As the COVID-19 vaccine becomes available to the public, immunity monitoring will play an important role in determining whether the vaccine is effective for an individual, and for how long.
Benjamin Larimer, Ph.D., researcher at the University of Alabama at Birmingham, has developed a technology with potential use as an in-home antibody test.
But, other researchers say getting control of COVID-19 will take more than widespread vaccination. For them, it will also require better understanding of why the disease causes no apparent symptoms in some people but leads to rapid multi-organ failure and death in others, as well as better insight into what treatments work best and for which patients.
To meet this unprecedented challenge, researchers at Massachusetts General Hospital (MGH), in collaboration with investigators from Brigham and Women’s Hospital and the University of Cyprus, have created a mathematical model based on biology that incorporates information about the known infectious machinery of SARS-CoV-2, the virus that causes COVID-19, and about the potential mechanisms of action of various treatments that have been tested in patients with COVID-19.
The model and its important clinical applications are described in the journal Proceedings of the National Academy of Sciences (PNAS).
Corresponding author Rakesh K. Jain, Ph.D., from the Edwin L. Steele Laboratories in the Department of Radiation Oncology at MGH and Harvard Medical School (HMS) says “our model predicts that antiviral and anti-inflammatory drugs that were first employed to treat COVID-19 might have limited efficacy, depending on the stage of the disease progression.”
Jain and colleagues found that in all patients, the viral load (the level of SARS-CoV-2 particles in the bloodstream) increases during early lung infection, but then may go in different directions starting after Day 5, depending on levels of key immune guardian cells, called T cells.
T cells are the first responders of the immune system that effectively coordinate other aspects of immunity. The T cell response is known as adaptive immunity because it is flexible and responds to immediate threats.
In patients younger than 35 who have healthy immune systems, a sustained recruitment of T cells occurs, accompanied by a reduction in viral load and inflammation and a decrease in nonspecific immune cells (so-called “innate” immunity).
All of these processes lead to lower risk for blood clot formation and to restoring oxygen levels in lung tissues, and these patients tend to recover.
In contrast, people who have higher levels of inflammation at the time of infection—such as those with diabetes, obesity or high blood pressure—or whose immune systems are tilted toward more active innate immune responses but less effective adaptive immune responses tend to have poor outcomes.
The investigators also sought to answer the question of why men tend have more severe COVID-19 compared with women, and found that although the adaptive immune response is not as vigorous in women as in men, women have lower levels of a protein called TMPRSS2 that allows SARS-CoV-2 to enter and infect normal cells.
Based on their findings, Jain and colleagues propose that optimal treatment for older patients—who are likely to already have inflammation and impaired immune responses compared with younger patients—should include the clot-preventing drug heparin and/or the use of an immune response-modifying drug (checkpoint inhibitor) in early stages of the disease, and the anti-inflammatory drug dexamethasone at later stages.
In patients with pre-existing conditions such as obesity, diabetes and high blood pressure or immune system abnormalities, treatment might also include drugs specifically targeted against inflammation-promoting substances (cytokines, such as interleukin-6) in the body, as well as drugs that can inhibit the renin-angiotensin system (the body’s main blood pressure control mechanism), thereby preventing activation of abnormal blood pressure and resistance to blood flow that can occur in response to viral infections.
This work shows how tools originally developed for cancer research can be useful for understanding COVID-19: The model was first created to analyze involvement of the renin angiotensin system in the development of fibrous tissues in tumors, but was modified to include SARS-CoV-2 infection and COVID-19-specific mechanisms.
The team is further developing the model and plans to use it to examine the dynamics of the immune system in response to different types of COVID-19 vaccines as well as cancer-specific comorbidities that might require special considerations for treatment.
However, Larimer’s diagnostic test is an accurate and reliable method for determining whether individuals are protected against COVID-19. The technology identifies neutralising antibodies—those that block the virus from infecting cells. Emerging research suggests neutralising antibodies offer the best protection against the virus.
The most widely used antibody tests today do not specifically identify neutralising antibodies. Currently, these neutralising antibodies can only be measured at a high level of accuracy using complicated and time-consuming laboratory tests not available to the general public.
According to Larimer, existing antibody tests use a broad approach to locating antibodies, which attach to very small and distinct pieces of the virus. Current tests can mistake antibodies for other viruses, such as the common cold, for COVID-19 antibodies, leading to possible false-positive results.
To create the new test, Larimer began breaking down the COVID-19 virus into small pieces to identify the exact locations where antibodies attached to the virus.
The results were better than Larimer’s team anticipated, with the test detecting 20 percent more positive cases than the current gold-standard clinical antibody test. The ability to specifically recognize even small amounts of antibodies accurately is an important achievement, according to Larimer.
“The goal of every vaccine is to get the body to produce antibodies, which serve as a first line of defense against the virus”, said Larimer, an assistant professor in the UAB Department of Radiology Division of Advanced Medical Imaging Research. “Tests that specifically detect these antibodies can be used to measure whether a vaccine works, and possibly predict how long its protection will last.”
Immunity to COVID-19 is not anticipated to last forever, and immunity monitoring could continue for several years, even after widespread administration of a vaccine.
Clinical trials indicated that COVID-19 vaccines may be remarkably successful; however, even 95 percent effectiveness will leave millions of Americans unprotected. Antibody testing helps determine efficacy and should help indicate whether a person is protected against the virus.
Larimer hopes to transition his team’s technology to an inexpensive and easy-to-use test that will provide in-home immunity monitoring for the general public. The UAB Research Foundation has filed a provisional patent application for the technology.
