The urgency of understanding COVID-19 has been an unusual and intense time for researchers and scientists. While we are wearing masks, social distancing, and taking other measures to avoid infection with the SARS-CoV-2 virus, incredible work is going on behind the scenes in scientific laboratories, including at the Yale School of Medicine, where research on matters ranging from viral spread and severity of illness, to treatments to vaccines has been an important contributor globally. This is where researchers are putting in long hours to identify treatments, develop vaccines, and answer key questions: How does the virus replicate? How do variants develop? And how can we control them?
Researchers are looking at things like RNA strands, spike proteins, and host cells as they study a virus that can seem, at times, like a moving target.
Akiko Iwasaki, PhD, a professor of immunobiology at Yale School of Medicine and an investigator of the Howard Hughes Medical Institute, turned her focus to SARS-CoV-2 soon after reading the first reports coming out of China, before COVID-19 surfaced in the United States. Though she has long been recognized for her work within the scientific community, her work around COVID-19 has raised her media profile considerably. She is frequently quoted by newspapers and reporters, and has amassed a huge Twitter following of people seeking out her research updates. (Iwasaki believes that public education is a key ingredient for slowing the spread of the virus.)
Iwasaki’s primary mission is to contribute to a greater understanding of SARS-CoV-2 to aid in prevention and treatment of the disease, and she has tackled this from many different angles.
Since early 2020, when the virus officially became a pandemic, she and her team have published almost two dozen papers addressing a variety of COVID-19-related questions, ranging from a new mouse model to help researchers replicate and study how the virus works in humans, to the use of a saliva test not only for diagnosis, but also to determine who will develop complications from the disease. And in December, she and her team contributed to a growing body of knowledge about how autoimmunity plays a role in severe COVID-19 illness.
She spoke to us about her work and addressed some of the concerns people have about the evolving virus right now.
What is it like to be involved in a subject where everyone has such immediate interest in your research?
It is both an incredible opportunity and equally a weighty responsibility to be an expert in a field everyone is interested in during the pandemic. I am doing my best to communicate the science behind the virus, immunity, and vaccines in a way that everyone can understand. I feel it is a duty of a scientist to communicate the data in a clear and evidence-based manner to the public. I also think it is important to communicate data in a manner that does not stir up unnecessary fear and panic.
At this point, what are the most important questions about COVID-19?
There are so many important questions about COVID-19 at this point. The viral variants, vaccine efficacy, whether vaccines prevent transmission, better therapeutic strategies, and finding the pathobiology of long COVID.
Long after COVID-19 is controlled by vaccines, we may still potentially have millions of people around the world who will continue to suffer from long and debilitating symptoms. We need better diagnosis and treatment for long COVID.
You’ve studied COVID-19 from a variety of angles, including the work you published that identified why men are at higher risk.
We knew early in the COVID-19 outbreak that men were at higher risk for lethal outcomes—in fact, they are 1.7 times more likely to die from the disease than women. We wanted to know why, so we detailed the specific molecular differences in the immune system responses of men and women, and figured out which molecules offered protection and which were associated with poor outcomes.
Basic differences in biology are a clear part of this: Women have two X chromosomes, which are rich in immune response genes, while men have one copy. The female hormone estrogen helps protect against bad outcomes. And age influences how men respond to the virus—we knew that the gene expression pattern that controls the first line of defense against pathogens decreased dramatically in men starting in their early 60s, about six years earlier than it does in women. We summarized these insights in January of this year in Science.
Another question you’ve looked at is whether people who recover from COVID-19 can be infected again.
Some viruses provide lifelong immunity, but this is not necessarily the case with SARS-CoV-2. I published a commentary in The Lancet Infectious Diseases about the growing evidence that people can be reinfected with COVID-19—the first case in this country was a 25-year-old man in Nevada who recovered but tested positive again 48 days after his initial test.
Unfortunately, his reinfection resulted in worse disease that required oxygen support and hospitalization. That’s concerning, even though we keep in mind that reinfections are most likely to be identified in people who have symptoms and we may not know how many reinfections are asymptomatic.
These cases raise questions. One example: Can reinfected people transmit the virus to others in the same way as they could the first time they were infected? We don’t know, but these questions are important for the vaccines, so we need to study them.
What about the recent cases in Manaus, Brazil?
The recent spread of the P.1 variant in Manaus highlights the need to study how reinfections can be prevented. In that region, 76% of people were infected with the original SARS-CoV-2 by October of 2020. Yet, in late December of 2020, the P.1 variant started to reinfect the people and is now killing so many people in Manaus. This suggests that pre-existing immunity was not effective in fighting the new variant, and requires investigation as to what failed.
What would you tell people who are concerned about the variants, or mutations?
They should know that mutations are universal in viruses. When a virus enters a host cell and replicates and makes copies of the viral genome, it inevitably introduces some errors to the code. Many of these errors are harmful to the virus, and the mutations that are created are usually eliminated (so the mutation is not passed along to the next person to be infected). However, there are some mutations that are beneficial to the virus, allowing better replication and spread throughout the host, and they can become more fit than the original virus. When these mutations happen, they become the dominant strain of the virus, since they're more capable of spreading and infecting others.
How did the SARS-CoV-2 virus mutate?
