Coronavirus Research Tracking - 19 February
Transmission via surfaces, saliva & other diagnostic tests, treatments, innate immunity, variants, vaccination challenges
In this week’s eclectic Research Tracker are papers about surface transmission, saliva and breath tests, current and new treatments, differences in initial immune responses between younger and older people, the effects of Neandertal haplotypes, more new variants, the impacts of recent variants or specific mutations, and vaccination challenges.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
WHO investigation
Science has published an interview with one of the WHO team members who investigated the origins of SARS-CoV-2. He explains why it is very unlikely that the pandemic was started by the virus being on frozen food or escaped from a lab, and additional research that is needed to determine when the virus started to circulate in people.
A draft report is expected to be released next week.
Risks of transmission from surfaces and objects
Following the “Valentines day outbreak” in Auckland there has been renewed discussion about SARS-CoV-2 infections from objects and surfaces (aka “fomites”).
There have been few recent research articles on this issue. The current consensus is that while possible, infection with SARS-CoV-2 from surfaces appears to be rare.
An assessment published in Environmental Science and Technology Letters concludes that the risk of becoming infected from a surface is low (less than one in a million).
A commentary in the Journal of Occupational and Environmental Hygiene discusses evidence that respiratory viruses are quickly inactivated after contact with skin.
China’s CDC reported in January that viral RNA was detected rarely (in 0.048% of samples) on food or food packaging. They listed four infection cases in 2020 that were linked to frozen food or their packaging, but the evidence was circumstantial rather than definitive.
In the 5 Feb Tracker we referenced a News feature in Nature that discussed the limited evidence that infections from surfaces or clothing are a significant transmission pathway. Regular and comprehensive handwashing remains an effective practice to reduce the risk of infection.
Saliva tests
The Science Media Centre published an Expert Reaction on saliva testing, with reference to two tests being trialled in New Zealand. These two tests are reported to have high levels of accuracy and sensitivity, so can complement existing nasopharyngeal tests.
In January the Tracker noted a review in JAMA Internal Medicine that found saliva tests can be as sensitive and accurate as nasopharyngeal tests.
An electronic nose
An electronic nose that may be able to distinguish between infected and uninfected people is described in a pre-print paper. The technique detects volatile organic compounds characteristic of viral infections. In validation tests involving 1,800 people it had a sensitivity of about 99% and a specificity of 80%.
However, the authors note that they haven’t yet tested the ability of the test to distinguish SARS-CoV-2 infections from other respiratory viruses.
Canine noses appear very good at detecting Covid-19, but a news item in Nature noted that larger tests are required.
Review of diagnostic tests
A review of diagnostics tests in Nature Materials describes the current range of methods for detecting SARS-CoV-2 infections. It notes that many methods have only been tested using small sample sizes, so further work is required before reliable clinical or surveillance use.
Covid-19 treatments
The US National Institute of Health published a report of the range of therapeutic options for treating Covid-19, and their effectiveness. The British Medical Journal also has a living systematic review of drug treatments, last updated in December.
So far, dexamethasone and remdesivir are the only drugs with strong evidence of effectiveness, and these are only useful under particular circumstances.
The Your Local Epidemiologist blog site summarises these two reviews.
The anti-inflammatory tocilizumab can help patients with severe Covid-19
The monoclonal antibody tocilizumab, used to treat rheumatoid arthritis, appears effective in helping Covid-19 patients with serious symptoms, according to preliminary results involving 4116 patients from the RECOVERY trial (not yet peer-reviewed). Within 28 days of treatment it reduced the risk of death, the need for ventilation, and length of hospital stay.
A commentary in Science notes that the reported 4% absolute reduction in mortality is significant. But it also points out that tocilizumab costs 100 times more than dexamethasone.
Infection in ferrets can be prevented by a lipopeptide
A lipopeptide that blocks the fusion between the virus and host cell prevents ferrets from becoming infected reports a paper published in Science. The lipopeptide, administered as a nasal spray, uses a seven amino acid repeat unit found at one end of the spike protein. It prevents the spike protein adopting the right shape that leads to fusion with the cell. Only small numbers of ferrets were tested and further research is also needed to find the best formulation of the lipopeptide.
Developing broader protection against coronaviruses
Nanoparticles that contain the receptor-binding domain of several different coronavirus spike proteins were shown to elicit strong immune responses to several coronaviruses in lab mouse tests. The research, published in Science, indicates that this approach may help protect against future coronavirus pandemics.
Another approach to developing broader protection was also published in Science. This involved using directed evolution in laboratory experiments to create antibodies against SARS-CoV-2 that are more potent and broader acting. One of these antibodies was able to neutralise a variety of SARS-CoV-1 and SARS-CoV-2-related coronavirus receptor-binding domains. The antibody also provided protection from severe SARS-CoV-1 and SARS-CoV-2 induced disease in mice.
A third paper (not yet peer-reviewed) describes an antibody from a Covid-19 patient that is able to neutralise both SARS-CoV-2 and SARS-CoV-1 pseudoviruses. The authors suggest that a combination of such cross-neutralising antibodies that target different parts of the virus may provide protection against a range of SARS-CoV-2 variants, and future new coronaviruses.
Innate Immunity
Covid-19 and the human innate immune system
A review published in Cell summarises what is known and still uncertain about innate immune responses during the five phases of Covid-19 progression from infection to restoration of homeostasis.
The innate immune system involves cells that respond to infections before antibodies are produced.
Young peoples’ innate immune system responds differently
The innate immune system of children responds differently to the virus a paper in Nature Communications reports.
