Despite exposure to the coronavirus, some individuals never get infected—and a growing body of research on this "never Covid" cohort seeks to understand the potential factors that make these people less susceptible to infection than others.

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What the first Covid-19 'human challenge' revealed about infection

Earlier this month, researchers from the United Kingdom published early results of the first "human challenge" trial for Covid-19, in which volunteers were deliberately exposed to the coronavirus.

For the study, researchers gave 34 individuals ages 18 to 30 a low dosage of a strain of the coronavirus that was prevalent in the United Kingdom in early 2020—approximately equivalent to the amount of virus that would be present in one respiratory droplet.

Of the participants, 18 were infected by the dose, with first symptoms developing and PCR tests returning positive results less than two days after exposure, on average. The speed of infection surprised researchers, as previous epidemiological research had suggested the virus's incubation period was around five days.

The most common symptoms reported by the participants were sore throats, runny noses, and sneezing. Fever was reported as well but was less common, and none of the participants developed a persistent cough.

The remaining 16 participants were not infected despite their exposure to the virus, the researchers reported. According to Peter Openshaw, a professor of experimental medicine at Imperial College London (ICL) and one of the study's authors, researchers are now focusing on this group with apparent resistance to answer "[w]hy ... some people are more vulnerable [to coronavirus infection] than others."

Potential factors protecting the 'never Covid' cohort

Current research focusing on the "never Covid" cohort, or people who seem immune to the coronavirus, suggests there may be multiple factors influencing an individual's susceptibility to infection.

1. Cross immunity from other types of coronaviruses

A small study published in Nature Communications suggests that immunity against common cold coronaviruses may also provide some protection against SARS-CoV-2 infection.

For the study, researchers analyzed blood samples from 52 participants who lived with someone with a confirmed Covid-19 diagnosis in September 2020. Of the 26 participants who did not develop Covid-19, researchers observed "significantly higher levels" of pre-existing T-cells found after common cold coronaviruses.

"We found that high levels of pre-existing T cells, created by the body when infected with other human coronaviruses like the common cold, can protect against Covid-19 infection," said Rhia Kundu, a researcher from ICL's National Heart and Lung Institute and the study's first author.

2. Genetic variations

Multiple genetic variations could also impact a person's susceptibility to coronavirus infection, Axios reports.

According to Gigi Gronvall, an immunologist and senior scholar the Johns Hopkins Center for Health Security, a genetic predisposition against infection "is seen in other diseases where people have one or multiple factors that interfere with virus binding to cells or being transported within."

Separately, Danny Altmann, a professor of immunology at ICL, and his colleagues plan to soon publish research on immunogenetics, or the relationship between genetics and the immune system, and coronavirus infection.

According to Altmann, the research focused on human leukocyte antigens (HLA) and how they affect a person's response to the coronavirus, with some HLA types affecting what kind of infection (symptomatic or asymptomatic) a person experiences.

“The key genes that control your immune response are called HLA genes. They matter for determining your response on encounter with SARS-CoV-2," Altmann said. "For example, people with the gene HLA-DRB1*1302 are significantly more likely to have symptomatic infection."

3. Mucosal immunity

Mucosal immunity may also play an important role in protecting against the coronavirus, which enters a person's body through their nose or mouth.

According to Openshaw, a healthy mucosal system will be able to respond to a range of pathogens and "counter the infection before the immune system involving antibody and T-cells and all of those other things has time to step in."

Currently, nasal vaccines and boosters are being tested as a way to increase mucosal immunity, which could more effectively prevent infection, Axios reports.

4. Environmental circumstances

According to Openshaw, various environmental factors may also influence the likelihood of an individual becoming infected. These factors include where the virus settled on a person's body, how large the virus particle was, the amount of virus person was exposed to, and how long a person was exposed to the virus.

Ultimately, while research into the "never Covid" cohort is important, health experts say the most important tools for preventing coronavirus infection continue to be vaccination, including boosters, and other safety measures, such as wearing masks, proper hand hygiene, and good ventilation. (O'Reilly, Axios, 2/10; Ellyatt, CNBC, 2/5; NBC 5 Chicago, 2/3; Killingley et al., Nature Portfolio, 2/1)