As new strains of covid wreak havoc, Nature looks back at the key findings of the disease and the nature of infection.
Let’s take a look how.
Immune cells gone wild are tied to COVID lung damage
Some of the severe respiratory symptoms of COVID-19 seem to result from the activity of specific immune cells, which can cause long-term inflammation of the lungs.
Alexander Misharin at Northwestern University in Evanston, Illinois, and his colleagues examined fluid from the lungs of 88 people with severe pneumonia caused by SARS-CoV-2 infection (R. A. Grant et al. Nature https://doi.org/fqds; 2021). Most of these individuals had high numbers of a certain type of T cell, a class of immune cells, in their lungs. The researchers also found that nearly 70% of alveolar macrophages, a type of immune cell that is located in the tiny air sacs of the lungs, contained SARS-CoV-2. The cells harbouring the virus showed relatively high expression of genes involved in inflammation.
The findings suggest that, once the virus reaches the lungs, it can infect macrophages, which respond by producing inflammatory molecules that attract T cells. T cells, in turn, produce a protein that stimulates macrophages to make more inflammatory molecules. This persistent lung inflammation could lead to some of the life-threatening consequences of SARS-CoV-2 infection.
Traitorous antibodies are linked to COVID death
Antibodies normally attack pathogens, but, sometimes, rogue antibodies instead besiege bodily components such as immune cells. Now, a new study adds to the growing body of research tying these ‘autoantibodies’ to poor outcomes in people with COVID-19.
Ana Rodriguez and David Lee at the NYU Grossman School of Medicine in New York City and their colleagues studied autoantibody levels in blood serum collected from 86 people who required hospitalization for COVID-19. The researchers were particularly interested in autoantibodies against the protein annexin A2, which helps to stabilize cell-membrane structure. It also plays a part in ensuring the integrity of tiny blood vessels in the lungs. Blocking annexin A2 leads to lung injury, a hallmark of COVID-19.
The scientists found that the level of anti-annexin A2 antibodies was, on average, higher in the individuals who eventually died of COVID-19 than in those who survived — a difference that was statistically significant (M. Zuniga et al. Preprint at medRxiv https://doi.org/fqdd; 2021).
More research is necessary to establish a clear causal link between the virus SARS-CoV-2 and autoantibodies against annexin A2, which are relatively rare. The findings have not yet been peer reviewed.
Quick treatment with antibody-laden blood cuts risk of severe COVID
A clinical trial in older adults with COVID-19 shows that an early dose of blood plasma from recovered people helps to prevent the progression to severe disease.
The plasma of people who have recovered from COVID-19 contains antibodies against SARS-CoV-2. But treatment with such plasma has had mixed results, and some scientists have suggested that plasma needs to be given early in the disease course to be effective. Fernando Polack at Fundación INFANT in Buenos Aires and his colleagues conducted a rigorous clinical trial to assess the effect of treatment with plasma within 72 hours of symptom onset. Participants included people over the age of 75 and those between 65 and 74 with at least one pre-existing condition such as diabetes (R. Libster et al. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2033700; 2021).
Severe COVID-19 developed in 16% of the 80 study participants who received plasma and 31% of the 80 participants in the placebo group. The team found that donor plasma containing higher concentrations of antibodies against SARS-CoV-2 was associated with a greater reduction in the risk of developing severe disease — providing evidence that the antibodies themselves are responsible for the therapeutic effect.
Evidence grows of a new coronavirus variant’s swift spread
Two independent analyses have found that a new SARS-CoV-2 variant overtaking the United Kingdom is indeed more transmissible than other forms of the virus.
Eric Volz and Neil Ferguson at Imperial College London and their colleagues examined nearly 2,000 genomes of the variant, which has been labelled variant of concern 202012/01. The genomes were collected in the United Kingdom between October and early December 2020. The team also analysed the results of roughly 275,000 UK COVID-19 tests administered in late 2020 (E. Volz et al. Preprint at medRxiv https://doi.org/ghrqv8; 2021).
Estimating the variant’s frequency over time, the authors concluded that it is roughly 50% more transmissible than other variants. The authors also found that a UK lockdown in November curbed COVID-19 cases caused by most viral variants — but cases linked to the new variant rose. The findings have not yet been peer reviewed.
A separate team also used genomic and other data to analyse the variant’s spread in the last few months of 2020. Nicholas Davies and his colleagues at the London School of Hygiene and Tropical Medicine estimated that the new variant is 56% more transmissible than other variants (N. Davies et al. Preprint at medRxiv https://doi.org/fp3v; 2020). The authors found no evidence that the variant of concern causes more severe COVID-19 than other variants. The findings are now under peer review.
