Virus World

Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks, give rise to highly divergent lineages and contribute to cases with post-acute COVID-19 sequelae (long COVID). However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown. Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as ‘persistent infections’ as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all.

Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1–0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people. This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution. Using viral sequence data, individuals with persistent SARS-CoV-2 infections were identified, and had higher odds of self-reporting long COVID, in a large community surveillance study.

Published in Nature (Feb. 21, 2024):

https://doi.org/10.1038/s41586-024-07029-4 

Children have largely avoided severe COVID-19 symptoms because they have a strong initial 'innate' immune reaction that quickly defeats the virus. And now, researchers led by scientists at the Garvan Institute of Medical Research have uncovered what this might mean for the immune system. Unlike those of adults, children's immune systems don't remember the virus and don't adapt, so when they're next exposed to SARS-CoV-2, their body still treats it as a new threat, the scientists found. "Because children haven't been exposed to many viruses, their immune system is still 'naive'. And because they don't develop memory T cells, they are at risk of getting sick when they become reinfected. With each new infectious episode as they get older, there is a risk of their T cells becoming 'exhausted' and ineffective, like the T cells in older people. This is why we think it's important to vaccinate children," he says. The immune system has two modes. The innate immune system is the first line of defense, comprising physical barriers such as skin and mucosal surfaces that block viruses from entering. It is also composed of cells that make chemicals to signal to other cells and ward off the viruses. The innate immune system does not distinguish between one type of virus or another.

The second line of defense comprises B and T cells of the adaptive immune system. These cells have specific receptors that can recognize and distinguish different parts of a virus and generate a rapid response to neutralize or limit it. Infants start with an immune system blank slate, which has a much higher proportion of naïve T cells, the researchers found. As they move through childhood into adulthood and become exposed to more viruses, the naïve T cells are replaced by memory T cells that are locked in to making responses to viruses they have seen before. "Over time, as you get infections, your immune system becomes more 'educated', allowing you to make a faster immune response that's tightly matched to the viruses that have infected you before," says Associate Professor Philip Britton, pediatric infectious diseases physician at the Children's Hospital at Westmead, and clinical lead in the study. "Children's immune systems move from relying mostly on the innate system, to needing the adaptive system as a backup as they grow older and are unable to clear viruses as rapidly." In the new study, published in the journal Clinical Immunology, Professor Phan, Associate Professor Britton and colleagues took a deep dive to investigate T cells and cellular immune responses of a small group of children and their household family contacts who had mild or no symptoms from coronavirus (SARS-CoV-2) infection.

The researchers sequenced white blood cell samples to analyze T cells in children and adults at the time of acute infection and one month later. Because they studied household family contacts who were infected, researchers could control for the impact of genetic or environmental influences on the immune response. They found that children had many different naive T cells to fight SARS-CoV-2 and made poor memory T cell responses to the virus after they had recovered, whereas the adults had few naïve T cells but made good memory T cell responses after recovery. Interestingly, the findings point to why older adults can have a kind of immune over-reaction to SARS-CoV-2. "When adults are infected for the first time with SARS-CoV-2, their memory T cells recognize only what they've seen before – like a familiar part of the coronavirus that is shared with the common cold coronaviruses," Professor Phan says. "This may lock the immune system in to a misdirected response that is not specific to SARS-CoV-2. It provides an opportunity for the virus to escape and multiply unchecked to cause more severe symptoms as the immune system ramps up to try and fix the problem."

Cited research published in  Clinical Immunology (jan. 2023):

https://doi.org/10.1016/j.clim.2022.109209

First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes. We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders)

The risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection. Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. The constellation of findings show that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Preprint available (June 17, 2022) in Research  Square

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Interpretation

New study data show that vaccination offers better protection against COVID-19 than prior infection, the CDC said Friday. The data are from a study published in MMWR that included 246 previously infected Kentucky residents. Study participants who were unvaccinated were 2.34 times more likely to be reinfected with SARS-CoV-2, researchers reported.  “If you have had COVID-19 before, please still get vaccinated,” CDC Director Rochelle Walensky, MD, MPH, said in a statement. “This study shows you are twice as likely to get infected again if you are unvaccinated. Getting the vaccine is the best way to protect yourself and others around you, especially as the more contagious delta variant spreads around the country.”

