It has been about one year since SARS-CoV-2 hit the U.S. and, in that time, there have been over 100M reported cases and over 2M deaths globally. As the world races to develop solutions, including therapies and vaccines, our greatest defense has been our own immune systems. We have gained a tremendous amount of knowledge by studying, with speed and scale, how the immune system responds to the virus – not just on an individual level, but across the population. This knowledge is informing the answers to some of our most pressing questions, including:
At the recent Precision Medicine World Conference, experts from around the globe gathered virtually to share insights gleaned over the past year from the lab, clinic, and bedsides of those battling COVID-19. In a panel moderated by Dr. Andrew von Eschenbach, president of Samaritan Health and former commissioner of the FDA, I had the opportunity to participate along with esteemed colleagues Catherine Blish, Akiko Iwasaki, and Mathai Mammen to address these questions and more, including how these learnings might affect the future of medicine.
The bottom line – our learnings thus far will impact not only our ongoing response to new variants of this virus, but they will also shape the way we approach treating a whole spectrum of diseases moving forward. Read on for key highlights from this discussion.
While we are getting better at identifying correlates of disease severity with COVID–19, it remains difficult to predict how an individual may or may not respond to infection. Certain patients experience a mild illness or no symptoms at all while others are catapulted into respiratory, cardiac or other organ distress with potential dire and even long-term sequalae. As Andy so eloquently framed the conundrum: it’s not just the seed that matters, but also the soil. How the virus takes hold is highly dependent on the host and how and when their own immune system responds.
There are many factors contributing to such diversity of response. For starters, there is a tremendous amount of variability in the early innate response to the virus that kickstarts the broader immune system’s defense. Studies have found that the virus has been able to evade innate immune recognition and early type 1 interferon response in people who get severe COVID. This can lead to other types of hyper-inflammatory reactions that are less adapted to fighting this virus and ultimately end up harming patients instead of helping. Co-morbidities also play a major role and may hasten these hyper immune responses.
The work we are doing at Adaptive to decode the T–cell response to COVID-19 has shown that the adaptive immune system demonstrates a range of response to infection. For instance, in some patients who get really sick, there can be a blunting of the T-cell signal. For those in whom the T-cell signal returns, they tend to recover, but in those in whom it does not return, they tend to do much worse. It is not known whether this is causative or associative, but this underscores the pivotal protective capacity of T cells and the potential clinical utility in determining prognosis. If we can figure out who is having which response and why, this information will help inform how we manage and treat disease.
Now that we have multiple vaccine options available to the public, we face a new question – how long are we protected? While we have typically looked to antibodies to help inform this question, we have learned that we also need to look at the T cells to fully understand the immune response. Specifically, does a person have T cells that are specific to this virus, and from which part of the virus is a T-cell response being induced? This is critical information for vaccine developers in the planning and rational design of future vaccines and boosters.
Early on, the spike protein of the coronavirus received the most attention from vaccine developers, understandably, given the historical appreciation of the importance of this viral component to replication and the need to move quickly. Many experts have noted that since only a portion of the total T-cell response is spike protein-derived in a native response to infection, future and continued development of vaccines should optimize for the immune response induced by binding antibodies, neutralizing antibodies and T cells, focusing on the breadth and depth of the response. Breadth is likely to be very important for long-term durability and effectiveness, especially with new and emerging variants. Adaptive is beginning to address this consideration by analyzing blood samples from those who have had infection with the new strains compared to earlier, dominant strains of SARS-CoV-2. As we learn more about the immune response to vaccines and primary infection it is certain that T cells will continue to play a key role in this new phase of understanding and controlling this pandemic.
As we’ve seen in other disease areas such as cancer, immune profiling may dictate which therapeutic is appropriate for an individual person. This specific level of information can alter the course of a disease. Beyond oncology, we are learning how our immune systems respond to a whole spectrum of diseases. COVID-19 has accelerated our research and understanding of the synergies between therapeutics and the populations they aim to serve. Simply put, there is ‘no one size fits all’ when it comes to addressing most diseases.
As in many other disease areas, getting over the initial illness doesn’t necessarily mean you are out of the woods. This is becoming increasingly evident with the tens of thousands of people – often referred to as “long haulers” – who are now experiencing symptoms months after the onset of COVID-19. Published studies and the largest grassroots patient advocacy group, Survivor Corps, have uncovered nearly 100 symptoms reported even after tests no longer detect the virus, including muscle fatigue, shortness of breath, and cardiovascular problems. This is an important area for continued research, and one that Adaptive is already studying to better understand the role of the T cell in long COVID. The other public health piece of this – and it is a significant one – is organizing post-care facilities that address these long-term consequences.
The most heartening part of this past year is watching the science and public health communities come together to accelerate innovation. We’ve leaned into the lessons from other public health crises – HIV, cancer and other diseases – and what we’re learning, and sharing about the immune response to this virus is certain to have applications far beyond this pandemic and into the next generation of therapeutics. We can all agree that we must remain in this, together.
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