Coronavirus Research Tracking - 31 July

Looking for the virus source, the roles of children in transmission, interferon treatments, and vaccine trials on macaques.

In this week’s Research Tracker we look at recent papers on viral origins, viral tests, aspects of infectivity, interferons as treatments, and testing vaccines on macaques.

The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre. 

The missing link

A detailed phylogenetic analysis of SARS-CoV-2, bat and pangolin coronaviruses just published in Nature Microbiology indicates that we haven’t yet found SARS-CoV-2’s closest viral ancestor. The researchers infer that the pangolin is unlikely to have been an intermediate host before the virus infected people. 

The similarities between the pangolin and SARS-CoV-2 spike protein sequences reflect an older relationship, obscured in some bat virus sequences by recombination. 

The researchers estimate that SARS-CoV-2 and the virus it is most similar to (RaTG13, from a horseshoe bat) possibly diverged from each other between 40 and 70 years ago. This suggests that there are other bat coronaviruses more closely related to Covid-19 that haven’t yet been found.

This may fit with some epidemiologists’ views that SARS-CoV-2 may have arisen in Southeast Asia (Vietnam, Laos or Myanmar) rather than China, and infected some people earlier without causing disease.

Quick and simple tests for the virus

Rapid tests that don’t require PCR or other laboratory equipment are being developed. An obstacle is that some specialised equipment, or electricity, is needed meaning that they can’t be used everywhere. A paper (not yet peer reviewed) describes how a simple centrifuge, necessary for these tests, can be made from a hand-powered torch.

People become less infective a week after symptoms appear

A review has looked at studies that reported the shedding of SARS-CoV-2. It found the virus was shed from the upper respiratory tract for on average 17 days, with maximum levels of shedding within the first week.

While the virus could be shed for over 80 days, live virus was not reported from nine days after symptoms developed. The study has not been peer reviewed, and the authors acknowledge that some of the studies they included involved treatments that may have affected the shedding of the virus. The review doesn’t cover shedding of those in pre-symptomatic stages, or those who are asymptomatic.

A study (also not yet peer reviewed) of nursing homes and aged care facilities found that viral levels can vary 250 million fold between infected people. There was, though, no relation between virus levels and Covid-19 symptoms, at least at the time of testing.

Are young children more or less likely to spread infections?

A large study, published in Emerging and Infectious Diseases, examined infection and transmission within South Korean households when there were restrictions on work and travel. It found that children under 10 had the lowest rates of passing the virus on to others in their household (5.3% of their contacts became infected). The biggest spreaders were 10-19 year olds (18.6%). The reasons for the differences are not known, and these patterns may not apply in other countries or circumstances.  

This is illustrated by an Italian study (in pre-print) that found that children up to 14 were the most likely to spread the virus. The number of cases was, though, small. The authors suggest that young children were less likely to follow social distancing precautions, and so more likely to spread the virus.

Research just published in JAMA Pediatrics found that children under five with mild or moderate Covid-19 had higher viral levels in the upper respiratory tract than older children and adults. The authors note that young children with high levels of respiratory syncytial virus are more likely to spread infections, and this may be the case for SARS-CoV-2 too.

Interferons as potential treatments

Certain types of interferons are being considered as treatments to reduce the severity of Covid-19 infections. Interferons are one group of cytokine molecules that are released when cells become infected with viruses and help regulate immune responses. 

Strong type-I interferon responses are known to be important for protecting against development of severe disease following viral infections. 

SARS-CoV-2 infection is reported to suppress the expression of type-I and type-III interferons, and increase the expression of interleukin-6 and other chemokines, resulting in greater inflammatory responses.

A French study, published in Science, found that none of the hospitalised Covid-19 patients had Interferon-beta in peripheral blood. Those with more severe conditions also had low levels of interferon-alpha, along with high levels of tumour necrosis factor-alpha and interleukin-6, leading to excessive inflammation.

But some conflicting reports on interferon expression

However, other studies published in Nature and Immunity, report that interferon-alpha levels were higher in patients with severe symptoms. The Nature paper also reported that interferon-alpha levels declined in those with moderate symptoms. 

As a non-immunologist these results strike me as contradictory. The differences may be due to different methods, or the numbers or types of patients being studied. But as the Nature and Immunity papers show, through looking at the expression of many different genes, immune responses to infection are very complex.

Meanwhile, a small trial treating patients with a synthetic interferon is reporting some success. The results haven’t been published yet, but are reported in a news article in Science. Other trials of interferons are also underway.

Screening for other possible treatments

High Throughput screening of 12,000 existing small molecules that had some clinical testing, or FDA approval, for other conditions were tested for activity against SARS-CoV-2. Thirteen showed potential promise, and their existing safety data may help speed up clinical testing. The study was published in Nature.

Three challenge trials on vaccinated macaques

Normally, you’d expect animal trials to be reported before human ones. However, that’s not the case during the pandemic.

Moderna’s mRNA-1273 vaccine was tested on a small number of rhesus macaques who were then infected with the virus. All the vaccinated animals produced neutralising antibodies, and type 1 T helper cells, demonstrating strong humoral and cellular immune responses.

All of the vaccinated animals had only limited inflammation, suggestive of a balanced immune response. The animals receiving the higher dose of the vaccine did not have replicating virus in their noses two days after infection. The results are reported in the New England Journal of Medicine.

Oxford’s and AstraZeneca’s vaccine was also tested and challenged in macaques, with the results reported in Nature. Vaccination resulted in a balanced immune response. After being infected with the virus, vaccinated animals developed lower viral loads in the lungs and did not develop pneumonia, in contrast with unvaccinated animals. However, unlike Moderna’s vaccine, vaccination did not affect viral shedding from the upper respiratory tract, and so vaccinated animals may still be infectious.

Two injections of the Oxford vaccine 28 days apart appeared to result in a stronger immune response than a single dose. There was no evidence that vaccination resulted in excessive inflammatory responses after infection.

In the same issue of Nature the results of a challenge trial in macaques of another adenovirus vaccine vector is also reported. Based on adenovirus serotype 26, seven vaccine constructs with different lengths or parts of the spike protein were tested. These trials involved single vaccinations.

The seven vaccines elicited neutralising antibodies. One of the vaccines (called Ad26.COV2.S) resulted in no virus being detected in the lower respiratory tract and three of four animals had no virus in their upper respiratory tract. The other vaccines were not as effective. Ad26.COV2.S is entering human clinical trials.

Addendum: Derek Lowe’s blog on Science Translational Medicine compares the results of these trials, as well as two others.

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