Coronavirus Research Tracking - 12 March
Vaccination impacts, variant effects, viral evolution, therapeutic trials, Long Covid
This Research Tracker covers papers on the impacts of vaccination, how well monoclonal antibodies and sera neutralise different variants, the increased risk from B.1.1.7, viral evolution during the pandemic, trials of convalescent plasma and interleukin-6 receptor blockers, and Long Covid.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Effect of vaccinations in Israel
An analysis from Israel, not yet peer reviewed, illustrates the effectiveness of vaccination. Two months after vaccinations commenced 85% of individuals older than 60 years old have already been vaccinated. Compared to values during their peak of infections, there was an approximately 77% drop in cases, 68% decline in hospitalisations, and a 67% reduction in severe hospitalisations. Cities where vaccinations started earlier showed larger reductions than cities which started vaccinating later.
Antibodies, sera and variants
A study published in Cell Reports found that while mutations seen in the B.1.1.7 variant can reduce the effectiveness of some monoclonal antibodies, the neutralisation ability of sera from previously infected people is less affected. This is due to sera having many different antibodies with different binding sites and effects.
Similar results are reported in Nature. This paper also found that for the B.1.351 variant neutralisation by convalescent plasma is 9.4 fold-lower than for earlier variants, and sera from vaccinees (given Pfizer/BioNTech or Moderna vaccines) has 10.3-12.4 fold-lower neutralisation activity.
However, another study published in Nature reports that sera from people vaccinated with the mRNA vaccines has weaker neutralising ability against the B.1.1.7 spike protein variant. Introducing the E484K mutation into a pseudovirus version of that variant reduced neutralisation activity further.
A study published in the New England Journal of Medicine reports that good neutralisation of the B.1.1.7 and P.1 variants may occur after having both doses of the Pfizer/BioNTech vaccine. Lower, but still “robust”, neutralisation of the B.1.351 variant was observed. These conclusions are based on lab tests where the spike protein mutations were introduced into an earlier variant.
This study also found that the mutations K417N, E484K, and N501Y in the receptor-binding domain had the largest effects on neutralisation. Limitations in the study (and other similar ones) include the focus on antibody responses, rather than other immune responses, and not investigating the effects of mutations outside of the spike protein.
A paper published in Nature Medicine reports that many highly neutralising monoclonal antibodies that target the receptor-binding domain and N-terminal domain of the spike protein, and most convalescent sera and mRNA vaccine-induced sera showed reduced inhibitory activity against viruses containing the E484K spike mutation (such as B.1.351 and P.1).
However, the authors note that it is still uncertain whether cell-based neutralisation assays predict antibody-mediated protection, so animal experiments are needed.
An investigation of antibodies produced after infection by the B.1.351 variant reports that they display good neutralisation activity against an earlier variant and the P.1 variant. The paper, not yet peer reviewed, suggests that vaccines designed against the B.1.351 variant may have broad effectiveness.
The journal Science has a useful summary of the degree of immune evasion for different variants. It notes that studies often use different tests for neutralisation, making them hard to compare.
Strong immune responses to first dose of mRNA vaccines in those previously infected
Several additional studies have demonstrated that a single dose of either the Moderna or Pfizer/BioNTech vaccine given to previously infected people can generate similar (or better) levels of antibodies and neutralisation activity as two doses given to uninfected people.
Study 1, not yet peer reviewed
Study 2, also not yet peer-reviewed
A study published in the New England Journal of Medicine
Some caution in interpreting the results is required because studies may focus more on people who had mild Covid-19, and they have only examined antibody responses not other immune system responses. Longer term immune responses to one or two doses have also not been studied.
Vaccination strategies
A paper in Science models different vaccination strategies. Decisions to delay giving the second dose of a two-dose vaccine should be based on the evidence for the strength of immunity generated by the first dose. A weak immune boost after the first dose is likely to lead to a resurgence in infections, and potentially new variants that evade immune responses.
Indicators of effective immunity
The search for good indicators for protective immunity continues. A paper in Science Advances evaluated the diversity, binding and neutralisation activities over time of antibodies collected from 11 hospitalised Covid-19 patients, seven of whom recovered and four died. The study found that antibodies that bound strongly to the pre-fusion form of the spike protein were associated with faster recovery and improved clinical outcomes, and so may be an indicator of disease progression in more serious cases.
Greater risk of death from B.1.1.7 variant
A paper published in the British Medical Journal found that people infected with the B.1.1.7 variant have an increased risk of death. The study involved nearly 55,000 matched pairs of Covid-19 patients who were not initially hospitalised. The increased risk of death was calculated to about 64%, though there was considerable variation. Mortality rates between variants were similar in the first two weeks after infection was confirmed, with B.1.1.7 causing greater mortality between days 15 and 28.
The absolute risk of death due to B.1.1.7, remains relatively low, increasing from 2.5 to 4.1 deaths per 1,000 cases.
Another study, not yet peer reviewed, came to a very similar conclusion.