A less-sensitive COVID test could help to curb outbreaks
Rapid COVID-19 tests that trade away a degree of reliability for speed could prove a valuable public-health tool in communities that are hit hard by the disease.
In one week, Diane Havlir at the University of California, San Francisco, and her colleagues tested about 3,300 people in the city for SARS-CoV-2 (G. Pilarowski et al. Clin. Inf. Dis. https://doi.org/fpzv; 2020). All the study volunteers had two tests: the gold-standard PCR test, which typically returns results in two to four days in the United States; and a rapid test that detects viral proteins called antigens and returned results in roughly one hour. The rapid test, BinaxNOW, is made by Abbott Laboratories in Abbott Park, Illinois.
The rapid test detected 89% of the 237 people who tested positive with PCR — and it detected all of those who had high levels of the virus. Within two hours of a positive rapid-test result, participants received a phone call advising them to isolate themselves. This swift response meant people were less likely to spread the infection than they might have been had they waited for a PCR result. Approximately 1% of the positive rapid antigen tests were not confirmed by PCR — meaning they were wrong.
Study author Havlir disclosed that she receives non-financial support from Abbott that is not related to the paper.
A vaccine works quickly to ward off COVID-19
An RNA-based vaccine recently approved by US regulators can provide protection against COVID-19 within two weeks of the first dose, according to the results of a large clinical trial.
On 18 December, the US Food and Drug Administration granted an emergency-use authorization to a vaccine made by Moderna in Cambridge, Massachusetts. Shortly thereafter, Lindsey Baden at Brigham and Women’s Hospital in Boston, Massachusetts, Hana El Sahly at Baylor College of Medicine in Houston, Texas, and their colleagues published the results of a vaccine trial that enrolled more than 30,000 volunteers. Half received two doses of a placebo and half received two doses of the vaccine, 28 days apart (L. R. Baden et al. N. Engl. J. Med. https://doi.org/ghrg8m; 2020).
The vaccine was 94% effective at preventing symptomatic COVID-19, and preliminary analysis hints that just one dose of the vaccine might also provide some defence against asymptomatic disease, the authors write. All 30 trial participants who developed severe COVID-19 were in the placebo arm.
About half of volunteers who received the vaccine experienced side effects such as headaches after their second dose. But serious side effects were rare and occurred as frequently in the placebo group as in the vaccinated group.
How 90% of French COVID cases evaded detection
In the weeks after France ended its first lockdown, nine residents with COVID-19 symptoms went undetected for every person confirmed to have the disease — despite a nationwide surveillance programme.
France reopened in May but adopted a strategy of testing, contact tracing and case isolation to keep the coronavirus in check. To assess the results, Vittoria Colizza at the Pierre Louis Institute of Epidemiology and Public Health in Paris and her colleagues modelled COVID-19 transmission in France between mid-May and late June. They found that the national testing campaign missed some 90,000 people with COVID-19 who showed symptoms at a time when infections in the country were declining (G. Pullano et al. Nature https://doi.org/fn9k; 2020).
The findings show that a low rate of positive test results does not always equate to a high rate of detected cases. The results also suggest that many people with symptoms of COVID-19 did not seek medical advice or testing.
Countries need to implement more aggressive and efficient testing of people with suspected infections if surveillance is to be a useful tool for fighting the pandemic, the researchers say.
Stay-at-home orders have limited value for curbing COVID
An analysis of COVID-19 data from 41 countries has identified 3 measures that each substantially cut viral transmission: school and university closures, restricting gatherings to no more than 10 people and shutting businesses. But adding stay-at-home orders to those actions brought only marginal benefit.
Questions linger about the relative effectiveness of specific measures to reduce the spread of SARS-CoV-2. To pinpoint the most useful, Jan Brauner at the University of Oxford, UK, and his colleagues modelled the number of new SARS-CoV-2 infections in 41 countries between 22 January and either 30 May or the first easing of restrictions (J. M. Brauner et al. Science https://doi.org/ghp2p7; 2020). The team also examined when each country implemented seven common anti-transmission measures.
By combining the two data sets, the researchers found that closing schools and universities had a “large effect” in dampening viral spread. Most countries closed schools and universities in quick succession, making it impossible for the team to disentangle the effects of each type of closure.
In countries that closed schools and businesses and restricted gatherings, a stay-at-home order did little more to reduce transmission, the authors found.
