31st July - the COVID-19 coronavirus compendium

More vaccines, infections in emergency medical services, and undiagnosed cases in Brazil

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This week we learnt that four vaccines have been tested in non-human primates, more than 40% of emergency medical service responders in New York have taken sick leave for COVID-19, and most cases of respiratory disease in low income parts of Brazil are undiagnosed, although they are presumably due to SARS-CoV-2.

Vaccines

The ChAdOx1nCoV-19 vaccine, based on a chimpanzee Adenovirus, was tested in mice and monkeys and shown to induce a robust humoral and cellular immune response. Vaccinated monkeys showed no evidence of pneumonia when infected, nor any evidence of immune-enhanced disease, although the vaccine did not entirely prevent infection. Despite a reduction in virus shedding from the lungs, nasal shedding was similar in vaccinated and control animals, suggesting that the vaccine may prevent disease, but not infection or transmission. Human studies have already begun, with more than 8000 volunteers already signed up. The same vaccine was also shown to induce humoral and cellular immune responses in mice and pigs in a second study, with a second dose of the vaccine increasing neutralising antibodies in pigs.

Another adenovirus-based vaccine, this time based on serotype 26, was developed and tested in rhesus macaques. Vaccinated animals showed little or no virus replication from bronchiolar lavage or nasal swabs, showing a high level of protection in this animal model. This vaccine is also being tested in humans.

An mRNA vaccine, mRNA-127, was tested in non-human primates, and found to induce a Th1-based response. Vaccinated animals were protected from pneumonia, and shed no or little virus upon challenge. A lipid-nanoparticle-encapsulated mRNA vaccine was also developed, shown to be thermostable, and tested in mice and monkeys. Two doses of the vaccine provided complete protection in mice, and a robust immune response was induced in mice and monkeys. This vaccine is also being tested in phase 1 clinical trials.

A soluble receptor binding domain of the coronavirus spike protein was produced in baculovirus and then used to immune mice and monkeys, in this case Macaca mulatta. Antibodies produced against this vaccine were shown to block interaction with ACE-2 and the immunised monkeys shed little virus upon infection.

A machine learning approach to peptide vaccine formulations was presented, together with an online vaccine evaluation tool.

Immunology

T cells reactive against SARS-CoV-2 were detected in 83% of patients with COVID-19, but also in 35% of healthy donors, suggesting cross reactivity with human coronaviruses 229E and OC42. It is not known if this cross reactivity from a past common cold infection provides any protection from COVID-19.

Levels of the C5a anaphylatoxin and its receptor, CD88, were higher in severe COVID-19 patients than those with mild disease. Inhibition of this pathway prevented acute lung injury in infected mice, suggesting that this pathway may be important in COVID-19 disease. Another study also looked at the immune correlates of disease and found that a maladaptive immune response was associated with severe COVID-19.

Immune evasion

The ORF6 protein of SARS-CoV-2 inhibited type I interferon production and interferon-beta treatment blocked SARS-CoV-2 replication in tissue culture.

The papain-like protease PLpro of SARS-CoV-2 was shown to attenuate type I interferon responses by cleaving ISG15 from IRF3. The protease PLpro of SARS-1 acts in a different way, by targeting ubiquitin.

Genomics

A rare loss of function mutation in TLR7 was associated with severe COVID-19 in 4 young male patients in the Netherlands. The genetic mutation impaired type I and II interferon responses in these previously healthy men.

The lineage of coronaviruses that gave rise to SARS-CoV-2 has been circulating in bats for decades, since around 1948, according to an analysis of bat coronavirus genomes. The precise ancestor of SARS-CoV-2 has yet to be identified.

Treatments

The lectin FRIL, isolated from hyacinth beans, has anti-viral activity against both influenza and SARS-CoV-2, by binding to N-type glycans on the viral receptors.

Dexamethasone is a promising treatment for late stage COVID-19 disease, but its use can increase the risk of hyperinfection with Strongyloides, a parasitic worm, which is endemic in many parts of the world. Treatment of at-risk patients with ivermectin, an anti-parasitic drug, may be warranted.

Diagnostics

18% of UK healthcare workers tested positive for a past infection with SARS-CoV-2, based on serology testing. 45% of symptomatic cases tested positive, as did 10% of healthcare workers with no symptoms. False negatives were repeatedly identified, where a PCR positive sample subsequently tested negative by serology, and the authors caution that serology studies should remain in a healthcare setting to avoid misleading results.

