Coronavirus Research Tracking - 18 December
Covid reviews, susceptibility and immunity, genome integration, phase 3 vaccine trial results
In this week’s Research Tracker we look at a series of Nature articles reviewing important Covid-19 science highlights and unforeseen responses, Covid-19 resistance in young people and susceptibility in other animals, virus integration into the genome, vaccine trials, and correlates of immunity.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Nature’s year in review
The journal Nature identified science-related Covid highlights. As well as 10 people who helped shape science in 2020, including Jacinda Ardern for her crisis leadership.
Nature also highlights two papers in Science on interferon deficiencies that it considers as one of the top discoveries of 2020. We covered these papers in the 2 October Tracker.
What health experts couldn't predict
In another year in review article, this time in Nature Medicine, five things that were less predictable about the pandemic are described:
The failures in the UK and US responses
Insufficient attention to prevention (though this was really a case of ignoring rather than not being predictable)
Arguments about the choice between health or the economy
Underplaying the importance of travel bans and border measures
The difficulty of creating a joined-up international strategy
Locked-down researcher stories
Many researchers have had their projects disrupted by lockdowns and other constraints. This article in Knowable describes how scientists in a range of fields from several countries have adapted to, or had their research disrupted by, the pandemic.
Good reportage on the pandemic
Ed Yong, who has done excellent reporting on the pandemic in The Atlantic, has curated stories from other journalists that have produced great stories during different stages of the pandemic.
How young people avoid severe Covid-19
A news item in Nature reviews a range of studies looking at infections in young people. While they become infected and show symptoms, the virus is often eliminated very quickly. A variety of factors may be involved in this.
Their innate immune system (antibodies) is often stronger than adults, their more naive adaptive immune system (T cells) may react more quickly, and/or antibodies from other coronaviruses are providing some protection. Children also have fewer ACE2 receptors in their noses, so may be infected with a lower dose of SARS-CoV-2 than adults. These ideas are untested at this stage.
What animals are susceptible to Covid-19?
A variety of animals (domesticated or captive) have become infected with SARS-CoV-2 - dogs, cats, rhesus macaques, lions, tigers, puma, mink, Syrian hamsters. Captive snow leopards are the latest species to test positive.
A study, published in September, compared the ACE2 receptors in a variety of species to identify which animals may be most susceptible to infection with SARS-CoV-2. The great apes, and other primates, are very susceptible based on this analysis, although there are no reports of infections in them so far. Other species, such as some dolphins and whales, may also be at high risk.
Contact tracing - people plus apps make the best tracing team
An article in Scientific American describes how both people and technology are essential for effective contact tracing. It notes that human contact tracers have two key advantages over contact tracing apps: trust and efficacy. People are more likely to be trusted than companies providing the app or the reliability of the apps themselves. Human tracers also track down people who have been exposed, while apps require the exposed person to take action.
SARS-CoV-2 fragments may sometimes integrate into human genome
A pre-print paper from MIT reports finding fragments of the virus integrated into chromosomes in cell lines and cells obtained from patients. This can occur due to reverse transcriptases already in the cells (from other viruses or mobile genetic elements) converting the RNA into DNA. The researchers showed that SARS-CoV-2 infection or cytokines can activate some of these enzymes.
The integrated viral sequences appear to be fragments, and so can’t produce the complete virus. But these fragments may be transcribed later and could account for the detection of viral RNA long after an infection.
A commentary on this paper in Science notes that these results are mostly based on lab studies, but are intriguing nonetheless. These observations are likely to stimulate further discussion and studies into coronavirus genome integration.
Identical twins (maybe), different outcomes
An interesting case report in Annals of Internal Medicine describes presumed identical male 60 year old twins who became infected at the same time. They live together, work at the same place, and are assumed to have been infected by the same person. Both were hospitalised in the same hospital, but one was discharged after two weeks while the other required longer intensive care and had a long period of recovery. Viral loads at admission were similar. Reasons for the different clinical outcomes are unknown. A genetic test to confirm that they were identical twins was not done.
Bad cases of Covid-19 don’t have the same immune responses as influenza
Viral infections typically lead to infected people producing antiviral interferons followed by pro-inflammatory responses. A study published in Nature Immunology finds this is the case for influenza but not in moderate to severe cases of Covid-19.
This confirms earlier research about “unbalanced”, “uncoordinated”, or “untuned” immune responses in some Covid-19 patients. These result in poor control of viral replication and excessive inflammatory responses, leading to serious tissue and organ damage.