In the study, Alyson M. Cavanaugh, PhD, DPT, MPH, a CDC Epidemic Intelligence Service officer embedded with the Kentucky Department for Public Health, and colleagues assessed reinfections among Kentucky residents aged 18 years or older who had an initial case between March to December 2020 and a subsequent positive test in May or June of this year. They included a control group of people who were not reinfected in that time period. Overall, there were 246 case patients included in the study and 492 patients in the control group. Among the case patients, 20.3% were fully vaccinated compared with 34.3% of those in the control group, showing that the unvaccinated participants were more likely to become reinfected compared with people who were fully vaccinated (OR, 2.34; 95% CI, 1.58-3.47). Participants who were partially vaccinated were 1.56 more likely to become reinfected (95% CI, 0.81-3.01). “All eligible persons should be offered vaccination, including those with previous SARS-CoV-2 infection, to reduce their risk for future infection,” Cavanaugh and colleagues wrote.

Cited Research Published in MMWR (August 6, 2021):

https://www.cdc.gov/mmwr/volumes/70/wr/mm7032e1.htm

Although antibodies induced by SARS-CoV-2 infection are largely protective, they do not completely protect against reinfection in young people, as evidenced through a longitudinal, prospective study of more than 3,000 young, healthy members of the US Marines Corps conducted by researchers at the Icahn School of Medicine at Mount Sinai and the Naval Medical Research Center, published April 15 in The Lancet Respiratory Medicine.  "Our findings indicate that reinfection by SARS-CoV-2 in health young adults is common" says Stuart Sealfon, MD, the Sara B. and Seth M. Glickenhaus Professor of Neurology at the Icahn School of Medicine at Mount Sinai and senior author of the paper. "Despite a prior COVID-19 infection, young people can catch the virus again and may still transmit it to others. This is an important point to know and remember as vaccine rollouts continue. Young people should get the vaccine whenever possible, since vaccination is necessary to boost immune responses, prevent reinfection, and reduce transmission."

The study, conducted between May and November 2020, revealed that around 10 percent (19 out of 189) of participants who were previously infected with SARS-CoV-s (seropositive) became reinfected, compared with new infections in 50 percent (1.079 out of 2,247) of participants who had not been previously infected (seronegative). While seronegative study participants had a five times greater risk of infection than seropositive participants, the study showed that seropositive people are still at risk of reinfection. The study population consisted of 3,249 predominantly male, 18-20-year-old Marine recruits who, upon arrival at a Marine-supervised two-week quarantine prior to entering basic training, were assessed for baseline SARS-CoV-2 IgG seropositivity (defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent [ELISA] assays.) The presence of SARS-CoV-2 was assessed by PCR at initiation, middle and end of quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, the study team performed three bi-weekly PCR tests in both seronegative and seropositive groups once recruits left quarantine and entered basic training. Recruits who tested positive for a new second COVID-19 infection during the study were isolated and the study team followed up with additional testing. Levels of neutralising antibodies were also taken from subsequently infected seropositive and selected seropositive participants who were not reinfected during the study period.  Of the 2,346 Marines followed long enough for this analysis of reinfection rate, 189 were seropositive and 2,247 were seronegative at the start of the study. Across both groups of recruits, there were 1,098 (45%) new infections during the study. Among the seropositive participants, 19 (10%) tested positive for a second infection during the study. Of the recruits who were seronegative, 1,079 (48%) became infected during the study.

To understand why these reinfections occurred, the authors studied the reinfected and not infected participants' antibody responses. They found that, among the seropositive group, participants who became reinfected had lower antibody levels against the SARS-CoV-2 virus than those who did not become reinfected. In addition, in the seropositive group, neutralising antibodies were less common (neutralising antibodies were detected in 45 (83%) of 54 uninfected, and in six (32%) of 19 reinfected participants during the six weeks of observation). Comparing new infections between seropositive and seronegative participants, the authors found that viral load (the amount of measurable SARS-CoV-2 virus) in reinfected seropositive recruits was on average only 10 times lower than in infected seronegative participants, which could mean that some reinfected individuals could still have a capacity to transmit infection. The authors note that this will need further investigation. In the study, most new COVID-19 cases were asymptomatic—84% (16 out of 19 participants) in the seropositive group vs 68% (732 out of 1,079 participants) in the seronegative group—or had mild symptoms and none were hospitalised. The authors note some limitations to their study, including that it likely underestimates the risk of reinfection in previously infected individuals because it does not account for people with very love antibody levels following their past infection. They strongly suggest that even young people with previous SARS-CoV-2 infection be a target of vaccination since efforts must be made to prevent transmission and prevent infection amongst this group.