A study from Houston found that 5.4% of COVID-19-facing healthcare workers tested positive for the virus by RT-PCR, compared to less than 1% of non-COVID-19-facing workers, suggesting hospital transmission.

A new technique to detect SARS-CoV-2 using MALDI-MS, which is widely available in low and middle income countries, was developed with machine learning techniques and shown to have 94% accuracy.

Structural biology

A stable coronavirus spike protein trapped in the pre-fusion state was designed and expressed. This could be a useful tool for serological assays and as a potential immunogen. Another group published a crystal structure of the spike in complex with an antibody, EY6A, isolated from a patient, which identified a major neutralising epitope.

The crystal structure of the SARS-CoV-2 2′-O-RNA methyltransferase in complex with cofactors and with an inhibitor was published, which may aid drug design.

Another structure showed how the viral non-structural protein 16 (nsp16), in conjunction with nsp10, methylates virally encoded mRNAs. The structure of the viral replication-transcription complex was also solved, which may also provide an anti-viral target.

Transmission

A description of the outbreak in Brazil was published, which found that testing was more common in richer parts of the country, but found a high incidence of respiratory viruses of unknown aetiology in poorer areas. This suggests that testing is being directed at richer areas, rather than in areas where the virus is more prevalent.

The global spread of the virus was modelled using online information from official websites, press releases, press conferences, and social media feeds of government agencies. Using this method, they estimated that two thirds of early cases came from travel links to China, Italy, or Iran, and that 75% of transmission occurred within households.

A mathematical modelling study predicted that a person with a typical viral load who breathes normally poses a low risk for transmission, even in a poorly ventilated closed environment. The risk from coughing was predicted to be much higher.

Social distancing

US states that closed schools had fewer cases and deaths from COVID-19, although other interventions may have also played a role.

Mobile phone data was used to model the effect of non-pharmaceutical interventions on the control of the COVID-19 outbreak in Shenzhen, China.

Healthcare

Nursing homes that reported COVID-19 cases had a history of higher rates of complaints than those that did not report any cases, although the greatest predictor of cases was the county-level rates of the virus.

35% of firefighters and 41% of emergency medical service responders in New York took medical leave for confirmed or suspected COVID-19, 4 of whom died. This leaves a reduced workforce to cope with increased demand, especially for emergency medical services.

Masks

Wearing masks was associated with reduced face-touching behaviour, especially touching of the eyes, nose and mouse, according to an analysis of thousands of CCTV images from several countries across the world.

Risk factors

COVID-19 mortality amongst Black, Latinx, and Asian individuals in the US has been underestimated, because of the weighting algorithm used by CDC, according to a new study. The weighting algorithm fails to take into account the geographical distribution of ethnic groups, which is itself due to systemic racism and discrimination. Another study found that poorer US counties with a substantial non-White population had fatality rates 9 times higher than poorer US counties that were substantially White.

Prevalence of cancer was not associated with an increased risk of infection, but was associated with an increased risk of hospitalisation and death, in a study of more than 84,000 Italians infected with the virus. Overweight and obese people infected with COVID-19 had significantly increased mortality, in a study from New York City, although the effect was seen in men and not women.

People with inflammatory diseases of the joints, gut and skin who were taking cytokine inhibitors to treat their illness were less likely to have seroconverted to SARS-CoV-2, compared to those who were not taking the drugs, and to the general population. This suggests that the anti-inflammatory drugs may partially protect from infection.

Children are less likely to be infected with SARS-CoV-2 and less likely to have severe COVID-19 disease. A new study compared the levels of viral nucleic acid in children of different ages, although their use of the CT value as a proxy for viral replication has been questioned by some.

Clinical trials

1551 clinical trials for COVID-19 are registered on clinicaltrials.gov, most of which appear low quality. Rapid data sharing ahead of peer review could mitigate this, as would multicentre registries to allow larger, coordinated, trials.

Animal models

SARS-CoV-2 was adapted to growing in BALB/c mice by serial passage, in order to provide an animal model for vaccine and other testing.

Clinical findings

A large study of the outbreak in Germany found that 22% of hospitalised patients died, despite no hospitals being overwhelmed with COVID-19 cases. Common co-morbidities were also described.

78% of recovered COVID-19 patients had cardiac involvement, including myocardial inflammation, based on MRI scanning, showing the potential for long term cardiovascular consequences of infection. Another study found evidence of viral RNA in the myocardium during autopsy, although the significance of this is unknown.

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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