Coronavirus Research Tracking - 5 February
Vaccine trials, other therapies, viral loads, decline in mortality risk, B.1.1.7 risks
Reports of the Tracker’s demise were premature. Weekly reports will continue for (hopefully) most of this year.
This week’s Research Tracker covers papers about newer vaccine clinical trials, studies of other therapies, viral load and disease outcome, decline in risk of death from Covid-19, and increased transmission and disease severity associated with B.1.1.7.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Vaccine Tracker
To help keep track of the numbers of vaccinations in different countries The Economist has developed a vaccine tracker.
Clinical trial results for Novavax, Janssen’s and Sputnik V vaccines
Clinical trial data from a range of other vaccine candidates are emerging. Some of the reports were made available via Press Releases. But there has been some independent knowledgeable commentary on them. For example, Derek Lowe has looked at the data released by Novavax and Johnson and Johnson (with Janssen). A news item published in Nature also looked at the Novavax results.
Novavax
The Novavax vaccine is a protein-based vaccine. It consists of nanoparticles of spike proteins and an adjuvant to stimulate an immune response. The J&J/Janssen vaccine is a single dose viral vector vaccine based on the ADenovirus 26 virus with the SARS-CoV-2 spike protein.
The Novavax UK trial (involving about 15,000 people), showed 89% efficacy according to the company. Importantly around half of the participants were infected with the B.1.1.7 variant, inciting that this vaccine can neutralise the variant. A smaller trial in South Africa indicates less effectiveness (49%) against the B.1.351 variant .
Johnson & Johnson/Janssen
The J&J/Janssen vaccine results indicated that the vaccine was 66% effective overall at preventing moderate to severe disease 28 days after vaccination. But efficacy varied between regions. It was more effective in a US trial than in trials in Latin America and South Africa. These results probably reflect, in part at least, the different viral strains in each region. According to the company the vaccine appears to do very well at preventing severe disease.
A paper, not yet peer-reviewed, on the J&J/Janssen vaccine reports that it provided at least 6 months protection against lung infections in 28 rhesus macaques. This protection could be predicted based on the levels of binding and neutralising antibodies vaccinated animals, so measuring these antibodies after vaccination may be a useful indicator of effectiveness. The virus was still present in the upper respiratory tract, although at lower levels than in unvaccinated animals.
Sputnik V
Results of a randomised, double-blind Phase 3 trial of the Russian “Sputnik V” (or, Gam-COVID-Vac) vaccine (a recombinant adenovirus-based vaccine) were published in The Lancet. This vaccine has been developed in two forms, liquid and freeze-dried versions, with the trial evaluating the liquid formulation.
The trial involved a first dose using a recombinant adenovirus 26 containing the spike protein, followed 21 days later by a dose of recombinant adenovirus 5 with the spike protein. The paper reports results of infections on day 21 (ie, the day of the second vaccination).
Sixteen (0·1%) of 14,964 participants in the vaccinated group and 62 (1·3%) of 4,902 in the placebo group became infected, resulting in a vaccine efficacy score of 91·6%. None of the vaccinated participants developed severe Covid-19, suggesting that the vaccine helps reduce disease severity. No serious side effects were reported to be vaccine-related.
AstraZeneca/Oxford vaccine - impacts of timing of the second dose
A pre-publication version of a paper submitted, but not yet peer-reviewed, to The Lancet updates the results of Phase 3 trials of the AstraZeneca/Oxford vaccine (based on a chimpanzee adenovirus). The paper includes data from all four trials.
It focuses on whether delaying receiving the second dose for up to 3 months affects protection. The trials were not set up to study this, but the variability in timing of participants receiving second doses made this analysis feasible. The authors note that these are “exploratory analyses”.
The results indicate that antibody binding is about twice as strong when the second dose is given after three months compared to if it was given within 6 weeks of the first.
Vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76%. After the second vaccination efficacy was higher (82.4% overall) when the interval between shots was 3 months or more.
The study also reports that viral loads were reduced by 67% in nasal swabs after the first vaccination compared to unvaccinated participants. This is suggestive of reduced infectivity, but does not prove transmission is reduced by this vaccine.
Commentary on this paper was gathered by the UK’s Science Media Centre. Some of the commentators note that there are some weaknesses in the paper which may be addressed following peer review.