The types of cells responding to infections were monitored over time in 48 children (under 17 years old) with mild symptoms, and compared with 70 adults. Children showed greater activation of neutrophils, natural killer and dendritic cells. This suggests that the immune system in children more rapidly attacks and neutralises the virus, which along with them having fewer ACE2 receptors could explain why young people appear to be less affected by SARS-CoV-2.
The study also showed that being exposed to, but not infected by, the virus causes changes in immune cell populations. After exposure both children and adults produce certain types of neutrophils for up to seven weeks. The implications of this requires further research.
Neandertal haplotype provides some protection
A paper published in the Proceedings of the National Academy of Sciences reports that a haplotype at a region on chromosome 12 is associated with a degree of protection from severe Covid-19. The relative risk of needing intensive care is reduced by about 22% per copy of the haplotype. This haplotype appears to be derived from Neandertals. It was previously shown to provide some protection to three other RNA viruses (West Nile virus, hepatitis C virus, SARS-CoV) and genes in the region encode for enzymes that are induced by interferons and activated by double-stranded RNA (though coronaviruses are single-stranded).
Last year the same authors wrote a paper describing how a region of chromosome 3 that is linked to a greater risk of hospitalisation with Covid-19 also traces back to Neandertals.
Effects of mutations
The impacts of specific variants and individual mutations continue to be investigated.
The infection period of B.1.1.7 may be longer
A report from Harvard University suggests that people infected with the B.1.1.7 variant may be more infectious because it has a longer period of high level viral loads. For B.1.1.7, the mean time to peak viral concentration was 5.3 days, compared to two days for non-B.1.1.7 variants. The mean overall duration of infection was 13.3 days for B.1.1.7 and 8.2 days for other variants.
The results are based on only 7 people with the B.1.1.7 variant and 58 people infected with other variants.
B.1.351 resistance to antibodies
Another study (not yet peer-reviewed) has demonstrated that the South African B.1.351 variant is resistant to many antibodies.
Monoclonal antibodies that target the receptor-binding domain, along with convalescent plasma and sera from vaccinated people appear to be relatively effective against the B.1.1.7 variant. However, it is resistant to antibodies that target the N-terminal domain of the spike protein.
The B.1.351 variant is markedly more resistant to monoclonal antibodies, convalescent plasma and sera from vaccinated people, with up to 12-fold increases in resistance to neutralisation.
The E484K mutation appears to be the main factor that disrupts antibody binding to the receptor-binding domain.
D614G makes spike protein more resistant to degradation
The D614G mutation (now very common), and its potential to increase the infectivity of the virus, created a lot of interest last year. The new variants have dominated the news more recently.
However, a paper just published in eLife reports that the 614G mutation increased transmissibility of the virus up to eight-fold in various cell cultures, when compared to the original virus. The 614G mutation also appears to make the spike protein more resistant to cleavage when copies are made in the cells, leading to virus particles with more spike proteins.
N501Y leads to stronger binding
A paper (not yet peer-reviewed) reports that the N501Y mutation (present in the B.1.1.7, B.1.351 and P.1 variants) leads to stronger binding between the spike protein’s receptor-binding domain and the ACE2 receptor. Binding was four-fold stronger when tests were performed using living cells.
The two studies described above focus on one or a few mutations only. The impacts of these mutations may be affected by other parts of the virus in actual infections. This is a more difficult area of research to conduct.
More new variants
Analysis of US sequences (not yet peer-reviewed) has identified seven independent mutation events that changed the spike protein amino acid at position 677 from glutamine (“Q”) to histidine (“H”) or proline (“P”) between August and November last year. The 677H mutation also occurs elsewhere, but doesn’t always persist. It is unknown whether the mutations at this site change infectivity or disease severity.
Another variant - B.1.525 - has also just been described. The earliest genome sequence dates back to 15 December, and it has now been found in 13 countries on five continents. It includes several mutations deemed to be of “biological significance”; that is, they may be associated with greater infectivity or pathogenicity. These include the E484K, Q677H and F888L mutations, and several deletions that have been previously reported in other variants. No information is available yet on whether this variant is more transmissible or is able to evade immune responses.
Vaccinations
Reports of anaphylaxis in the USA
A report published in JAMA Insights reports cases of anaphylaxis in the US associated with vaccinations of the Pfizer-BioNTech and Moderna vaccines. From nearly 10 million doses of the Pfizer-BioNTech vaccine there were 4.7 cases of anaphylaxis per million doses, while after 7.5 million shots the Moderna vaccine had 2.5 cases per million. There were no deaths due to anaphylaxis.
Thirty two per cent of the 66 anaphylaxis cases had earlier episodes of anaphylaxis from other exposures.
Overcoming Covid Vaccine Hesitancy
An essay published in the New England Journal of Medicine notes that with vaccine hesitancy, correcting misinformation or using emotional approaches don’t usually work. While recommendations from clinicians are usually very influential in increasing vaccination, evidence-based information will not persuade everyone.
Providing more or “better” information, or changing the message is less important that addressing the questions, concerns, beliefs, and historical forces that lead to hesitancy or refusal. The author recommends that “before you attempt to persuade, try to understand.”
Vaccination production and distribution challenges
A commentary in The Lancet identifies challenges to vaccine production, affordability, allocation and distribution. The paper includes characteristics of 26 leading vaccine candidates and how they can contribute to global immunity, and the trade-offs involved.
International Science Council to develop Covid-19 Scenarios
A commentary in The Lancet suggests that SARS-CoV-2 and Covid-19 may not be easily eradicated because of potential animal reservoirs, insufficient vaccinations, and immune escape. To help decision makers the International Science Council will be developing scenarios that cover a range of Covid-19 situations over the next three to five years. Two distinguished New Zealand researchers are involved.
Covid nerd zone
A Covid-19 Disease Map is being developed. This collaborative enterprise shows the molecular mechanisms associated with different disease conditions.