24th July - the COVID-19 coronavirus compendium

Serology testing in the USA, two adenovirus vaccines, and how the virus alters cell metabolism

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This week we learnt that the prevalence of SARS-CoV-2 in the US ranges from 1-7% depending on the city, two adenovirus-based vaccines induced immune responses in humans in clinical trials, and that the virus alters cell metabolism, perhaps explaining why people with diabetes are at an increased risk of severe COVID-19. 

Diagnostics

A serology survey of more than 16,000 people in the US determined the prevalence of antibodies against SARS-CoV-2 in the population, from 1% in the San Francisco bay area to 7% in New York City. More than 10 times more infections were identified using serology than case report data, showing that the number of infections is vastly underestimated. However, the majority of the country is still susceptible to the virus.

A new serological test based on the ability of antibodies to inhibit the interaction between the coronavirus spike protein and ACE-2 was developed. The test does not require high containment facilities, is cheap and quick, and has already been commercialised. The authors have written a Behind the Paper describing their experiences.

Home testing for SARS-CoV-2 with a midnasal swab was comparable to clinician collected nasopharangeal swabs in this study from Washington State.

Transmission

The spread of the outbreak in Brazil was studied in detail. Interventions reduced the reproductive number in São Paulo and Rio de Janeiro, but it still remains between 1 and 1.6, showing that transmission continues and current interventions are inadequate. An analysis of over 400 viral genomes found that the virus was introduced more than 100 times into the country.

Serial intervals, that is the time between illness onset in successive cases, shortened in China from almost 8 days to 2 to 3 days, due to non-pharmaceutical interventions. Tracking the serial interval may allow more accurate estimations of reproduction numbers.

Social distancing

Coordinating synchronised intermittent lockdowns across Europe would reduce the number of lockdown periods needed to end community transmission of SARS-CoV-2, according to a modelling study using mobile phone data from Vodafone and mobility data from Google.

Immunology

The immune responses to COVID-19 and influenza virus were characterised and compared in a study using single cell sequencing of peripheral blood mononuclear cells. COVID-19 was characterised by activation of the STAT1/IRF3 pathway, whereas influenza induced STAT3/NFκB.

Lymphocyte antigen 6 complex, locus E (LY6E) was shown to be a potent interferon-stimulated molecule that restricts coronavirus infection both in cells and in mice.

Metabolism

A mechanism by which SARS-CoV-2 alters cell metabolism was described in detail. Monocytes infected with SARS-CoV-2 become highly glycolytic which triggers mitochondrial reactive oxygen species, which in turn stabilises HIF-1α, part of the hypoxic response. HIF-1α then alters monocyte metabolism, inhibiting the T cell response and reducing epithelial cell survival. These metabolic changes following virus infection may explain why diabetes and obesity are risk factors for severe COVID-19 and suggests that targeting of HIF-1α may have therapeutic potential.

Bats

Clues as to how bats may harbour so many viruses, including coronaviruses, were found in new genomes of six bat species. Evidence of past infection with many viruses, including retroviruses, was found in their genomes, as well as adaptations in immune genes.

Treatments

A screen of 12,000 FDA-approved drugs found several that can inhibit virus replication in cells. The PIKfyve kinase inhibitor, apilimod, had promising anti-viral effects in a primary human lung explant model. Testing in humans is now needed.

Early treatment with IFN-α2b, a type of interferon used to treat hepatitis C virus infections, was associated with reduced COVID-19 mortality, whereas late treatment more than 5 days after admission was associated with increased mortality. This study of 446 patients in China therefore provides optimism and also caution on the use of interferon, which is naturally produced by the body in response to virus infections.

COVID-19 patients treated with interleukin-7 showed restored lymphocyte levels and did not contribute to hypercytokinaemia. No effect on mortality was seen in this small study.

A clinical trial found that hydroxychloroquine, either with or without azithromycin, did not improve clinical status in COVID-19 patients. The trial in Brazil also found that the QT interval was prolonged and liver enzymes elevated in the treatment group.

Two new studies shed light on why chloroquine and hydroxychloroquine are not effective against SARS-CoV-2. The first found that Vero cells, commonly used in the lab, do not support a productive coronavirus infection unless engineered to express TMPRSS2. Once expressing TMPRSS2, which allow entry of the virus, chloroquine does not block viral infection, refuting previous studies.