Self-sabotaging antibodies are linked to severe COVID
Antibodies usually fight off infection, but occasionally the immune system makes some that erroneously attack the body’s own organs and even the immune system itself. New results show that these ‘autoantibodies’ might explain why some people have a severe reaction to infection with SARS-CoV-2.
Akiko Iwasaki and Aaron Ring at the Yale School of Medicine in New Haven, Connecticut, and their colleagues studied 194 people with COVID-19 and found that the most seriously ill had high levels of autoantibody activity (E. Y. Wang et al. Preprint at medRxiv https://doi.org/fnkt; 2020). Some of the autoantibodies attacked the body’s immune cells, hampering the ability to fight off infection. Others attacked the central nervous system, the heart, the liver or connective tissue.
No single autoantibody was common enough to be used to distinguish people with COVID-19 from uninfected people. The authors say the diversity of autoantibodies could explain the various disease states that follow COVID-19.
A drug duo that helps people with severe COVID
A combination of the drugs baricitinib and remdesivir shaved one day off the recovery of people hospitalized with COVID-19.
The US National Institutes of Health recommends remdesivir as a treatment for some people with COVID-19. But questions linger about remdesivir’s effectiveness, and the World Health Organization cautions against its use.
To test it as part of a combination therapy, Andre Kalil at the University of Nebraska Medical Center in Omaha and his colleagues gave remdesivir and the anti-inflammatory drug baricitinib to roughly 500 people hospitalized with moderate or severe COVID-19 (A. C. Kalil et al. N. Engl. J. Med. https://doi.org/ghpbd2; 2020). Some 500 people in a control group received remdesivir and a placebo. The team monitored how long it took participants to recover enough to go without sustained medical care.
Those who took both drugs had a median time to recovery of seven days, compared with eight days for those who took only remdesivir. But for people who were on the edge of requiring invasive ventilation, median recovery time fell from 18 days on remdesivir alone to 10 days on both drugs.
How to save the most lives when a COVID vaccine is scarce
Front-line health-care workers will probably be the first to get COVID-19 vaccines, but who should be next in the queue when supplies are limited? Models suggest that it should be elderly people.
Kate Bubar and Daniel Larremore at the University of Colorado Boulder and their colleagues modelled the effects of rolling out a vaccine if various age groups are given priority (K. M. Bubar et al. Preprint at medRxiv https://doi.org/ghj6xw; 2020). The researchers also examined the influence of the rate of viral spread in the population, the speed of vaccine delivery and the effectiveness of the protection offered by the vaccine.
The team found that in most scenarios, giving the jabs to people older than 60 before those in other age groups saved the greatest number of lives. But to prevent as many people as possible from getting infected, countries should prioritize younger age groups, according to the analysis.
Targeting people who have not been infected with SARS-CoV-2 to receive the vaccine might cut deaths and infections in hard-hit regions further, the researchers say. This could be achieved by testing for antibodies against SARS-CoV-2, which indicates a history of recent infection. The findings have not yet been peer reviewed.
A coronavirus vaccine shows lasting benefit
People given a front-runner COVID-19 vaccine still had high levels of potent antibodies against the coronavirus four months after their first jab.
Biotech firm Moderna in Cambridge, Massachusetts, has reported that its vaccine is more than 94% effective at preventing COVID-19. To gauge whether this protection lasts, Alicia Widge at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and her colleagues analysed blood from 34 study volunteers who received two doses of the vaccine one month apart (A. T. Widge et al. N. Engl. J. Med. https://doi.org/ghnhnv; 2020).
The volunteers’ levels of antibodies that latch on to a key SARS-CoV-2 protein peaked 1–2 weeks after the second jab and fell only slightly in the subsequent 2.5 months. Four months after the first jab, their blood still contained ‘neutralizing’ antibodies that disable the virus, and none of the participants had experienced any serious vaccine-related side effects.
The results show that the vaccine could provide a “durable” antibody response, the authors write.
Just a pinch of antibodies can protect against COVID
Low levels of antibodies to the new coronavirus might be sufficient to protect against COVID-19, according to a study of infected monkeys. The study also found that immune cells called T cells contribute to immunity to the virus, particularly when antibody levels are low.
There is no easy way to predict which aspects of an immune response will provide protection against an infectious disease. Dan Barouch at Harvard Medical School in Boston, Massachusetts, and his colleagues sought to understand which immune elements defend against COVID-19 using rhesus macaques (Macaca multatta).
