Coronavirus Research Tracking - 2 October
Interferon disruption, vaccine progress, and estimating infectiousness
In this week’s Research Tracker we look mainly at papers about the effects of disrupted production of type I interferons. But also a diversity of other papers, including one describing some benefits of lockdowns for scientists.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Disrupted type I interferon production linked to severe disease
Type I interferons usually inhibit viral replication, but SARS-CoV-2 doesn’t appear to stimulate their production as much as some other viruses. This appears to allow the virus to spread more quickly in the body early in the infection.
Several papers have shown that type I interferons can be suppressed even further by host genetics, and is associated with more severe Covid-19 disease.
Briefly mentioned in last week’s Highlights was a paper reporting an association between rare genetic mutations, low type I interferon production and serious Covid-19 symptoms.
A companion paper from the same research team in the same issue of Science reported that 10% of nearly 1,000 patients with severe Covid-19 had auto-antibodies against some type I interferons. This prevented the interferons from binding to the virus.
Most (95%) of those with the auto-antibodies were men, suggesting their production was associated with the X chromosome. The auto-antibodies also tended to be more likely to be found in patients over 65. This research needs to be expanded to test more patients with severe Covid-19.
A discussion of the two papers notes that nearly 14% of the patients with serious Covid-19 in these two studies are linked to type I interferon disruptions. This is a surprisingly high proportion. It illustrates that even with a naturally poor type I interferon response to the virus there can be a fine balance between mild and serious disease.
Additional evidence for an X chromosome link to interferon
A short case study on two sets of brothers, published in July in the Journal of the American Medical Association, provides correlative support for an X chromosome association with type I interferon production. Two sets of brothers from unrelated families required intensive care for serious Covid-19 conditions, and one died.
Genome sequencing revealed that all had rare loss of function mutations at the same locus on their X chromosome. The mutations affected the regulation of type I interferon genes. All four patients had significantly lower levels of circulating type I interferon than normal, and low levels (but not significantly so) of a type II interferon.
Interferons also activate some T cells
Other research, published in Science Immunology, reports that Mucosa-associated invariant T cells in the blood are significantly lower in Covid-19 patients with moderate or severe disease. These T cells are a standard part of the immune response to microbial infections, and are thought to be activated by type I interferons and cytokines.
The current vaccine landscape
Updates on clinical trial progress for many of the vaccine candidates are available:
The London School of Hygiene and Tropical Medicine lists 45 in clinical testing
Biorender lists 51 in human trials
An overview in Nature provides more information on seven of the vaccines in advanced clinical trials. It notes that, based on Phase 2 trials, the Covid-19 vaccines that have produced the strongest immune response have been adjuvanted protein-based vaccines (like Novavax’s nanoparticle NVX-CoV2373). These have also been the ones to produce milder adverse reactions.
The rarity of elderly in clinical trials
An opinion in the JAMA Internal Medicine highlights the exclusion of people over 65 from vaccine and treatment trials. Reviewing Covid-19 clinical trials it found that just over half of 847 trials had a high risk of excluding older people.
An article in the New England Journal of Medicine reports on the effects of the mRNA-1273 vaccine on 40 people over the age of 56. Adverse reactions were mild to moderate and the stronger 100-μg dose elicited higher concentrations of binding and neutralising antibodies than the 25-μg dose. These results were similar to those seen in younger people.
Older children more likely to become infected than those under 12
A CDC study of nearly 300,000 children (5-17 years) in the US who tested positive for SARS-CoV-2 found that 1.2% were hospitalised, 0.1% were admitted to intensive care, and less than 0.1% died. Nearly twice as many young people aged 12-17 were infected as 5-11 year olds.
Three percent of those infected had at least one underlying health condition, such as asthma. This rose to 16% in children who were hospitalised, and 26-27% in those in ICU or who died. In comparison, about half of children who die from influenza have an underlying health condition.
Autopsies confirm systemic inflammation from Covid-19
A report in The Lancet Microbe summarises the results of autopsies of 21 people who died from Covid-19. All showed extensive inflammation across several organs, and had high numbers of neutrophils (white blood cells associated with infections). The authors conclude that Covid-19 is a systemic disease caused by a maladaptive immune response.
Assessing infectiousness from PCR tests
A paper published in Clinical Infectious Diseases demonstrates that detecting the virus earlier in PCR reactions correlates with greater infectiousness in cultured cells. The authors suggest that the cycle time value (the number of PCR cycles till the virus is detected) could be a useful indicator of infectiousness, and so reporting it may help better manage infections.
Some scientists don’t think there is sufficient evidence to make this claim, as discussed in Science.
A not yet peer reviewed review of studies on this topic finds that there is a suggestive link between cycle time and infectiousness. However, the quality of the individual studies are too variable to reach a firm conclusion at the moment.
Research benefits from lockdown
A commentary in Cell describes some of the positive research aspects that the authors have seen from lockdown restrictions. These include better one-on-one meetings, greater access to experts online, and better opportunities to participate in professional group meetings online.