The second study found that hydroxychloroquine is not anti-viral in human airway epithelium and does not reduce viral load in macaques, either alone or in combination with azithromycin.

Receptor

19 potent neutralising antibodies were isolated from 5 COVID-19 patients. They bound to the receptor binding domain, the N-terminal domain, or domains at the top of the spike, showing that various parts of the spike can be targeted. Such antibodies could be used as a therapeutic.

An antibody against SARS-CoV-2 was shown to reduce virus titres in infected mice. The antibody acts by preventing attachment of SARS-CoV-2 to its host cell receptors.

A stably expressed coronavirus spike protein was produced, named HexaPro, with mutations to increase protein yields. The protein can be stored at room temperature and could be a valuable tool for vaccine development and serological testing.

Soluble spike receptor binding domains were generated locked into either the “up” or “down” position, providing a framework for rational design of potential vaccine candidates. Another study found that the spike protein is decorated with N-glycans, which may protect against host immune responses.

Vaccines

Two adenovirus-based SARS-CoV-2 vaccines were tested in humans. The ChAdOx1 vaccine from the Jenner Institute at the University of Oxford is based on a chimpanzee adenovirus expressing the SARS-CoV-2 spike protein and was given to 500 participants, with a further 500 given a meningococcal vaccine as a control group. The vaccine was safe and induced good humoral and cellular immune responses.

The second was a human adenovirus based vector and was tested in 500 people in China. The vaccine was safe and induced an immune response, including neutralising antibodies, in the vast majority of participants, paving the way for a phase 3 trial. Several vaccines have now been shown to induce an immune response in humans, but it is not yet known if any of them offer protection from infection.

At-risk groups

The risk of death from COVID-19 in care homes was 13 times higher than amongst adults over 69 years living in the community, according to research from Ontario, Canada.

Cancer increased the risk of death from COVID-19 in those under 65 years, but not in those over 65. Deaths from cancer are predicted to increase due to longer waiting times, unless additional capacity if provided.

Genomics

Genetic variability in ACE-2, the coronavirus receptor, was identified in the Italian population. The authors provide some evidence that this variation may affect severity of COVID-19, although further research is needed.

Model systems

SARS-CoV-2 was shown to grow in, and remodel, human airway epithelium. This model system was then used to show that remdesivir, both alone, and in combination with diltiazem, reduced virus growth. Diltiazem is an anti-hypertensive drug that induces an interferon response and is being tested as a potential influenza treatment, and so will now be tested against COVID-19 in clinical trials.

Virology

The non-structural protein, Nsp1, of coronaviruses is important for virulence by shutting down host mRNA translation. The structural basis for this effect was identified, showing that this host mRNA shutoff also reduces the innate immune response.

286 host proteins that are targeted by SARS-CoV-2 were identified, providing a library of potential drug targets.

Pregnancy

8% of mothers tested positive for SARS-CoV-2, but none passed the virus on to their babies, in a study of more than 1400 deliveries in New York City. Hygiene precautions were taken and breastfeeding was allowed, combined with parental education.

Mental health

The prevalence of mental distress in the UK increased during the pandemic, with the largest increases in those aged 18-34, women, and people living with young children.

Clinical findings

16% of hospitalised COVID-19 cases in New York City had a thrombotic event; those with such an event had an in hospital fatality rate of 43%, much higher than the 21% fatality rate in those without thrombosis.

The incidence of severe diabetic ketoacidosis was higher in children in Germany during the coronavirus pandemic than in previous years. There could be many causes for this, including reduced medical services.

Go to the profile of Ben Johnson

Ben Johnson

Head of Communities & Engagement, Springer Nature

I gained my first degree in virology from the University of Warwick and a PhD in influenza virus immune evasion from Public Health England and the University of Reading, UK. My research interests then moved on to smallpox vaccines, viral ion channels, and cell adhesion, while a postdoc at Imperial College London. I joined open access publisher BioMed Central in 2011 as an Acquisitions Editor and then Associate Publisher, and was responsible for launching new journals, including Microbiome, Zoological Letters, and Movement Ecology. I have been Head of Communities & Engagement at Springer Nature since 2016, running our online community blogs, and a Consulting Editor at Nature Medicine since June 2020, handling COVID-19 papers. I am based in our London office.

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