Investigating the Immune Response to SARS-CoV-2

A new test detects exposure to viruses that cause COVID-19 and their relatives. Research using it could aid efforts to protect against infections.    

A team at the Frederick National Laboratory for Cancer Research developed a test capable of assessing exposure to the virus that causes COVID-19 and to a selection of its variants and viral relatives, all from a minute amount of blood. The broad scope of this test could, if approved for clinical use, make it an important tool for better understanding the immune response to pandemic virus SARS-CoV-2 and COVID-19 vaccines — insight that could ultimately inform strategies for preventing infections.   

The test, which the researchers described recently in Microbiology Spectrum, includes 15 targets, which are proteins from viruses including SARS-CoV-2, SARS-CoV-1, MERS, and seasonal coronaviruses. However, the technology the researchers use can accommodate many more targets.   

“We wanted to make the test as usable as possible,” says corresponding author Ligia Pinto, who led the FNL team. “The more viral proteins you can include, the more questions and relationships you can explore to create a more comprehensive view of the immune response, for individuals or within the population.”   

In turn, data from such research can help guide public health recommendations, such as the timing for booster shots or a call for the development of new vaccines, she says.    

Evidence of an encounter  

When confronted by a virus or some other pathogen, the immune system develops proteins known as antibodies that recognize and latch onto specific parts of the invader. During an infection, our immune system generates different types of antibodies, some of which more effectively block the virus than others. The presence of an antibody in blood indicates that someone has encountered a particular virus, or, in some cases, received a vaccine against it. As the presence of antibodies decay differently for different individuals in response to different vaccines and virus, a strong response may be indicative of a recent infection or vaccination.    

Viruses, meanwhile, evolve to evade the immune system’s defenses. SARS-CoV-2 spawned many variants capable of causing new infections in those who have contracted the original version or been vaccinated. Likewise, SARS-CoV-2 belongs to a wider family that includes the agents of an earlier SARS outbreak in 2002, as well as the common cold.    

Pinto’s laboratory, which includes study co-author immunologist Troy Kemp, specializes in assessing immunity to the cancer-causing human papillomavirus, HPV. When the pandemic hit, they applied this expertise to SARS-CoV-2.    

Assessing antibodies  

The blood tests used in doctors’ offices and other medical settings typically focus on the presence or absence of antibodies. Research to robustly characterize the immune response to infection and vaccination, however, requires more sophisticated tools.  

To help meet that need, the team turned to a platform in which the antibodies’ targets, in this case viral proteins, are attached to tiny beads. Because this platform can potentially accommodate 500 different markers, the test has the potential to target antibodies toward just as many viral proteins. Fluorescence from the beads indicates both the identity of antibodies and their abundance, from within a sample equivalent to a fraction of a drop of blood. 

By including four viral proteins from the original SARS-CoV-2, they designed the test to look deeply at the immune response to this virus. They gave it breadth by including other members of its family, the coronaviruses, including the first SARS and agents of the common cold. The initial version of the test included two variants of SARS-CoV-2 that emerged after the pandemic began. The researchers are now working to add more variants, including Omicron, the version of the virus that dominates infections in the United States.

They refined and improved the test using samples from people who had not encountered these viruses, as well as from those who were known to be infected and possessed antibodies against them. Then, they used 160 antibody-negative and 60 antibody-positive samples to determine if the test’s components could accurately identify those known to contain the right antibodies, without accidentally flagging those that did not.   

“In many cases, we met or exceeded the criteria the FDA has established for Emergency Use Authorization (EUA),” Kemp says, noting that practical constraints hampered their ability to develop a test to reliably recognize exposure to cold viruses. “These infections are so ubiquitous that it’s extremely difficult to find samples without antibodies for them.” 

Looking ahead  

This test, and others like it, will help researchers examine many aspects of the immune response, both to natural infection and to vaccination, according to Pinto. Such studies could, for example, investigate potential links between exposure to other coronaviruses and the degree of immune protection against SARS-CoV-2. Or they could examine how the protection offered by antibodies against one of  
SARS-CoV-2’s proteins compared to that conferred by antibodies to another target within the same virus.    

Meanwhile, other studies could use the test to assess the effectiveness of vaccination, by, for example, comparing the responses elicited by different vaccines, different vaccine doses, or as part of efforts to establish the threshold at which protection becomes inadequate.   

Since COVID-19 first emerged late in 2019, researchers have made progress understanding immunity to it, but there is much more to do. “Three years of building knowledge is nothing, we are still in a very intensive phase of research,” Pinto says.