Immune to COVID-19: Why some people test negative when everyone around them is testing positive

Almost everyone knows someone who has repeatedly been exposed to SARS-CoV-2, and yet has somehow avoided succumbing to COVID-19. But whether they completely avoided infection, or merely managed to clear the virus before it caused any symptoms, or became detectable using routine tests, was uncertain.

However, recent research is starting to shed light on why some people are seemingly immune to COVID-19, with implications for testing and the development of future treatments.

Test performance

One obvious explanation why someone might test negative when everyone else in the household, school class, or workplace is testing positive, is that they aren’t swabbing their nose and/or throat correctly, and therefore, aren’t picking up enough viral particles to register a positive result.

Another is that they’re testing too early. Once the virus has gained a foothold in the body, it can take up to two weeks for someone to develop symptoms, although the average incubation period for COVID-19 is five to six days. During this time, the virus is producing multiple copies of itself, and, even though PCR tests are extremely sensitive, a certain threshold of viral particles is must be reached before someone returns a positive test. Six days after the onset of symptoms is considered optimal timing for PCR tests – although many people will test positive sooner than this.

Rapid clearance

Yet, there may be others who never register a positive result because the body clears the virus before it has managed to generate significant copies of itself. According to a recently published study in the journal Nature, past exposure to other coronaviruses, such as those responsible for causing the common cold, may speed up the clearance of SARS-CoV-2, boosting the likelihood of this scenario.

Leo Swadling and colleagues at University College London, UK, monitored the immune responses of 731 healthcare workers during the first wave of the pandemic – all of whom were at high risk of becoming infected. Fifty-eight of these individuals never tested positive, or developed detectable levels of antibodies against the virus, during the study period. However, they did show elevated levels of memory T cells specific to a complex of proteins involved in viral replication, which are highly conserved (similar) across different members of the coronavirus family. Their T cell responses were also stronger compared to healthcare workers who tested positive.

Memory T cells help to protect us against pathogens we’ve previously encountered, by remembering what they look like, and rapidly converting into large numbers of effector T cells that target and destroy infected cells should we encounter it again. So, the existence of coronavirus-specific memory T cells in these individuals could suggest that prior exposure to a different coronavirus, such as one that causes the common cold, enables them to rapidly clear SARS-CoV-2 should they encounter it.

Designing vaccines that contain conserved epitopes (parts similar across more than one virus) to trigger an expansion of cross-reactive T cells could potentially offer protection against a range of existing and emerging coronaviruses, the authors suggested.

Genetic resistance

Some people may also be innately more resistant to SARS-CoV-2 infection because of the genes they possess. In October, researchers launched a global search for people who have spent prolonged periods in close contact with someone who had COVID-19, yet never tested positive themselves, such as those who were married to an infected partner.

Once such individuals have been identified, the researchers will compare their genomes with those of people who have been infected, to identify genetic variants that might confer resistance. Already, the researchers have some ideas about where to begin their search.

One hypothesis is that they might harbour differences in the ACE2 receptor that the virus latches onto to gain entry to human cells. Another is that they have particularly powerful innate immune responses – a first line of defence against invading pathogens – particularly in the cells lining their upper respiratory tract.

Viral load

Of course, there are also some individuals who develop Covid-like symptoms, but continue to test negative for SARS-CoV-2. Some of them may even be admitted to hospital because they become so ill.

Assuming they’re swabbing correctly, and that a different virus isn’t the cause of their symptoms, it’s possible that they’re harbouring low levels of virus in their upper respiratory tract, yet the virus has managed to establish itself elsewhere.

Jiří Beneš at the Hospital Na Bulovce in Prague, Czech Republic, and colleagues studied 17 patients who were admitted to hospital with symptoms consistent with COVID-19, yet had received at least two consecutive negative PCR test results. All subsequently tested positive for antibodies against SARS-CoV-2.

“Our study showed that some patients with acute COVID-19 may test repeatedly negative by nasopharyngeal swab PCR. These cases should be interpreted as a low viral load in the upper respiratory tract rather than false negativity of PCR,” Beneš and colleagues wrote in Epidemiology, Microbiology, Immunology. In such cases, they recommend making a preliminary diagnosis of COVID-19 based on their clinical symptoms, epidemiological evidence, and comprehensive analysis of other laboratory tests and X-ray findings, with final confirmation based on antibody tests performed two weeks after the onset of symptoms.