The search for people who never get Covid-19

By Smriti Mallampaty

Imagine being born naturally resistant to SARS-CoV-2, and never having to worry about contracting Covid-19 or spreading the virus. If you have this superpower, researchers want to meet you, to enrol you in their study.

As described in a paper in Nature Immunology (1) this month, an international team of scientists has launched a global hunt for people who are genetically resistant to infection with the pandemic virus. The team hopes that identifying the genes protecting these individuals could lead to the development of virus-blocking drugs that not only protect people from Covid-19, but also prevent them from passing on the infection.

“It’s a terrific idea,” said Frederick National Laboratory for Cancer Research in Bethesda, Maryland Immunogeneticist Mary Carrington. “Really, a wise thing to do.”

But success isn’t guaranteed. If genetic resistance to the coronavirus SARS-CoV-2 exists, there may be “only a handful” of people with this trait, said Catholic University of Leuven in Belgium Paediatric Immunologist and Physician Isabelle Meyts, who is part of the consortium behind the effort.

“The question is how to find those people,” said University of Texas Health Science Centre at San Antonio Infectious Diseases Specialist Sunil Ahuja. “It’s very challenging. This is not for the faint of heart.”

Discordant couples

Nevertheless, the study authors, including Academy of Athens Biomedical Research Foundation Immunologist Evangelos Andreakos, say they are confident of tracking down their quarry. “Even if we identify one, it will be really major,” he said.

The first step is to narrow the search to people who have been exposed, without protection, to a sick person over an extended period, and have not tested positive or mounted an immune response against the virus. Of particular interest are people who shared a home and bed with an infected partner – pairs known as discordant couples.

The team of co-authors from 10 research centres across the world, from Brazil to Greece, have already recruited some 500 potential candidates, who might fit these criteria. And since the publication of their paper less than two weeks ago, another 600 people, including some from Russia and India, have contacted them, nominating themselves as possible candidates.

The response was a real surprise, said Rockefeller University in New York City Geneticist and study co-author Jean-Laurent Casanova. “I did not think for one second that people themselves, exposed and apparently not infected, would contact us.”

The goal is to have at least 1,000 recruits; Andreakos said they’ve already started analysing data.

A huge challenge ahead

But the researchers might have an almost impossible task, given the difficulties of proving that candidates were highly exposed to the virus, argued Ahuja. They will have to confirm that the sick partner was shedding high doses of live virus when the couple were interacting closely with one another.

Discordant couples are not uncommon, but it is rare to find those that meet these criteria and have been regularly tested, he said. The fact that many people have now been vaccinated, potentially masking any genetic resistance to the virus, further limits the pool of people to study, Ahuja added.

Once they have identified possible candidates, the researchers will compare the individuals’ genomes with those of people who have been infected, in search of genes associated with resistance. Any contender genes will be studied in cell and animal models to confirm a causal link to resistance and establish the mechanism of action.

Casanova’s team has previously identified rare mutations that make people more susceptible to severe Covid-19, but the researchers are now shifting gears from susceptibility to resistance.

In genetic surveys called genome-wide association studies (GWAS), other groups have scoured the DNA of tens of thousands of people in search of single-nucleotide changes – which typically only have a weak biological effect – and identified some possible candidates associated with reduced susceptibility to infection.

One of these is found in the gene responsible for the type-O blood group, but its protective effect is small, said Carrington, and it’s not clear how it is conferred.

Mechanisms of resistance

The researchers behind the new project have hypothesised the kind of resistance mechanisms they might find. The most obvious could be that some people don’t have a functioning ACE2 receptor, which SARS-CoV-2 uses to enter cells. In one GWAS, posted as a preprint (2), and therefore not peer reviewed, researchers identified a possible link between a rare mutation that probably reduces expression of the ACE2 gene and a diminished risk of infection.

This type of mechanism has previously been observed with HIV, the virus behind AIDS. Beginning in the 1990s, Ahuja and Carrington were involved in work that helped to identify a rare mutation that disables the CCR5 receptor on white blood cells, preventing HIV from entering them.

“That knowledge has been really useful,” said Carrington. It led to a class of HIV-blocking drugs and two people were also apparently cleared of HIV after receiving bone-marrow transplants from donors with two copies of the resistant genes.

Other people resistant to SARS-CoV-2 might have very powerful immune responses, especially in the cells lining the insides of their noses. Andreakos said some people might have mutations that ramp up genes that stop the virus from replicating and repackaging into new viral particles, or that break down viral RNA in the cell.

Despite the challenges ahead, he is optimistic about discovering people who are naturally resistant. “We are confident that we will find them,” he said.


  1. Andreakos. E. et al. Nature Immunology (2021)
  2. Horowitz, J. E. et al. Preprint at medRxiv (2021)

(The writer has an MSc in environmental technology from Imperial College London. This article was first published by Nature on 29 October 2021)