The team collected antibodies from macaques that were recovering from SARS-CoV-2 infection and gave the antibodies to uninfected macaques (K. McMahan et al. Nature https://doi.org/fmjk; 2020). The antibodies protected the recipient animals from infection and boosted a host of immune responses, including the activation of antibody-dependent natural killer cells. Higher doses of antibodies conferred greater protection than did lower doses.
When the researchers reduced the recovering macaques’ levels of CD8+ T cells, the animals’ immunity to re-infection fell. This suggests that these cells also contribute to coronavirus immunity.
Smell tests could sniff out rising COVID case counts
A fast, cheap test of a person’s ability to smell could help to stop COVID-19 outbreaks, according to models.
Previous studies have reported that more than three-quarters of people infected with SARS-CoV-2 lose some or all of their sense of smell — a statistic that holds true even for those who do not feel ill. This distinctive symptom prompted Roy Parker at the University of Colorado Boulder and his colleagues to model whether mass testing for loss of smell could help to quash an epidemic (D. B. Larremore et al. Preprint at medRxiv https://doi.org/fmbb; 2020).
The team’s simulations showed that a smell test administered every three days could prevent a spike in infections in a population of 20,000 people, assuming that at least 50% of infected people experienced a detectable loss of smell. The tests would also be effective for surveillance before mass events such as aeroplane flights, the modelling showed.
Study author Daniel Larremore disclosed that he advises test company Darwin Biosciences; author Derek Toomre disclosed that he is a founder of smell-test company u-Smell-it. The findings have not yet been peer reviewed.
The mutations that let the coronavirus give antibodies the slip
Scientists have identified a SARS-CoV-2 mutation that allows the virus to escape recognition by several antibodies manufactured as COVID-19 treatments.
The designer therapies called monoclonal antibodies are modelled on naturally occurring immune molecules. Jesse Bloom at the Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues mapped every possible SARS-CoV-2 mutation that could prevent binding by three monoclonal antibodies: one manufactured by Eli Lilly in Indianapolis, Indiana, and the two in a ‘cocktail’ made by Regeneron in Tarrytown, New York (T. N. Starr et al. Preprint at bioRxiv https://doi.org/fk6h; 2020).
The mutations affect a protein segment called the receptor-binding domain, which the virus uses to bind to and enter cells. The researchers found one mutation that caused the virus to escape recognition by Regeneron’s antibody cocktail, and a few others that helped it to escape one of the three antibodies.
Few of these mutations are circulating widely in infected people. But one is prevalent in Europe, and another has been detected in the Netherlands and Denmark, where it has been found in SARS-CoV-2 samples taken from mink and people working at mink farms. The findings have not yet been peer reviewed.
Why a sensitive COVID test can yield false negatives
The gold-standard method for diagnosing COVID-19 is the polymerase chain reaction (PCR) test, which detects the coronavirus’s genetic material in a nose or throat swab. Now, a survey of more than 15,000 people has singled out the people most likely to receive false negatives on the test.
Caitlin Dugdale at Massachusetts General Hospital in Boston and her colleagues looked at PCR test results from about 15,000 people who showed COVID-19 symptoms or were thought for other reasons to be infected with SARS-CoV-2 (C. M. Dugdale et al. Open Forum Infect. Dis. https://doi.org/fkw4; 2020). Nearly 2,700 individuals tested negative and had a second PCR test done within 2 weeks.
Among those who received a second test, 60 — or 2.2% — tested positive. Of these, 60% had their initial test either one day or less before symptom onset or more than 7 days after it, suggesting that the PCR test is most likely to yield a false negative in people tested early or late in the course of infection.
People with COVID-19 symptoms who test negative should be retested, especially in areas where the virus is widespread, the researchers say.
To avoid COVID, beware your nearest and dearest
A far-reaching study of SARS-CoV-2 transmission in China’s Hunan Province found that the encounters that were most likely to spread the coronavirus were those between members of the same household.
Kaiyuan Sun at the National Institutes of Health in Bethesda, Maryland, Hongjie Yu at Fudan University in Shanghai, China, and their colleagues analysed data from 1,178 people in Hunan who were infected with SARS-CoV-2 and more than 15,000 close contacts of the infected people (K. Sun et al. Science https://doi.org/fkwm; 2020). The team found that contacts between people who live together posed the greatest risk of transmission, followed by contacts between members of an extended family. The transmission risk was lower still for social contacts and community encounters, such as those on public transport. Every extra day of contact raised transmission risk by 10%, the team found.
The analysis suggests that Hunan’s lockdown actually increased the risk of viral spread within households, whose members spent more time than normal at home together during lockdown. But social and community transmission fell during the same period.
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