Phoebe Garrett has attended university lectures without catching Covid; she even hosted a party where everyone subsequently tested positive except her. “I think I’ve knowingly been exposed about four times,” the 22-year-old from High Wycombe said. In March 2021, she participated in the world’s first Covid-19 challenge trial, which involved dripping live virus into her nose and pegging her nostrils shut for several hours, in a deliberate effort to infect her. Still her body resisted. “We had multiple rounds of tests, and different methods of testing: throat swabs, nose swabs, other types of swabs that I’d never done before like nasal wicks – where you hold a swab in your nose for a minute – as well as blood tests, but I never developed symptoms, never tested positive,” Garrett said. “My mum has always said that our family never gets flu, and I’ve wondered if there’s maybe something behind that.” Most people know someone who has stubbornly resisted catching Covid, despite everyone around them falling sick. Precisely how they do this remains a mystery, but scientists are beginning to find some clues. The hope is that identifying these mechanisms could lead to the development of drugs that not only protect people from catching Covid, but also prevent them from passing it on. Garrett is not the only challenge trial participant to have avoided becoming infected. Of the 34 who were exposed to the virus, 16 failed to develop an infection (defined as two consecutive positive PCR tests) – although around half of them transiently tested positive for low levels of the virus, often several days after exposure. Possibly, this was a reflection of the immune system rapidly shutting down an embryonic infection. “In our previous studies with other viruses, we have seen early immune responses in the nose that are associated with resisting infection,” said Prof Christopher Chiu at Imperial College London, who led the study. “Together, these findings imply that there is a struggle between the virus and host, which in our ‘uninfected’ participants results in prevention of infection taking off.” Some of them also reported some mild symptoms, such as a stuffy nose, sore throat, tiredness, or headache – although, since these commonly occur in everyday life, they may have been unrelated to virus exposure. “Either way, levels of the virus didn’t climb high enough to trigger detectable levels of antibodies, T cells or inflammatory factors in the blood that are usually associated with symptoms,” Chiu said. Other studies also suggest it is possible to shake off Covid during the earliest stages of infection, before it establishes a proper foothold. For instance, during the first wave of the pandemic, Dr Leo Swadling at University College London and colleagues intensively monitored a group of healthcare workers who were regularly exposed to infected patients, but who never tested positive or developed antibodies themselves. Blood tests revealed that around 15% of them had T cells reactive against Sars-CoV-2, plus other markers of viral infection. Possibly, memory T-cells from previous coronavirus infections – ie those responsible for common colds – cross-reacted with the new coronavirus and protected them from Covid. Understanding how frequently people abort nascent Covid infections in the era of Omicron is complicated because it requires intensive testing – for the virus, antibodies, T cells and other markers of infection – and because so many people have been vaccinated. “It is likely vaccinated individuals are exposed to the virus, and block viral replication and detectable infection more commonly,” Swadling said. There is also no commercially available test that can distinguish between immunity triggered by vaccination and the different variants – so unless a person has recently tested positive, it is almost impossible to know if they have been exposed to Omicron or not. Seasonal coronaviruses may not be the only source of cross-protective immune responses. Prof Cecilia Söderberg-Nauclér, an immunologist at the Karolinska Institute in Stockholm, began investigating this possibility, after Sweden avoided being overwhelmed by cases during the pandemic’s first wave, despite its light-touch approach to restrictions. Mathematical modelling by her colleague, Marcus Carlsson at Lund University, suggested this pattern of infections could only be explained if a large proportion of people had some kind of protective immunity. Her team scoured databases of protein sequences from existing viruses, hunting for small segments (peptides) resembling those from the new coronavirus, to which antibodies were likely to bind. When they identified a six-amino acid peptide in a protein from H1N1 influenza that matched a crucial part of the coronavirus spike protein, “I almost fell out of my chair,” Söderberg-Nauclér said. They have since discovered antibodies to this peptide in up to 68% of blood donors from Stockholm. The research, which has not yet been peer-reviewed, could suggest that immune responses triggered by H1N1 influenza – which was responsible for the 2009-10 swine flu pandemic – and possibly related subsequent strains, may equip people with partial, though not complete, protection against Covid-19. “It provides a cushion, but it won’t protect you if an infected person coughs in your face,” Söderberg-Nauclér said. A small proportion of people may even be genetically resistant to Covid-19. In October, an international consortium of researchers launched a global hunt to find some of them, in the hope of identifying protective genes. “We are not looking for common gene variants that provide modest protection against infection, what we are looking for is potentially very rare gene variants that completely protect someone against infection,” said Prof András Spaan at the Rockefeller University in New York, who is leading the research. They are particularly interested in people who shared a home and bed with an infected person, and avoided infection themselves. “For instance, the other day I was talking to an elderly lady from the Netherlands, who took care of her husband during the first wave. The husband was eventually admitted to the ICU, but she spent the week before taking care of him, sharing the same room, and without access to face masks,” said Spaan. “We cannot explain why she did not get infected.” Such resistance is known to exist for other diseases, including HIV, malaria, and norovirus. In these cases, a genetic defect means some people lack a receptor used by the pathogen to enter cells, so they cannot be infected. “It could well be that, in some individuals, there is such a defect in a receptor used by Sars-CoV-2,” Spaan said. Identifying such genes could lead to the development of new treatments for Covid-19, in the same way that the identification of CCR5 receptor defects in HIV-resistant people has led to new ways of treating HIV. Spaan thinks it is unlikely that the majority of those who have avoided Covid are genetically resistant, even if they have some partial immune protection. This means there is no guarantee they will not eventually become infected – as Garrett found out in late January. Having dodged the virus for almost two years, she was shocked when a routine lateral flow test produced an ominous second red line. Shortly afterwards, she developed mild Covid symptoms, but has since recovered. The irony is that, having avoided catching Covid from close family, friends and in a specialist medical laboratory, it was probably a relative stranger who infected her. “I have no idea where I got it from; it could have been someone in my local choir, or maybe from the gym,” she said.