Study cited was published in The Lancet Respiratory Medicine (April 15, 2021):

https://doi.org/10.1016/S2213-2600(21)00158-2

Doctors in France are treating a critically ill patient infected with the South African coronavirus variant, four months after he recovered from COVID-19, in what study authors said was the first case of its kind.  The 58-year-old man had a history of asthma and initially tested positive for COVID-19 in September when he presented to medical staff with a fever and shortness of breath. The symptoms persisted only for a few days, and the man tested negative for COVID-19 twice in December 2020. However, he was admitted to hospital in January and diagnosed with the South African variant. The patient's condition worsened, and he is currently in a "critical condition" on a ventilator. 

"This is, to our knowledge, the first description of reinfection with the South African (variant) causing severe COVID-19, four months after a first mild infection," said authors of a study published this week in the journal Clinical Infectious Diseases. The 501Y.V2 coronavirus variant emerged late last year in South Africa and immediately provoked alarm among disease specialists. It has eight key mutations, one of which affects the virus' spike protein, making it more effective at binding to human cells and therefore more infectious. Vaccine manufacturers Pfizer/BioNTech and Moderna say their mRNA vaccines retain their effectiveness against the South African variants and another that emerged last year in Britain. However a study last week showed that AstraZeneca's vaccine failed to prevent mild and moderate cases of infection of the South African variant. "The impact of 501Y.V2 mutations on the effectiveness of vaccines developed based on earlier SARS-CoV-2 strains is still unknown," said the authors of the reinfection study.

Case study published in Clinical Infectious Diseases (Feb. 10, 2021):

https://doi.org/10.1093/cid/ciab129

Waning antibody levels or a poorly developed immune response to SARS-CoV-2 could put people at risk of reinfection, one case suggests. In March, a care-home resident in their sixties developed severe pneumonia and tested positive for the new coronavirus. The individual spent more than one month in hospital before testing negative. In July, the individual tested positive again, with milder symptoms of coughing and shortness of breath. Genomic analysis by Jason Goldman at the University of Washington, Seattle, and his colleagues (J. D. Goldman et al. Preprint at medRxiv https://doi.org/fbvj; 2020) showed that these were two separate infection events.

The team also found that after the second infection, the individual produced only low levels of antibodies, and that these decreased over time. The person might have had a similar response to the first infection, which could explain why the individual was not protected against the second infection, the authors say. The team also measured the individual’s neutralizing antibodies, which protect cells against infection. The person had lower levels of these potent antibodies against the version of SARS-CoV-2 that caused the first infection than against the version that caused the second infection. The researchers say that these measurements provide a useful benchmark for antibody levels that do not protect against reinfection. The research has not yet been peer reviewed.

Study available as preprint in medRxiv (Sept. 25, 2020):

https://doi.org/10.1101/2020.09.22.20192443

A 25-year-old Nevada man appears had coronavirus twice, researchers say. Genetic tests indicate the patient was infected with two different varieties of the virus, a team at the University of Nevada Reno School of Medicine and the Nevada State Public Health Laboratory reported.  The patient was first diagnosed with coronavirus in April after he had a sore throat, cough, headache, nausea and diarrhea, the researchers wrote in a pre-print study posted Thursday. He got better around April 27, and he tested negative for the virus twice afterwards.  He continued to feel well for about a month. Then on May 31 he sought care for fever, headache, dizziness, cough, nausea and diarrhea. Five days later, he was hospitalized and required ongoing oxygen support. He was tested again for Covid-19 and the results were positive.

A man in Hong Kong was found to be reinfected with COVID-19, but what that means for vaccines and immunity is unclear. Scientists have found the first solid evidence that people can be reinfected with the virus that causes COVID-19. A new study shows a 33-year-old man who was treated at the hospital for a mild case in March harbored the virus again when he was tested at the Hong Kong airport after returning from Europe on 15 August, less than 5 months later. He had no symptoms this time. Researchers had sequenced the virus, SARS-CoV-2, from the first infection; they did so again after the patient’s second diagnosis and found numerous differences between the two, bolstering the case that the patient had been infected a second time. “This case proves that at least some patients do not have life-long immunity,” Kelvin To, a clinical microbiologist at the University of Hong Kong (HKU) and one of the authors of a paper on the case, told Science today. Exactly what that finding means is unclear, however. To and his colleagues make some sweeping statements in their paper, parts of which Science has seen. “It is unlikely that herd immunity can eliminate SARS-CoV-2,” the authors write, referring to the idea that the epidemic will peter out once enough people have been infected and become immune. “Second, vaccines may not be able to provide life-long protection against COVID-19.”

