Coronavirus Research Tracking - 6 January
More UK variant data; viral evolution; vaccine phase 3 results; factors affecting antibody success.
In this week’s Research Tracker we look at the recent analyses of the new UK variant, mutations that may reduce antibody binding, and a laboratory test of viral evolution. Also papers on data from the Phase 3 trials of the mRNA vaccines, greater infectivity of people with symptoms, the effects of timing of antibody appearance and sugar coatings on Covid-19 outcomes, and how CRISPR is helping understand infection processes.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
Greater infectivity of UK variant
An initial analysis of the B.1.1.7 variant in the UK indicates that it is more transmissible. Uncertainty remains over how much more transmissible it is. The paper (not yet peer-reviewed) also reports that a slightly greater proportion of people under 20 have become infected with this variant than for other viral variants.
The UK’s Science Media Centre has expert reactions to that pre-print.
Another paper (also not peer-reviewed) from a separate research team estimates that it may be 56% more transmissible in England than other variants (but this estimate is likely to change as infections spread). These authors suggest that primary and secondary schools and universities need to be closed, alongside other lockdown measures, to prevent uncontrolled spread.
While there is no evidence that this variant causes more severe disease, its higher level of transmission means that more people will become infected, and so more are likely to have severe symptoms and die.
Immune avoidance concerns for South African and Brazilian variants
A study (not yet published) examined how mutations in the spike protein’s receptor-binding domain affect binding of serum antibodies. Some mutations affect binding more than others, and there is variation in binding impact for the same mutations between different serum samples, and over time.
However, a few mutations do substantially reduce antibody binding. The study showed that several mutations at one site in the domain - E484 - can reduce binding more than 10 fold. Both the recent South African variant 501Y.V2 and another from Brazil have mutations at this site. Further research is needed to understand whether variants with mutations at E484 can avoid immune system responses.
Viral evolution in the lab
A study of SARS-CoV-2 evolution in the lab is reported in a pre-print paper. This involved incubating wild-type viral strains with plasma from patients recovering from Covid-19. The plasma sample that showed the strongest neutralising activity was then used to test whether the virus could become immune to it by repeatedly challenging viral samples with it.
The experiments found that after seven challenges an amino acid deletion in the spike protein appeared that reduced the neutralisation ability of the plasma by half. A second mutation - at the E484 site - occurred after five more cycles, resulting in a four-fold decrease in neutralisation activity. Later an insertion mutation of 11 amino acids resulted in the plasma no longer being able to neutralise the virus. These mutations did not affect the ability of the variant to infect a cell line.
Safety and efficacy of the BioNTech/Pfizer vaccine
While Phase 3 results were reported by news conferences last year, scientific papers describing the results have only recently been published. Results from Phase 3 trials of the BioNTech/Pfizer vaccine were published in the New England Journal of Medicine. Out of 21,720 people who received the BNT162b2 vaccine (two injections 21 days apart), 8 became infected after the second vaccination. In comparison, 162 of the 21,728 who received a saline placebo became infected. Vaccine efficacy (ability to prevent infection) after both mRNA injections was calculated to be 95%. Efficacy after the first injection was 52%.
One person who received the vaccines developed severe Covid-19, while 9 who received the placebo did. Reported adverse reactions to vaccination were generally mild and short-term.
Safety and efficacy of the Moderna vaccine
Results from Moderna’s Phase 3 trial were also published in the New England Journal of Medicine. Eleven people out of more than 15,000 who received the mRNA-1273 vaccine (two injections 28 days apart) developed Covid-19 symptoms, while 185 of the 15,000 who were given the saline placebo developed Covid-19, 30 of whom developed severe Covid-19. Vaccine efficacy was calculated to be 94%.
Vaccination-related adverse events were reported by 8.2% of those receiving the mRNA-1273 vaccine, and 4.5% of those receiving the placebo. The most common reported adverse effects were fatigue and headaches. The incidence of more severe reactions were the same (0.3%) for the two groups.
In data reported by the FDA, the Moderna vaccine appears to reduce asymptomatic infections by about two thirds.
A separate smaller study of the safety of the Moderna vaccine on older people was also published in the New England Journal of Medicine. This involved 40 older adults (one group of 56 to 70 year olds, and a group of over 70s). Adverse events associated with the vaccine were mainly mild or moderate and similar to those seen in younger people. Those vaccinated also developed similar immune responses as younger people, indicating the vaccine is likely to be as effective for many older people.
People with Covid-19 symptoms may be more infective than asymptomatic carriers
A study in Singapore, published in The Lancet, studied patterns of transmission of 628 people with SARS-CoV-2 (with or without symptoms), and 3,790 quarantined close contacts. Infection among close contacts of a symptomatic index case was 3.85 times higher than for close contacts of an infected person who was asymptomatic. Viral levels were not always measured so the cause of the different levels of infectiousness are not known.
Infection generates antibody memory cells
A study published in Science Immunology reports the persistence of B memory cells (which produce antibodies) for at least 8 months. While antibody levels against SARS-CoV-2 decline over time, the detection of the memory cells indicate that longer term immunity against the virus has developed.
Antibody timing is important
An analysis (not yet peer-reviewed) of humoral immune responses in 209 Covid-19 patients (asymptomatic, mild, moderate and severe) found that levels of antibodies were less important in determining outcome than the timing of their appearance. Patients who died from Covid-19 usually developed robust IgG and neutralising antibody responses, but these were delayed compared to those who recovered.
Patients who developed neutralising antibodies within 14 days of symptoms were most likely to recover. Why delayed neutralising responses are ineffective is uncertain, but the authors suggest that the virus might become inaccessible to the antibodies after a certain time point.
Sugars on antibodies affect outcomes too
Adding carbohydrates, such as sugars, to proteins is often an important step in establishing their structure and function. Research published in Science finds that IgG antibodies that do not have fucose sugar molecules attached to them are associated with more severe Covid-19 outcomes. These “afucosylated” antibodies while being more potent can also lead to antibody-dependent cellular cytotoxicity, meaning they can get rid of the virus but also start damaging cells and tissues.
Typically about 6% of IgG antibodies in humans are afucosylated, and are formed to bind to whole viruses (as opposed to fragments of viruses or bacteria). However, critically ill Covid-19 patients had higher levels of afucosylated IgG antibodies against SARS-CoV-2 than patients with mild symptoms. The former also had stronger pro-inflammatory cytokine responses, which may contribute to a “cytokine storm”.
How CRISPR techniques are helping study infection processes
A short article in Cell summarises several papers that have used CRISPR-Cas9 techniques to identify host genes that are involved in helping SARS-CoV-2 enter cells, translate their RNA, replicate, exit the cells, or help regulate these processes. These studies support the use of existing drugs to treat Covid-19, or suggest additional drugs to try.
The authors also note that this approach to studying SARS-CoV-2 infection may also help identify shared viral pathways that may help in the development of antiviral treatments that could be rapidly deployed for a subsequent different viral pandemic.