Therapies
Trials of a variety of other treatments are also continuing. Several of these are summarised below.
Heparin
The anticoagulant heparin may be an effective treatment for hospitalised patients with moderate Covid-19. The results of an interim analysis from three independent randomised open label trials (ie, doctors and patients were aware of what treatment they were getting) were reported in a press release and PowerPoint presentation.
Patients were assessed over 21 days and compared with patients who received a lower dose as part of normal clinical care. Mortality of patients with moderate Covid-19 receiving the higher dose was 5.7%, compared with 7.7% of those receiving the standard dose. While this seems small, it is a substantial improvement compared to the benefit seen for the steroid dexamethasone, according to a commentary on the results.
The high dose heparin treatment worsened the condition of patients in intensive care units. The point at which high doses of heparin should be stopped if a patient's condition worsens is unclear at this stage.
Zinc as a treatment supplement
A zinc supplement may improve the effects of two drugs in treating Covid-19. The not yet peer-reviewed paper examined how well an anthelmintic drug (triclabendazole) and an antiprotozoal drug emetine inhibited ACE2 expressions in a human lung cell line. Their ability to suppress expression was improved by zinc.
Colchicine
A randomized, double-blind trial involving non-hospitalized patients with COVID- 19 reports that colchicine (an anti-inflammatory used to treat conditions such as gout) can reduce the risk of death or hospitalisation. Of patients with confirmed infections 4.6% who were treated with colchicine were hospitalised or died within 30 days, compared with 6.0% who didn’t. This is a significant difference. The paper has not yet been peer-reviewed.
Convalescent plasma
A systematic review (not yet peer reviewed) of 30 studies of the effect of convalescent plasma indicates that the treatment can reduce mortality in hospitalised Covid-19 patients. The paper notes their results differ from earlier reviews which found insufficient evidence of benefits. The authors consider this reflects their inclusion of a larger number of studies (due to less stringent selection criteria).
Limitations of systematic reviews are that they include studies with different methodologies, patient groups, and study sizes. As such their conclusions may not be as definitive as a single large scale case-controlled randomized double-blind clinical trial.
Too much focus on surfaces?
An editorial in Nature suggests that too much attention has been given to virus transmission from surfaces when there is recognition that air-borne transmission is the main infection route. It advocates that the focus of reducing transmission should be on improving ventilation or installing rigorously tested air purifiers rather than on surface sterilisation.
Viral load may be an indicator of Covid-19 outcome
A paper published in the Proceedings of the National Academy of Sciences reports that the majority of 655 hospitalized patients in a French study have a high viral load peak close to symptom onset. In patients 65 and older the viral load and viral shedding declines more slowly (16 days to clear the virus compared to 13 days in younger patients).
A model based on the data indicates that viral dynamics after hospitalisation can predict patient outcome. The authors suggest that treatments that reduce viral levels quickly are likely to improve patient outcomes.
Covid-19 mortality declined during 2020
A review of studies, published in Anaesthesia, of Covid-19 patients admitted to intensive care units finds that mortality decreased between May and September 2020, from 41.6% to 35.5%. This reduction was lower than decline the observed up to May, suggesting mortality rates may be reaching a plateau between 30 and 40%.
There was considerable variability in mortality between regions, with 62% seen in the Middle East compared to 33% in Europe. The paper notes the scarcity of studies on mortality from the Southern hemisphere, where the pandemic developed later.
The authors suggest that the reductions in mortality are associated with the greater use of steroids (such as dexamethasone), changes in oxygen therapy and fluids management, and how the risk of blood clots is managed.
The review does not include studies involving the recently identified variants of concern. It also points out that studies of Covid-19 mortality don’t report results in standardised ways making it difficult to compare studies in terms of underlying risk factors or disease severity.
The UK variant may be more transmissible and cause more serious conditions
Two technical reports from the UK on the B.1.1.7 variant note its higher transmissibility and an increased risk of death. Public Health England estimates that infectivity is 25% to 40% higher in variants that have the spike gene deletion mutation seen in B.1.1.7.
The New and Emerging Respiratory Virus Threats Advisory Group concluded, in a 21 January meeting, that there is a “realistic possibility” that infection with B.1.1.7 is associated with an increased risk of death, compared to infection with variants that are of less concern. They also emphasise that the absolute risk of death remains low for SARS-CoV-2 variants.