Moon Nahm, M.D., is testing a hypothesis as to why older patients with COVID-19 fare worse than younger patients: bad antibodies.Why does a person's risk for severe illness from COVID-19 increase with age? The trend is clear: 8 of 10 COVID-19 deaths reported in the United States has been in adults 65 or older, according to the Centers for Disease Control and Prevention (CDC). But many explanations, often competing, have been put forward to explain these data.
Moon Nahm, M.D., suspects the answer could be bad antibodies. Nahm, professor in the Division of Pulmonary, Allergy and Critical Care and director of UAB's Bacterial Respiratory Pathogen Reference Laboratory and the World Health Organization Pneumococcal Reference Laboratory, has studied antibodies for his entire career. "I'm an antibody guy," Nahm said.
As such, he has a hypothesis about the relationship between age and response to infection with SARS-CoV-2, the virus that causes COVID-19. "Older people have immune memory to other related viruses, and that memory prevents them from making the best antibodies against SARS-CoV-2," Nahm said. In addition to SARS-CoV-2, there are six other coronaviruses that are known to infect humans, including two that cause the common cold. A faulty immunological memory of infection in older people may bias their bodies to make antibodies that are not as effective at blocking SARS-CoV-2 from infecting their cells, Nahm said.
He will explore that hypothesis in a new project, Clonal Diversity of Human Antibodies to SARS-CoV-2 S-Protein, that was one of 10 awardees in the second round of UAB's funding for urgent high-impact COVID-19 research projects.
Send in the clones
Understanding antibody response to SARS-CoV-2 is important to vaccine development. When the immune system comes across a foreign object, or antigen, such as SARS-CoV-2, it sends pieces to the antigen-recognizing B cells. If one of those B cells recognizes SARS-CoV-2 (by binding to a part of it), it will produce millions of identical copies of an antibody — clones — against the invader. These clones then head out into the rest of the body, latch onto SARS-CoV-2 and mark them for destruction by other parts of the immune system.
Ideally, there would be only one exact match between an antigen and a B cell. In practice, more than one B cell may be able to bind to SARS-CoV-2, including memory B cells that may contain the pattern to recognize another coronavirus. Antibody clones produced by these memory B cells may be able to bind SARS-CoV-2 as well, but because the structure of the virus is not the same as the one they saw previously, these antibodies might not be very effective at eliminating the new viral threat.
A model of the SARS-CoV-2 spike protein. Nahm's project will catalog the different antibodies capable of binding to this protein in samples from patients with COVID-19. Image courtesy National Institutes of Health.To test his hypothesis, Nahm's lab is studying serum from patients who have been diagnosed with COVID-19. Most important, he will separate each individual antibody clone that shows reactivity to SARS-CoV-2 in those samples. The number of clones seen in each person varies, but probably ranges between five and 20, Nahm said. Studying antibody responses without taking this step, as other researchers have done, "is difficult because you are looking at the average behavior, rather than the behavior of individual clones," Nahm said.
"We have the capability in our lab of separating individual antibody clones using a technology called iso-electric focusing," Nahm said. Each clone has different electrical charge properties, Nahm explained. "We can take advantage of that to separate them and study each individual clone for its functional properties, such as protective properties or the ability to make an infection worse."
From $100 per dose to $2
Nahm's lab has the iso-electric focusing equipment and expertise, given his long history of working with pneumococcus, also known as Streptococcus pneumoniae, a bacterium that is the most common cause of bloodstream infections, pneumonia, meningitis and middle ear infections in young children, according to the CDC. Each year, an estimated 1.6 million people die from pneumococcal infections, primarily children and older adults.
UAB urgent research grants against COVID-19This study is one of 10 pilot projects recently funded by $402,000 in donations as part of the second round of UAB's urgent, high-impact COVID-19 grant initiative. This follows 14 projects funded in the first round of urgent, high-impact COVID-19 grants. |
It turns out that pneumococcus strains contain 100 different types of protective capsule, which the bacteria use to avoid recognition by the immune system. (Nine of those types were discovered by Nahm and his lab, including the 100th, reported in May 2020. Nahm is working on the 101st capsule type.) Making a new pneumococcus vaccine is an exercise in introducing antibodies that can recognize as many of these capsules as possible; current vaccines for adults target the 23 most dangerous capsule types, while childhood vaccines target the 13 that are most dangerous for young people.
Making pneumococcal vaccines cheaper — therefore expanding their use in developing countries — is one aim of Nahm's WHO Pneumococcal Reference Laboratory, which was called a "national treasure" in a National Institutes of Health review. The cost of pneumococcus vaccines "used to be $100 per dose – now the lowest is down to $2 per dose," Nahm said. The reduced costs are due, in large part, to the immunological tests developed by Nahm's lab.
"When you make a pneumococcal vaccine for the first time, you have to do extensive studies with Phase I, Phase II and Phase III clinical trials," Nahm said. "That takes five to 10 years, but the part that takes the most amount of time is Phase III, where you study thousands of people and then watch the effect of the vaccine over several years. Once we in the global research community found better ways to measure immune response to pneumococcal vaccines, we got together and said, we can just license the vaccine based on Phase I and II studies, as long as the proper immunological testing is done."
Understanding antibodies is essential
Nahm's lab invented, standardized and popularized these tests, which characterize the antibody clones generated in response to a vaccine, for pneumococcal vaccines. "That really reduces the cost and time necessary for vaccine production," he said.
| "A basic understanding of what kind of antibodies are made in response to SARS-CoV-2 is essential. One thing we are really worried about with a coronavirus vaccine is the antibodies made by the vaccine may not work. They may even make the situation worse." |
Similar tests could be crucial in helping develop and verify the safety of COVID-19 vaccines, Nahm said. "A basic understanding of what kind of antibodies are made in response to SARS-CoV-2 is essential," he noted. "One thing we are really worried about with a coronavirus vaccine is the antibodies made by the vaccine may not work. They may even make the situation worse."
One recent example is a vaccine against the dengue virus, which successfully completed clinical trials with a good safety profile in the early to mid 2010s. But after the Philippine government launched a mass immunization program with the vaccine in 2016, "it was found that the vaccine made infection worse in some people and it had to be pulled from usage," Nahm said.
Proper testing can help avoid such a disaster with COVID-19 vaccines. “This pilot funding from UAB will allow us to gather the data necessary for future grant applications to continue the work,” Nahm said.