Viral evolution
A study, published in Science, found that despite high viral loads early in infection there is little genetic variation in SARS-CoV-2 genomes within individuals. Variants that emerge within an infected person often quickly disappear, unless they have better transmissibility in which case they can become dominant. The analysis suggests that paths of transmission could be established by tracing uncommon variant viruses between individuals.
Another analysis, not yet peer reviewed, reports that there was a significant shift in selective pressures acting on SARS-CoV-2 about 11 months after the virus emerged. This may be due to increased seropositivity and/or relaxation of transmission prevention measures beginning in October 2020. An alternative hypothesis is that chronic infections, lasting at least five months, could also explain the emergence of variants of concern toward the end of 2020.
The paper describes both independent convergent and divergent mutations in the 501.Y lineage (containing the B.1.1.7, B.1.351, and P.1 variants). The authors propose that variants with a larger range of mutations can be expected to occur, and some of these may lead to greater transmissibility, disease severity and/or immune evasion.
Convalescent plasma is not an effective Covid-19 treatment
A randomised control trial of the effect of convalescent plasma treatment found that it did not reduce Covid-19 mortality or improve other outcomes when given to hospitalised patients. The trial involved 5,700 patients receiving convalescent plasma and was part of the UK’s RECOVERY trial. Whether there are benefits from receiving convalescent plasma early after infection and before severe symptoms develop was not tested. The results have not yet been peer reviewed.
Mixed results for therapies blocking the Interleukin-6 receptor
A study published in the New England Journal of Medicine reports that two monoclonal antibodies (sarilumab and tocilizumab) that target the Interleukin-6 receptor improved the outcomes and survival of critically ill Covid-19 patients.
In the 19 Feb Tracker we reported another trial with tocilizumab that demonstrated benefits, while also noting its high cost.
However, two studies recently published in The Lancet Respiratory Medicine did not show beneficial effects of these treatments. The study investigating sarilumab included patients from 11 countries who were receiving supplemental oxygen (and not as critically ill as in the NEJM study). Its focus was on whether sarilumab improved the speed of recovery. The authors discuss a range of possibilities why this trial may not have shown benefits from sarilumab.
The paper describing the tocilizumab trial involved patients with moderate to severe Covid-19. Ninety were treated with tocilizumab, and patient progression and outcomes were no different from those receiving standard care. Analyses did indicate that patients who quickly developed severe disease could benefit from tocilizumab, but further research is required.
A commentary in The Lancet Respiratory Medicine discusses the different results, noting that trial designs were different, and that the standard of care has changed over time. More of the patients in the NEJM study received steroids along with the antibody treatment than in The Lancet studies, and that in part may affect results. The commentary also points out that the trials still provide valuable information for future research and treatments.
Long Covid
Several papers on “Long Covid” (where symptoms last beyond four weeks) have appeared in the past week.
One study, not yet peer reviewed, looked at early immune responses as a predictor. It reports that in the patients it studied weak initial antibody responses, lower inflammation during the acute stage of Covid-19, and having persistent inflammation after 1-2 months are associated with developing Long Covid. Being female is also an important risk factor (probably due to the different immune responses to viral infections, as noted in the 5 March Tracker)
Another study, also not yet peer-reviewed, focused on symptoms early in infection in adults. It found that 32% of Long Covid cases originally were asymptomatic, and women were more likely to develop Long Covid. Early symptoms that were often (but not always) associated with developing Long Covid included palpitations, chronic rhinitis (nasal inflammation), dysgeusia (disrupted sense of taste), chills, insomnia, hyperhidrosis (excessive sweating), anxiety, sore throat, and headaches. Long haul symptoms may also change over time.
A study of 510 children (mean age 10) with Long Covid, not yet peer reviewed, reported that symptoms persisted for a mean of 8 months. Nearly all (94.9%) had at least four symptoms, with the most common symptoms being fatigue, headaches, muscle and joint pain, rashes and heart palpitations, and lack of concentration and short term memory problems. These are similar to Long Covid symptoms in adults. The study relied on parents reporting their children’s symptoms and Covid-19 tests.
A study published in Nature Medicine used data from a Covid symptom reporting App to determine the incidence of Long Covid. Out of a sub-group of 4,300 participants 13.3% reported symptoms lasting at least 4 weeks, 4.5% for at least 8 weeks and 2.3% for 12 weeks or longer.
This study was based on self-reporting rather than clinical observations, and was not representative of the general population, with more women and fewer people over 70 participating. The proportions with Long Covid in this study are lower than other studies. Some scientists and participants are pointing out that in this study those who stopped using the App were classified as recovered, which may under-represent incidence.
Reduction in mortality as pandemic progressed in the US
A study in JAMA Network Open found in-hospital mortality for Covid-19 patients in the US fell from 22.1% in March 2020 to 6.5% in August. The paper notes that care of Covid-19 patients changed rapidly as the pandemic progressed, which is likely to explain the trend.