But it’s too early to draw those conclusions, says Columbia University virologist Angela Rasmussen. “I disagree that this has huge implications across the board for vaccines and immunity,” she wrote in an email, because the patient described in the study may be a rare example of people not mounting a good immune response to the first infection. Mark Slifka, a viral immunologist at Oregon Health & Science University, says his takeaway from the paper is the opposite of what the authors write: “Even though [the patient] got infected with a very different strain that’s distinct from the first time around, they were protected from disease,” he says. “That is good news.” Fueling the debate over the importance of the case is that the paper on it isn’t public yet, which means scientists can’t scrutinize its data in full. HKU put out a press release about the study today and said the paper had been accepted for publication by the journal Clinical Infectious Diseases. To confirmed that a few pages of the manuscript circulating online were from the paper but said he could not make the full text available. “This is why I loathe data disclosure by press release,” Rasmussen wrote. “It seems designed to stoke sensationalism by leaving all these provocative questions unanswered, some of which could probably be answered by just reading the paper and examining the figures.” There have been several reports of COVID-19 patients testing positive for SARS-CoV-2 again after apparently clearing their infection, but in those cases there was less time between the tests and researchers did not have sequences of the viruses to confirm there were two different infections. Many of these cases were likely testing errors, says Jeffrey Barrett, a genomic epidemiologist at the Wellcome Sanger Institute: “I wasn’t convinced by any of them.” 

In the current case, the press release and paper excerpts say, the HKU scientists found 24 differences between the first and second viral genome, including one in the first virus that truncates a gene known as ORF8. “There’s sort of no chance that it’s the same infection twice,” Barrett says. “It is much more convincing than any other anecdotal reports that have come out so far,” agrees virologist Charlotte Houldcroft of the University of Cambridge. Even if the finding settles the question of whether people can be reinfected with the pandemic virus, it raises many additional questions: How often does this happen? Do people have milder infections, or no symptoms at all, the second time around? Can they still infect others? If natural infection does not always confer solid protection, will that be true for vaccines as well? To says he believes reinfections are not rare—just difficult to find. “This case is very special because he was screened at the airport,” he says. “Under normal circumstances, he may not even have been aware that he was infected again.” If reinfections are more likely to lead to asymptomatic cases, To notes, they may be tougher to spot. In a press conference on Monday morning, epidemiologist Maria Van Kerkhove of the World Health Organization warned against jumping to conclusions. “We need to look at this at a population level,” she said. Given that there have been more than 24 million reported SARS-CoV-2 infections worldwide, a single reinfection report may signal a very rare event, Barrett says. “Biology is complicated. You always find some strange exceptions.” He hopes efforts like the COVID-19 Genomics UK Consortium, which is sequencing viral samples from tens of thousands of patients, will provide data on how often reinfection occurs. Houldcroft says studies in health care workers may be key, because they are most likely to be exposed repeatedly....

Background

Methods

Findings

Interpretation

This study estimates the effectiveness of previous infection with SARSCoV2 in preventing reinfection with Omicron BA.4/BA.5 subvariants using a test negative, case control study design. Cases (SARSCoV2 positive test results) and controls (SARSCoV2 negative test results) were matched according to sex, 10 year age group, nationality, comorbid condition count, calendar week of testing, method of testing, and reason for testing. Effectiveness was estimated using the S gene target failure (SGTF) infections between May 7, 2022 and July 4, 2022. SGTF status provides a proxy for BA.4/BA.5 infections, considering the negligible incidence of other SGTF variants during the study. Effectiveness was also estimated using all diagnosed infections between June 8, 2022 and July 4, 2022, when BA.4/BA.5 dominated incidence. Effectiveness of a previous pre-Omicron infection against symptomatic BA.4/BA.5 reinfection was 15.1% (95% CI: -47.1 to 50.9%), and against any BA.4/BA.5 reinfection irrespective of symptoms was 28.3% (95% CI: 11.4 to 41.9%).

Effectiveness of a previous Omicron infection against symptomatic BA.4/BA.5 reinfection was 76.1% (95% CI: 54.9 to 87.3%), and against any BA.4/BA.5 reinfection was 79.7% (95% CI: 74.3 to 83.9%). Results using all diagnosed infections when BA.4/BA.5 dominated incidence confirmed the same findings. Sensitivity analyses adjusting for vaccination status confirmed study results. Protection of a previous infection against BA.4/BA.5 reinfection was modest when the previous infection involved a preOmicron variant, but strong when the previous infection involved the Omicron BA.1 or BA.2 subvariants. Protection of a previous infection against BA.4/BA.5 was lower than that against BA.1/BA.2, consistent with BA.4/BA.5 greater capacity for immune system evasion than that of BA.1/BA.2.

