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When the COVID-19 virus invaded the world, everything about it was mysterious and imminently threatening. Many questions about the virus have been answered, but there are still more questions than answers.
One of the most significant and elusive questions has been why some people got COVID-19, some of them multiple times, while others escaped infection – even without immunization. The answer is another marvel of genetics.
Scientists at University College, London, Imperial College, London, and the Wellcome Sanger Institute (for genetic research) in Cambridge, collaborated to find the answer. They called their project a “challenge trial.” Volunteers were deliberately exposed to SARS-CoV-2, the virus causing COVID-19. Their intention was to study many aspects of the pathogen.
Experimental challenge with human pathogens requires careful ethical scrutiny and regulation but can deliver unparalleled information, such as enabling the rapid evaluation of vaccines, therapeutics, and diagnostics. Recognizing the potential benefits that might be derived from SARS-CoV-2 human challenge, the World Health Organization convened working groups early during the COVID-19 pandemic to consider the necessary ethical and practical issues. The key considerations were to balance scientific and public health benefits with ensuring that any risks to study participants (both known and uncertain) were minimized and managed.
Participants were healthy, unvaccinated volunteers, with no previous COVID infection. A nasal spray was used to administer what is described as “an extremely low dose” of SARS-CoV-2. They were quarantined and closely monitored.
The scientists collected samples from the mucus membranes of the throat/nose region and blood samples from volunteers, before viral exposure and at regular intervals after exposure. Genetic material was squeezed from individual cells to follow the course of the disease from exposure to recovery. Not all the volunteers tested positive for COVID.
Six of the 16 volunteers developed mild COVID, with a few days of symptoms like the common cold. They called this group the “sustained infection group.”
Ten of the volunteers developed what the scientists described as an “intermediate” infection, with single positive viral tests and limited symptoms, which were called the “transient infection group.”
The remainder of the volunteers had no symptoms and never tested positive for the virus. They were called the “abortive infection group,” the first people proved to have never tested positive after exposure.
Although the groups had different responses to infection, they shared some specific immune responses, with distinct timing that revealed patterns. The virus was detected briefly in the transient group, with a robust and immediate accumulation of immune cells on the day after the infection. It contrasted with the delayed response in the sustained infection group, in which the response started five days after infection, possible allowing the virus to take hold in these recipients.
In the sustained group, cells had an antiviral defense, called an “interferon” response, in both the nose and blood, which is one of the ways the body triggers the immune system to fight infections.
The research team also identified a specific gene called HLA-DQA2 which activated production of a protein to a much greater degree in the participants who did not develop sustained infection. That made the gene an instrument of protection, which may be used to identify individuals who are probably protected from severe COVID.
This invaluable information imparts new knowledge about how our bodies react to a virus, especially in the crucial first few days of infection. It is useful for studying new strains of COVID and other viruses. Also, by comparing volunteers who have never been exposed to the virus to those with immunity, new ways of inducing protection and more effective vaccines for SARS-CoV-2 and other new viruses can be developed. That means better preparedness to combat future pandemics.