Genetic links to severe Covid-19 found
A study, published in Nature, identifies particular gene variants and their expression patterns in patients that are linked to severe Covid-19. Researchers performed genome-wide association studies of 2,244 critically ill Covid-19 patients and found low expression of an interferon receptor gene and high expression of other genes associated with inflammatory responses. Low expression of another gene may affect the ability of the patients to destroy viral RNA.
As noted by the previous paper, the results indicate that severe Covid-19 involves at least two biological pathways. One involves decreased antiviral defences, and the other over-activation of host-driven inflammatory responses.
The authors suggest that drugs that boost interferon signalling, dampen harmful inflammatory pathways, and/or reduce monocyte levels in the lungs could help treat seriously ill Covid-19 patients.
More vaccine safety results
A paper on the safety and efficacy of BioNTech & Pfizer’s BNT162b2 mRNA vaccine was published in the New England Journal of Medicine. Just over 21,000 volunteers were given the vaccine, and another 21,000 a placebo.
The vaccine is reported as being 95% effective in preventing Covid-19. There were eight cases of Covid-19 at least seven days after the second dose among those receiving the vaccine, while 162 infections were observed in the placebo group.
Indications that the vaccine was providing immunity were seen from 12 days after the first vaccine shot (the second was given 21 days after the first). Adverse effects were generally short-term, mild-to-moderate pain at the injection site, fatigue, and headache.
An interim analysis of the safety and efficacy of the Oxford & AstraZeneca ChAdOx1 vaccine were reported in The Lancet. Trials from the UK and Brazil were analysed, and included older volunteers, a range of ethnicities and people with health conditions. The study reports on 5,800 volunteers receiving the Oxford vaccine and 5,800 receiving a meningococcal vaccine used as the control. AstraZeneca had previously indicated that due to an error in manufacturing some of the people in the UK trial had received half the initial vaccine dose.
For those receiving the two standard vaccine shots (28 days apart) vaccine efficacy was calculated to be 62·1%. In participants who received a low dose followed by a standard dose, efficacy was 90·0%. While the trials involved people over 55 there is as yet insufficient information to determine efficacy for older people. Serious adverse effects were reported, but were relatively small proportions of those vaccinated or given the control vaccine. One case of transverse myelitis is still being investigated.
Interested in more immunology, then read on …
Following disease progression and immune responses in lab primates
A paper in Nature Communications followed immune responses in the lungs of infected rhesus macaques and African green monkeys to better understand disease progression. The researchers found three phases of immune responses. The third phase leads to either greater anti-inflammatory activity and disease control, or more pro-inflammatory immune responses and worsening disease. A stronger initial host immune response was associated with more severe outcomes in infected animals.
Indicators of immune protection
While it is easy to detect and measure the levels of antibodies it remains a challenge to know what immune responses correlate with actual protection from infection. Two recent papers suggest possible correlations.
A paper on rhesus macaques in Nature indicates IgG levels may be a good indicator. Transferring IgG antibodies from infected macaques to uninfected ones prevented the latter from becoming infected in a dose dependent manner (ie, more antibodies, greater protection).
Cellular immunity was also shown to have a role. Reducing CD8+ T cells from plasma before giving it to uninfected macaques decreased their level of protection.
However, a human study indicates it's more complicated.
In a study of 113 people with Covid-19, published in Cell, those with severe conditions had increased inflammatory molecules, lymphopenia (reduced white blood cells), pro-inflammatory cytokines, and high anti-receptor binding site antibody levels.
While the most severely ill patients had the highest concentrations of anti-receptor binding domain (RBD) and anti-spike antibodies, the ability of the anti-RBD IgG antibodies to neutralise the virus was found to be very weak in these patients. In contrast, those with milder symptoms had lower antibody responses but their antibodies were more effective neutralisers. The reason for this is unclear, but measuring neutralisation ability may be a useful indicator of immunity and disease progression.
In contrast to the macaque study, these authors caution against convalescent plasma treatments unless neutralising potency and the presence of inflammatory cytokines are measured first. Donors may have poorly neutralising antibodies and/or high levels of inflammatory cytokines that may make the recipient more ill.
A third study, published in Science Immunology, also reports that increasing antibody levels correlate with increasing disease severity. It didn’t identify specific correlates of immunity, and neutralisation potency wasn’t measured. But the authors did suggest that low levels of antibodies that target parts of the spike protein away from the receptor binding domain early in infection may be particularly important in controlling infection.
Meri Kirihimete
Keep washing hands well, have a mask handy, and mind your distancing. If in doubt, get a Covid test. Stay safe, and be kind.