Preprint available at medRxiv (July 12, 2022):

https://doi.org/10.1101/2022.07.11.22277448 

Characteristics of people testing positive for COVID-19 from the Coronavirus (COVID-19) Infection Survey. 

The most recent update (May 25, 2022) by the UK Health Security agency shows an increasingly alarming rate of re-infections in the U.K. As compared to the pre-Omicron period, re-infection rates were nearly 8-fold greater in the period from December 20 2021 onwards. A total of 4729 reinfections were reported during the Omicron period, with 75% of the re-infections showing cycle threshold values (Ct) below 30, suggesting high viral loads. People with asymptomatic infections, or with prior infections with lower viral loads (Ct above 30) were more likely to be re-infected. Vaccinated individuals, or older people, were less likely to suffer re-infections. The findings highlight the ability of Omicron, and the newest Omicron sub-lineages, to escape immunity elicited by prior infections.

The risk of reinfection from the omicron coronavirus variant is three times higher than for any previous strain, according to a South African study of infections since the start of the pandemic. 

The finding provides evidence of omicron’s “ability to evade immunity from prior infection,” according to the authors, Juliet Pulliam of the South African Center for Epidemiological Modelling and Analysis and Harry Moultrie of the National Center for Communicable Diseases. The study was based on data collected through South Africa’s health system on about 2.8 million confirmed coronavirus infections between March 2020 and Nov. 27, including 35,670 suspected reinfections, the authors wrote in an emailed statement. They detected a significant increase in reinfections since the first known cases of omicron. “The reinfection risk profile of omicron is substantially higher than that associated with the beta and delta variants during the second and third waves, with observed numbers of reinfections falling well beyond the prediction intervals,” they wrote. “Our most urgent priority now is to quantify the extent of omicron’s immune escape for both natural and vaccine-derived immunity, as well as its transmissibility relative to other variants and impact on disease severity.” 

That strain has rapidly taken hold in Africa’s most-industrialized nation. New cases exceeded 11,000 on Thursday, compared with 585 two weeks ago, according to government data. In Gauteng, the nation’s richest province and its Covid-19 epicenter, each infected person on average is able to pass on the virus to another 2.33, according to the National Institute for Communicable Diseases. The beta or delta variants spread “primarily from increased transmissibility, rather than immune escape,” according to the research paper, which hasn’t been peer reviewed. South Africa announced the discovery of a new variant, later named omicron, on Nov. 25 as cases began to spike and the strain spread across the globe. National daily cases almost doubled on Wednesday, days after countries across the world halted flights to and from southern Africa. “This virus may be similar to delta in its ability to spread or in being contagious,” Anne von Gottberg, a clinical microbiologist at South Africa’s National Institute for Communicable Diseases, said at a briefing on Thursday. “However, it’s the susceptibility of the population that is greater now because previous infection used to protect against delta and now, with omicron, it doesn’t seem to be the case.”

Preprint available at medRxiv (Dec. 02, 2021):

https://doi.org/10.1101/2021.11.11.21266068

British scientists on Monday launched a trial which will deliberately expose participants who have already had COVID-19 to the coronavirus again to examine immune responses and see if people get reinfected.  In February, Britain became the first country in the world to give the go-ahead for so-called "challenge trials" in humans, in which volunteers are deliberately exposed to COVID-19 to advance research into the disease caused by the coronavirus. read more The study launched on Monday differs from the one announced in February as it seeks to reinfect people who have previously had COVID-19 in an effort to deepen understanding about immunity, rather than infecting people for the first time. "The information from this work will allow us to design better vaccines and treatments, and also to understand if people are protected after having COVID, and for how long," said Helen McShane, a University of Oxford vaccinologist and chief investigator on the study.  She added that the work would help understanding of what immune responses protect against reinfection.

The daily toll reached 1,641 on Tuesday, Brazil's highest figure since the pandemic started.  The health ministry said 1,641 people had died with Covid in the previous 24 hours. The record was reached as scientists said that a new variant first found in Brazil appears more contagious. Brazil, where more than a quarter of a million people have died with Covid, has the second highest coronavirus death toll after the United States.

