and incidence of the comorbidities that they have, much more out of proportion compared to the general population,” Fauci said.
Fauci then presented data on the rates of hospitalization per 100,000 population:
Hispanic/Latino – 387
American Indian/Alaska Native – 377
Black, Non-Hispanic – 376
Asian/Pacific Islander – 114
White, Non-Hispanic – 86
Watch Dr. Neuzil's presentation starting at 3:37:45 in the video above.
Neuzil: Why do vaccine experts believe a COVID-19 vaccine developed so much faster than any previous vaccine can be safe?
“This is an incredibly fast-moving field,” said Kathleen Neuzil as she began her presentation, titled “Coronavirus Vaccines Update.”
The focus of “all vaccines in any stage of clinical development,” Neuzil said, is the spike proteins that line the outside of the SARS-CoV-2 virus. These spikes “undergo substantial rearrangement to fuse the viral membrane with the host cell membrane,” she said. “We are learning more and more that a conformationally correct protein is critical to generate antibody-mediated immunity.”
Vaccine development is typically a lengthy, risky and expensive process that can last anywhere from 15 to 20 years. “So how are we safely reducing this to 18 months?” Neuzil said. There are two answers: One is science, and the other is an influx of resources, she explained.
On the science front, the rapid availability of the SARS-CoV-2 gene sequence means “we can take a vaccine we know how to manufacture and substitute a [genetic] sequence and do everything else the same way,” Neuzil said.
| “If you have a 50,000-person trial, you can get an answer in four months” as opposed to years for a typical trial, Neuzil said. That is simply because, with 50,000 people participating, it will take far less time for the events of interest to occur (statistical evidence that people who receive a vaccine have fewer or less severe infections than people who receive a placebo), Neuzil said. “Safety is not being compromised.” |
The influx of funding, international scientific cooperation and public-private partnerships means that phases that normally take years and happen in sequence can be overlapped to shorten the time required. Whereas manufacturers typically proceed slowly with the testing process because of the significant financial investment required for vaccine development, government guarantees to purchase doses have allowed companies to start up large-scale manufacturing processes “right from the beginning,” Neuzil said. These resources also allow for massive trials, involving up to 50,000 people, compared to a standard of 5,000 to 10,000 normally used in vaccine testing.
“If you have a 50,000-person trial, you can get an answer in four months” as opposed to years for a typical trial, Neuzil said. That is simply because, with 50,000 people participating, it will take far less time for the events of interest to occur (statistical evidence that people who receive a vaccine have fewer or less severe infections than people who receive a placebo), Neuzil said. “Safety is not being compromised.”
Neuzil and Fauci: When can we expect a vaccine?
There are a number of vaccine platforms being tested, Neuzil said, and they take varying amounts of time to move into production.
DNA- and RNA-based vaccines move the fastest. They have not yet been used for vaccines for other diseases, but “that’s largely not a science question but a business question,” Neuzil said. “If we already have eight to 10 different flu vaccines on the market, why invest to take a messenger RNA flu vaccine all the way to market?”
Replicating viral vectors, such as adenoviruses, have already been licensed and are used for other vaccine types, Neuzil said. They proceed at a medium speed but are highly scalable, unlike the DNA and RNA platforms.
The longest development times are needed for protein-based, inactivated and live attenuated vaccines, which are also highly scalable but “need lots of work” in developing a properly weakened but still effective therapy, Neuzil said.
The support framework for COVID vaccine development in the United States starts with the U.S. government’s Operation Warp Speed, a body charged with strategic approach and resource allocation, plus the ACTIV public-private partnership for consultation and consensus building. Trial design and execution falls in the purview of the COVID-19 Prevention Network (mentioned by Fauci in his talk), which includes existing groups such as the Infectious Diseases Clinical Research Consortium, the HIV Vaccine Trials Network and the HIV Prevention Trials Network. “UAB has been a major player in this aspect,” Neuzil said.
There are six vaccines in development with Operation Warp Speed, Neuzil said. In his talk, Fauci noted that almost all are already in the large-scale phase 2/3 clinical trials:
- Moderna: mRNA (in phase 2/3)
- Pfizer: mRNA (in phase 2/3)
- AstraZeneca: Adenovirus vector (in phase 2/3)
- Janssen: Adenovirus vector (in phase 2/3)
- Novavax: recombinant protein + adjuvant (in phase 2/3)
- Sanofi: recombinant protein + adjuvant (in phase 1/2)
“I can predict, I believe with some degree of certainty, that by the end of November/beginning of December we will know — based on the size of the trial and the rate of infections that are ongoing in this country — we will know if we have a safe and effective vaccine,” Fauci said. “I feel cautiously optimistic that we will have a safe and effective vaccine, even though you can never make absolute predictions when it comes to vaccinology. The reason I feel cautiously optimistic is that the data from the animal models as well as the early data that we got from the phase 1 trials showed that these candidates induce a degree of neutralizing antibody that is comparable if not exceeding what we see in natural infection in convalescent plasma.”
Neuzil: What do the current data show about the safety and effectiveness of these vaccines in clinical trials?
Preliminary reports about some of the vaccines have already been published, Neuzil said. Overall, “I can tell you these are more reactogenic” [that is, generating an immune response] than is typically seen in vaccines, she said. Some participants have had fevers in response to the vaccine, “particularly after a second dose,” she said. The most severe reactions were seen in early trials at high doses that were not used in later trials.
A report on phase 1 trials of Moderna’s vaccine was published published in the New England Journal of Medicine in July. Two doses of the vaccine will be needed to get the needed neutralizing antibody response with the Moderna vaccine, “but when you get it, it is similar in younger and older participants,” she said.
The mRNA vaccines, such as Moderna’s, “are furthest in testing and most likely to be approved first,” Neuzil said. “We see antibody responses after dose 1 and neutralizing antibodies after dose 2.”
With the AstraZeneca vaccine, which is delivered by adenovirus, “we see neutralizing responses ... after two doses,” Neuzil said. The phase 3 trial of this vaccine was paused after a neurological condition was seen in a participant to allow time to investigate whether this was caused by the vaccine. “That hold is now lifted,” Neuzil said.
The Janssen vaccine, another adenovirus vector-delivered vaccine, is the only one being tested that will be used as a single dose. “To have a single-dose vaccine, where immunity occurs faster, could be of great benefit,” Neuzil said. The vaccine was paused by the sponsor because of an unexplained illness in a participant; but it has now been cleared to go forward, and the trial will restart any day, Neuzil said.
The Novavax vaccine, the last with publicly available data, is very similar to a flu or RSV vaccine, Neuzil said. “It is quite immunogenic ... it takes two doses and requires an adjuvant,” she added.
“Safety assessments have been difficult because this is a new disease with poorly understood immunity, rare complications and long-term sequelae that are not well elucidated,” all of which makes it hard to differentiate vaccine-enhanced illness or side effects from other causes, Neuzil said.
The accelerated development of vaccines with new vaccine platforms has been challenging, but results have been positive from the massive clinical trials that are underway. This is critical, Neuzil concluded. “There are 7.5 billion people in the world and 350 million people in the United States,” she said. “We need all of these vaccines to work, and we need them to be accessible, affordable and globally available.”
