This week’s Research Tracker is a special Christmas edition. I highlight what I think have been some of the more significant or interesting papers and scientific issues related to SARS-CoV-2/Covid-19 this year.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
The first genome sequence
On 10 January the first SARS-CoV-2 genome sequence, generated by Yong-Zhen Zhang and colleagues, was shared online. As well as helping identify the virus’ origins and relationships it stimulated, within days, the development of potential vaccines, such as Moderna’s mRNA vaccine.
A paper on the genome sequence was published on February 3rd in Nature.
Early clinical effects and transmission dynamics described
Clinical features of Covid-19, based on patients in Wuhan, were published in several papers in The Lancet in January. One paper reported person-to-person transmission. Another described the common symptoms in 41 patients, and a third paper covered the epidemiological and clinical characteristics of 99 cases.
In late March a paper in the New England Journal of Medicine described the transmission dynamics of the first 425 confirmed cases, noting infection of close contacts. It estimated that the R0 number (how many people a person passes the infection onto) was 2.2.
A more comprehensive overview of symptoms was published in the Journal of the American Medical Association in June. Six clusters of symptoms were also described mid year, emphasising the complexity of Covid-19.
The Imperial College model
Imperial College London’s modelling, published on 16 March, indicated large numbers of deaths and the potential for overwhelmed health systems if no actions were taken to control spread of the virus. This prompted a rapid change in approach in the UK, and some other countries, away from adopting a herd immunity strategy.
Nick Wilson and Michael Baker modelled potential age-specific impacts in NZ on 16 March. Modelling work from Te Pūnaha Matatini also informed the government responses.
Modelling approaches to the pandemic were covered in a Special Report in Nature on 2 April.
Has a more infectious strain emerged?
A pre-print paper originally posted on 5 May suggested that the D614G amino acid change in the spike protein has resulted in a more readily transmissible virus. This generated a lot of media interest, as well as scientific critiques about the paper’s conclusion. The paper was published in Cell in July, but debate about a selective advantage continues.
Hydroxychloroquine paper retracted
A paper published on 22 May in The Lancet, reporting adverse events associated with using hydroxychloroquine and chloroquine to treat patients with COVID-19, was retracted on 4 June. The paper prompted 200 scientists to sign an open letter criticising the study. Two weeks later a paper in the New England Journal of Medicine by some of the same authors published was also retracted. The retractions were due to concerns about the reliability of the data and one of the authors refusing to share the original data.
The hydroxychloroquine paper was particularly significant because President Trump was promoting the drug, and the paper led to the World Health Organisation temporarily halting a clinical trial. Further research established that hydroxychloroquine is not an effective treatment.
The retractions from these prestigious journals sparked discussions about whether the scientific review processes for Covid-19 papers had been undermined by the extremely high levels of scientific and public interest. However, the rapid critiques by other scientists, quick retraction, and very few other retractions illustrates that scientific review processes usually work well.
First effective treatment for severe Covid-19 cases
In July a preliminary UK study was published in the New England Journal of Medicine that showed the steroid dexamethasone reduced deaths in hospitalised Covid-19 patients. This was the first evidence of an effective treatment for severe cases of Covid-19.
While promising vaccines are being rapidly developed, there are still only a few effective pharmaceutical therapies to treat Covid-19. This reflects the difficulties of treating a complex disease.
The UK’s efficient way for assessing treatments
Despite being regarded as a bureaucratic health system, the UK National Health Service’s RECOVERY clinical trials have been effective in quickly testing a range of potential treatments, such as dexamethasone. An article in Nature in August described the factors that have contributed to that. The RECOVERY trials provide a template for other rapid response clinical trials.
Important elements in the RECOVERY trials include reducing bureaucracy, leveraging data systems, involving patients in trial design and delivery, and maintaining transparency.
The WHO’s SOLIDARITY trial of existing antiviral drugs also started to better coordinate therapeutic trials across countries to provide reliable assessments of treatment effectiveness.
Inequities and happenstance
A paper in August, published in Scientific American, summarised some of the factors that influence greater exposure and disease severity in different groups. Genetics, gender, health and socio-economic inequalities all affect risks and outcomes.
Recognition of the “long-haulers” and their persisting symptoms were covered in September in Nature. These papers help emphasise that the causes and consequences of Covid-19 aren’t always easily and quickly addressed.
Early vaccine clinical trial data
In July encouraging results from Phase 1/2 clinical trials were reported for Moderna’s mRNA vaccine in the New England Journal of Medicine, BioNTech’s vaccine (pre-print), and Oxford’s vaccine in The Lancet. This is just six months after the genome sequence was described.
Results of the Phase 3 trials of all three of these vaccines were announced in November. The Lancet published an interim analysis of Oxford/AstraZeneca’s results on 8 December.
Does infection provide subsequent immunity?
The production of SARS-CoV-2-specific antibodies and T cells were reported in April in the journal Immunity. Evidence on the strength and length of protective immunity after infection took longer to appear.
In late May, an experimental study published in Science demonstrated that nine rhesus macaques that had recovered from Covid-19 quickly eliminated the virus when re-infected a month later.
However, it wasn’t until August that a pre-print paper provided evidence that people with SARS-CoV-2 neutralising antibodies did not become re-infected. One hundred and four members of a fishing crew became infected on board during a trip, but the three crew members who were shown to have neutralising antibodies before the trip were not re-infected. The research was subsequently published in Journal of Clinical Microbiology.
A paper published in October in Immunity showed that antibodies against SARS-CoV-2 could persist for at least 7 months.
Increasing sophistication of immunology research
I’ve been impressed at the increasing sophistication of studies of the immune responses to infection as the pandemic progressed. Since May these started to look at a broader range of cells, transcripts and cytokine responses, and emphasised the dynamics of the immune system as infection progressed, rather than just snapshots in time of immune cells and molecules.
A pre-print paper shared in May described the variability in immune profiles between patients and linked immunotypes with disease conditions. This was later published in Science.
Strong T cell responses despite relatively low antibody levels were described in June.
Unbalanced or “misfiring” immune responses in cases of severe Covid-19, resulting in under regulated cytokine production, were reported in papers in Nature in July, Nature Immunology and Nature Medicine in August, and Science in September. The technical skills associated with these studies were impressive.
While many of these studies focused on peripheral blood, which is easier to investigate, papers examining immune responses in the lungs also started to appear from August. These highlighted different immune responses in different tissues, noting the importance of studying immune reactions where the damage is occurring.
Personal favourite
My favourite paper was from May in Cell. This examined immune responses through experiments in cell lines and ferrets, and histological studies of lung tissue. It illustrated the power of a broad multidisciplinary approach to understand different stages of infection and disease progression.
Stay tuned
These are just a few of the interesting, important, and exceptional papers and developments from an incredible research effort.
I’ll continue to highlight new coronavirus research over the (southern) summer.