Large study of UK health-care workers suggests that most people are immune for months after catching COVID-19 for the first time. Most people who catch and recover from COVID-19 are likely to be immune for several months afterwards, a study of more than 20,000 health-care workers in the United Kingdom has found.  The study — called SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) and published on the preprint server medRxiv on 15 January1 — concluded that immune responses from past infection reduce the risk of catching the virus again by 83% for at least 5 months. Over the course of the past year, reports of repeat infections with SARS-CoV-2 have shaken confidence in the immune system’s ability to sustain its defences against the virus. The interim results from the study assuage some of those fears, said SIREN lead investigator Susan Hopkins, a senior medical adviser at Public Health England in London, at a press briefing. The data suggest that natural immunity might be as effective as vaccination, she added, at least over the five-month period the study has covered so far.  The data suggest that repeat infections are rare — they occurred in fewer than 1% of about 6,600 participants who had already been ill with COVID-19. But the researchers also found that people who become reinfected can carry high levels of the virus in their nose and throat, even when they do not show symptoms. Such viral loads have been associated with a high risk of transmitting the virus to others, said Hopkins. “Reinfection is pretty unusual, so that’s good news,” says immunologist John Wherry at the University of Pennsylvania in Philadelphia. “But you’re not free to run around without a mask.”

Regular screening

SIREN is the largest study of coronavirus reinfection that systematically screens for asymptomatic infections, said Hopkins. Every two to four weeks, participants undergo blood tests for SARS-CoV-2 antibodies as well as PCR tests to detect the virus itself. Over the 5 months, the team found 44 possible reinfections. In the group of 14,000 participants who had not been previously infected, 318 people tested positive for the virus. Some of the reinfections are still being evaluated, Hopkins said. All 44 are considered ‘possible’ reinfections, and were classified on the basis of PCR tests combined with screening measures to reduce the risk of re-detecting virus from the initial infection. So far, only 2 of these 44 cases have passed more stringent tests to be classified as ‘probable’. The study did not assess whether symptoms were better or worse during the second infection than during the first, but Hopkins notes that only about 30% of the people with possible reinfections reported any symptoms, compared with 78% of participants with first-time infections.  At the moment, the team does not have enough data to tease out who might be most at risk of reinfection. And immunologist George Kassiotis at the Francis Crick Institute in London notes that participants in the study were mainly women, and mostly under the age of 60. “This group is unlikely to experience the most severe form of COVID-19,” he says, “and may not be representative of the population as a whole.” Investigators are still collecting data; they hope to get a sense of how long immunity lasts and to investigate the effects of a SARS-CoV-2 variant called B.1.1.7 that emerged in 2020 and has rapidly spread across the country. Although there are many reasons to suspect that existing protection should cover new variants, it is possible that immune responses raised against one variant will be less effective against another, says Kassiotis. “It is still an open question.”

Preprint available in medRxiv (Jan. 15, 2021):

https://doi.org/10.1101/2021.01.13.21249642 

In late June, Sanne de Jong developed nausea, shortness of breath, sore muscles, and a runny nose. At first, she thought it might be lingering effects from her COVID-19 infection in the spring. De Jong, 22, had tested positive on 17 April and suffered mild symptoms for about 2 weeks. She tested negative on 2 May—just in time to say farewell to her dying grandmother—and returned to work as a nursing intern in a hospital in Rotterdam, the Netherlands. But when her symptoms re-emerged, her doctor suggested she get tested again. “A reinfection this soon would be peculiar, but not impossible,” she told De Jong, who by then had again lost her sense of smell and had abdominal pains and diarrhea.  The call from her municipal health service came on 3 July. De Jong had tested positive again. “You’re kidding me!” she recalls saying. Scientists are keenly interested in cases like hers, which are still rare but on the rise. Reinfections hint that immunity against COVID-19 may be fragile and wane relatively quickly, with implications not just for the risks facing recovered patients, but also for how long future vaccines might protect people. “The question everybody wants to answer is: Is that second one going to be less severe most of the time or not?” says Derek Cummings, who studies infectious disease dynamics at the University of Florida. “And what do reinfections teach us about SARS-CoV-2 immunity in general?”

South Korean scientists reported the first suspected reinfections in April, but it took until 24 August before a case was officially confirmed: a 33-year-old man who was treated at a Hong Kong hospital for a mild case in March and who tested positive again at the Hong Kong airport on 15 August after returning from a trip to Spain. Since then, at least 24 other reinfections have been officially confirmed—but scientists say that is definitely an underestimate. To count as a case of reinfection, a patient must have had a positive polymerase chain reaction (PCR) test twice with at least one symptom-free month in between. But virologist Chantal Reusken of the Dutch National Institute for Public Health and the Environment (RIVM) explains that a second test can also be positive because the patient has a residue of nonreplicating viral RNA from their original infection in their respiratory tract, because of an infection with two viruses at the same time or because they had suppressed but never fully cleared the virus. So most journals want to see two full virus sequences, from the first and second illnesses, that are sufficiently different, says Paul Moss, a hematologist at the University of Birmingham. “The bar is very high,” Moss says. “In many cases, the genetic material just isn’t there.” Even if it is, many labs don’t have the time or money to clinch the case. As a result, the number of genetically proven reinfections is orders of magnitude lower than that of suspected reinfections. The Netherlands alone has 50 such cases, Brazil 95, Sweden 150, Mexico 285, and Qatar at least 243.