SARS-CoV-2 has a very long RNA genome—there are about 30,000 nucleotides [these form the basic structural unit of nucleic acids such as RNA]. When the virus makes a copy of this genome, errors are introduced. But there are what you might call 'proofreading mechanisms' attached to the SARS-CoV-2 virus replication machinery, so it doesn't mutate that much. It accumulates only about two single-letter mutations per month in its genome, about half of the mutations of the flu. So, in this case the viral mutation is akin to a faulty spell-check mechanism. And SARS-CoV-2 has a good spell checker compared to other viruses.
So how do you explain the new variants of COVID-19?
It's an important question. We don't know exactly what the answer is, but there are many reasons how a mutation might arise in SARS-CoV-2. For example, we know immuno-compromised patients who carry the virus infection for an extended period of time have been observed to accumulate mutations, and that may be a source of these variants. It's also possible that as more and more people become immune to the virus—whether that’s because they’ve been infected or vaccinated—their immunity might put enough evolutionary pressure for the virus to escape the immune response. In other words, the immune system may force the selection of the virus that is able to evade immune detection and destruction. Only the virus that escapes immune detection can survive and replicate. Even in the absence of immune escape, variants that acquire a better ability to remain infectious longer within each infected person—or reach higher viral titers in the infected person—will have the advantage to spread.
We don't expect that you’ll need an annual vaccination for COVID-19 like you do with the flu vaccine. Akiko Iwasaki, PhD, a professor of immunobiology at Yale School of Medicine
Of course, when that happens, one infected person can replicate more virus and then breathe out or cough out more virus and transmit it to a larger number of people. That seems to be what’s occurring in multiple countries now. The mutated viruses are transmitting better and becoming dominant. That can lead not only to a greater number of people infected, but also to a proportionately greater number of people with severe and lethal disease over time. This is why it's so important to prevent the spread of this virus as quickly as possible.
Which SARS-CoV-2 mutations are you most concerned about?
The current Pfizer and Moderna vaccines appear to cover emergent variants such as the B.1.1.7 variant that was first detected in the United Kingdom almost as well as the original strain. These vaccines are mRNA vaccines that work by teaching cells how to make a protein that triggers an immune response, which then produces antibodies that protect against infection. But the variants that emerged in South Africa and potentially Brazil have the capacity to evade the antibodies that are generated by these vaccines. That’s why we have to be extra careful in containing these types of variants. If you look at the Johnson & Johnson vaccine, a one-shot adenovirus-vectored vaccine, the efficacy drops somewhat in regions where these variants are already dominant.
Fortunately, the mRNA and adenovirus vaccine strategies are very flexible and can accommodate new mutations and sequences that come up in the population. A vaccine company can clone a new variant sequence and use that to make a new version of the vaccine. In fact, many vaccine companies are already cloning the variant spike protein sequence into their new versions of the vaccine, and that potentially could be used as a booster shot for people in areas of the world affected by those variants.
Does this mean it is likely that we will need annual vaccinations like we have with the flu?
The influenza virus has the capacity to accumulate mutations over time, so that requires annual vaccinations for the new strain of virus each year. But coronaviruses, in general, don't accumulate as many mutations so rapidly. So, we don't expect that you’ll need an annual vaccination for COVID-19 like you do with the flu vaccine. However, we need to monitor the variants that are now emerging in many parts of the world. We may need vaccines tailored to the variants in a given region—and over time—to provide protective immunity.
How can we stay on top of virus mutations going forward?
I'm optimistic that our vaccine platforms allow for quick and effective implementation of new versions that will prevent variants that are on the rise. But we must be able to quickly identify new variants and then understand their genetic sequences. That’s why viral genome surveillance to monitor for mutations throughout the world is a such an important part of fighting this pandemic.
In the U.S., the CDC [Centers for Disease Control and Prevention] has been receiving SARS-CoV-2 samples regularly from state health departments and other public health agencies since November 2020 for sequencing, further characterization, and evaluation. In fact, my lab has been collaborating closely with Nathan Grubaugh’s group at Yale, which monitors for changes in viral genome sequences in real-time from local samples. Together, we are watching out—and testing—for variants that may evade existing immunity.
But the U.S. is way behind in this sequencing—isn’t that extremely worrisome?
Yes, it is. But the recent news that there will be an increase in federal funding to increase viral genome surveillance efforts is very encouraging.
[On February 17, the Department of Health and Human Services announced that the Biden Administration, through the CDC, "will invest about $200 million to expand genomic sequencing capabilities, including bioinformatics, reporting, and modeling, to increase sequencing three-fold per week."]
How can people who are not researchers fight COVID-19?
The key is to contain the viral spread as quickly as we can. This means everyone needs to intensify their efforts to protect themselves from the new variants. You need to keep following all of the CDC recommendations for wearing masks and washing hands, as well as keep maintaining a 6-foot 'social distance' from people, avoid crowds, especially indoors, and refrain from traveling. And you need to get the vaccine as soon as it becomes available to you, because right now, the vaccines appear to be effective against the variants in preventing severe and lethal disease.
What specific advice do you have for intensifying the precautions people have been taking in the past year?
Wear double masks—making sure they fit snugly and cover your nose and mouth entirely. Reduce the time you are indoors or interacting with people—think about reducing the number of minutes for each encounter. If you can order groceries delivered instead of going to the store, that is safer.