The Hong Kong patient’s second infection was milder than the first, which is what immunologists would expect, because the first infection typically generates some immunity. That may explain why reinfections are still relatively rare, says Maria Elena Bottazzi, a molecular virologist at Baylor College of Medicine and Texas Children’s Hospital. They could become more common over the next couple of months if early cases begin to lose their immunity. Reinfections with the four coronaviruses that cause the common cold occur after an average of 12 months, a team led by virologist Lia van der Hoek at Amsterdam University Medical Center recently showed. Van der Hoek thinks COVID-19 may follow that pattern: “I think we’d better prepare for a wave of reinfections over the coming months.” That’s “bad news for those who still believe in herd immunity through natural infections,” she adds, and a worrisome sign for vaccines....

There are now several cases of people becoming reinfected with Covid-19. But experts stress that’s not cause for panic. Here’s how to assess the news. Following the news this week of what appears to have been the first confirmed case of a Covid-19 reinfection, other researchers have been coming forward with their own reports. One in Belgium, another in the Netherlands. And now, one in Nevada. What caught experts’ attention about the case of the 25-year-old Reno man was not that he appears to have contracted SARS-CoV-2 (the name of the virus that causes Covid-19) a second time. Rather, it’s that his second bout was more serious than his first.  Immunologists had expected that if the immune response generated after an initial infection could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known reinfection case, in a 33-year-old Hong Kong man.  Still, despite what happened to the man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions. They always presumed people would become vulnerable to Covid-19 again some time after recovering from an initial case, based on how our immune systems respond to other respiratory viruses, including other coronaviruses. It’s possible that these early cases of reinfection are outliers and have features that won’t apply to the tens of millions of other people who have already shaken off Covid-19.  “There are millions and millions of cases,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health. The real question that should get the most focus, Mina said, is, “What happens to most people?” But with more reinfection reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.

What’s the deal with the Nevada case?

The Reno resident in question first tested positive for SARS-CoV-2 in April after coming down with a sore throat, cough, and headache, as well as nausea and diarrhea. He got better over time and later tested negative twice.  But then, some 48 days later, the man started experiencing headaches, cough, and other symptoms again. Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia. Researchers sequenced virus samples from both of his infections and found they were different, providing evidence that this was a new infection distinct from the first.

What happens when we get Covid-19 in the first case?

Researchers are finding that, generally, people who get Covid-19 develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the virus). This is what happens after other viral infections. In addition to fending off the virus the first time, that immune response also creates memories of the virus, should it try to invade a second time. It’s thought, then, that people who recover from Covid-19 will typically be protected from another case for some amount of time. With other coronaviruses, protection is thought to last for perhaps a little less than a year to about three years. But researchers can’t tell how long immunity will last with a new pathogen (like SARS-CoV-2) until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against Covid-19, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates of protection."

Why do experts expect second cases to be milder?

With other viruses, protective immunity doesn’t just vanish one day. Instead, it wanes over time. Researchers have then hypothesized that with SARS-CoV-2, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt infection entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other respiratory pathogens. And it’s why some researchers actually looked at the Hong Kong case with relief. The man had mild to moderate Covid-19 symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts said, of what you would want your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe. “The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first reinfection. “But the reinfection didn’t cause disease, so that’s the first point.” The Nevada case, then, provides a counterexample to that....

Two European patients are confirmed to have been re-infected with COVID-19, raising concerns about people's immunity to the coronavirus as the world struggles to tame the pandemic. The cases, in Belgium and the Netherlands, follow a report this week by researchers in Hong Kong about a man there who had contracted a different strain of the virus four and a half months after being declared recovered - the first such second infection to be documented. That has raised fears about the efficacy of potential vaccines against the virus, which has killed hundreds of thousands of people, though experts say there would need to be many more cases of re-infection for these to be justified. Belgian virologist Marc Van Ranst said the Belgian case was a woman who had contracted COVID-19 for the first time in March and then again with a different coronavirus strain in June. Further cases of re-infection were likely to surface, he said. Van Ranst told Reuters TV the woman, in her 50s, had very few antibodies after the first infection, although they might have limited the sickness. Re-infection cases were probably limited exceptions, he said, although it was too soon to tell and many were likely to surface in coming weeks.  He added that the new coronavirus appeared more stable than the influenza virus, but it was changing. 

“Viruses mutate and that means that a potential vaccine is not going to be a vaccine that will last forever, for 10 years, probably not even five years. Just as for flu, this will have to be redesigned quite regularly,” he said. Van Ranst, who sits on some Belgian COVID-19 committees, said vaccine designers would not be surprised. “We would have loved the virus to be more stable than it is, but you can’t force nature.”

Genetic Testing

The National Institute for Public Health in the Netherlands said it had also observed a Dutch case of re-infection with a different strain of the virus. “It is clear there has been a first and a second infection with a substantial quantity of virus. Enough to be able to determine the genetic code of the virus, that is what showed they were indeed different,” said Marion Koopmans, a leading virologist in the Netherlands and a member of the World Health Organization’s scientific advisory group. She added the elderly Dutch patient had a weakened immune system, which explained the patient’s situation. “People are worried and ask if re-infection is ‘standard’. I don’t think it is,” she added. WHO spokeswoman Margaret Harris told a U.N. briefing in Geneva regarding the Hong Kong case that, while there were anecdotal reports of re-infections, it was important to have clear documentation.

The case raises questions about the durability of immune protection from the coronavirus, though it remains unclear whether it's an outlier. Researchers in Hong Kong on Monday reported what appears to be the first confirmed case of Covid-19 reinfection, a 33-year-old man who was first infected by SARS-CoV-2 in late March and then, four and a half months later, seemingly contracted the virus again while traveling in Europe. The case raises questions about the durability of immune protection from the coronavirus. But it was also met with caution by other scientists, who questioned the extent to which the case pointed to broader concerns about reinfection. There have been scattered reports of cases of Covid-19 reinfection. Those reports, though, have been based on anecdotal evidence and largely attributed to flaws in testing. But in this case, researchers at the University of Hong Kong sequenced the virus from the patient’s two infections and found that they did not match, indicating the second infection was not tied to the first. There was a difference of 24 nucleotides — the “letters” that make up the virus’ RNA — between the two infections. “This is the world’s first documentation of a patient who recovered from Covid-19 but got another episode of Covid-19 afterwards,” the researchers said in a statement.

Experts cautioned that this patient’s case could be an outlier among the tens of millions of cases around the world and that immune protection may generally last longer than just a few months. They said that ongoing studies tracking patients who had recovered from Covid-19 would help reach more definitive conclusions. “There’s been more than 24 million cases reported to date,” Maria Van Kerkhove, a coronavirus expert at the World Health Organization, said at a briefing Monday, when asked about the Hong Kong report. “And we need to look at something like this at a population level.” The question of how long someone is protected from Covid-19 after being infected and recovering looms large. Studies are increasingly finding that most people who recover from the illness mount a robust immune response involving both antibodies (molecules that can block the virus from infecting cells again) and T cells (which can help clear the virus). This has suggested that people would be protected from another case for some amount of time. But based on what happens with other coronaviruses, experts knew that immunity to SARS-CoV-2 would not last forever. People generally become susceptible again to the coronaviruses that cause the common cold after a year or even less, while protection against SARS-1 and MERS appears to last for a few years. “What we are learning about infection is that people do develop an immune response, and what is not completely clear yet is how strong that immune response is and for how long that immune response lasts,” Van Kerkhove said. She added she was still reviewing the Hong Kong case.

The strength and durability of the immune response is also a crucial factor in how long vaccines will be effective for, and for how often people might need a booster dose. In the Hong Kong case, the man had traveled to Spain and returned to Hong Kong via the United Kingdom. A saliva sample was taken upon arrival in Hong Kong as part of a screening protocol and tested positive for SARS-CoV-2 on Aug. 15. During his second infection, the man did not have any symptoms. Some patients go through their course of Covid-19 without showing symptoms, but researchers have also hypothesized that secondary cases of the coronavirus will generally be milder than the first. Even if immune systems can’t stop the virus from infecting cells, they might still rally some level of response that keeps us from getting sicker. During his first case, the patient had classic Covid-19 symptoms of cough, fever, sore throat, and headache...

Original study published in Clinical Infect. Diseases (August 25, 2020):

https://doi.org/10.1093/cid/ciaa1275