Coronavirus Research Tracking - 9 April
Vaccines, T cells & variants, viral evolution, Long Covid, future pandemic risks
This Research Tracker includes reports on adverse reactions to vaccinations, the efficacy of vaccines against variants, and a new vaccine under development. There are also papers on T cell responses to variants, long term antibody responses, evolution of the virus, the incidence of Long Covid, estimating the number of viral particles in the world, risks of future pandemics, and a policy trade-off tool.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.
AstraZeneca vaccine and blood clot risks
The European Medicines Agency reported a link between the AstraZeneca/Oxford vaccine (now called Vaxzevria) and very rare occurrences of blood clots. It recommended that unusual blood clots and low blood platelets should be listed as very rare side effects. Most of the cases reported so far have occurred in women under 60 years of age within 2 weeks of receiving the first vaccination.
As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis and 53 cases of splanchnic vein thrombosis had been reported to EudraVigilance, with 18 fatalities reported up until 20 March. This is after around 34 million people had been vaccinated in Europe and the UK. EMA emphasised that the overall benefits of the vaccine in preventing Covid-19 outweigh the risks of side effects.
An hypothesis for the clotting risk is covered in this news article in Science. This is based on a paper, not yet peer reviewed, proposing the link between vaccination and blood clots.
A new nanoparticle vaccine
A nanoparticle vaccine containing the SARS-CoV-2 receptor binding domain (called REVC-128) produced potent neutralising antibodies two weeks after a single dose was given to mice. Mice injected with the spike protein not formulated as a nanoparticle produced a weaker immune response. The study, not yet peer reviewed, also reported that vaccinated hamsters had reduced viral loads and disease symptoms when challenged with the virus, compared with unvaccinated animals. Only small numbers of mice and hamsters were used in the trials.
Unlike the Novovax nanoparticle vaccine, which requires two doses, REVC-128 is a one-dose vaccine. The authors note that the ferritin backbone of the vaccine has been previously demonstrated to be safe in influenza vaccine trials. Small numbers of mice and hamsters were used in the trials.
Sputnik vaccine less effective against B.1.351
An assessment of the Sputnik-V vaccine, not yet peer reviewed, reports that it too is less effective against the B.1.351 variant and viruses with the E484K mutation.
Moderna and Novovax vaccines also less effective against B.1.351
The Moderna and Novovax vaccines demonstrated reasonable neutralisation ability against the B.1.429 variant and weaker neutralisation against B.1.351. The research was published in the New England Journal of Medicine.
BBIBP-CorV and CoronaVac vaccines also less effective B.1.351
A short letter in the New England Journal of Medicine reports that the BBIBP-CorV (from Sinopharm) or CoronaVac (from Sinovac) vaccines generated similar levels of neutralisation activity in lab trials. While both vaccines were often able to neutralise the B.1.1.7 variant, the B.1.351 variant was not as strongly neutralised. The CoronaVac vaccine appeared to generally generate weaker neutralisation activity than the Sinopharm vaccine. Pseudoviruses were used in the study, and only a relatively small number of donor sera were tested.
One dose of Pfizer vaccine may work well against variants if person previously infected
A small experiment involving six infected health care workers found that one dose of the Pfizer/BioNTech vaccine substantially increased neutralisation ability against the B.1.1.7, P.1 and B.1.351 variants. The research was published in the New England Journal of Medicine.
Moderna vaccine results in more minor adverse reactions than the Pfizer vaccine
An analysis of adverse reaction reports to the US CDC found that the Moderna vaccine is causing more side effects than the Pfizer/BioNTech vaccine. The research, published in JAMA Insights, found that reactions to both vaccines were more common after the second dose, with 74.8% of those receiving the vaccine reporting systemic reactions, compared with 64.2% for the Pfizer vaccine. Systemic reactions included fatigue, headache, myalgia, chills, fever, and joint pain. People over 65 were less likely to have side effects to the vaccines. The study excluded allergic reactions and anaphylaxis.
Moderna vaccine generates long lasting antibody response
Antibodies induced by the Moderna vaccine persist for at least six months according to a study in the New England Journal of Medicine. These results come from following up 33 participants in a Phase 1 clinical trial.
Weaker vaccines could still be useful
A paper in Nature Reviews Immunology suggests that even if vaccines do not provide complete protection against some variants they can still reduce the rate at which new variants are generated. It notes that for lower risk groups there is evidence that delaying the second dose of a two dose vaccine can still reduce the rate of immune escape by the virus. This assumes that mutations conferring vaccine escape are not exclusively linked to other fitness-enhancing mutations.
Most T cells still able to target variants …
A paper, not yet peer reviewed, reports that CD4+ and CD8+ T cells from small groups of convalescent or vaccinated people are not substantially affected by Covid-19 variants. Ninety three percent of CD4+ T cell and 97% of CD8+ T cell epitopes are completely conserved in the variants. For the epitopes that were affected by a mutation they predict that there will be no change in the binding ability of the corresponding Human Leukocyte Antigens.
… but two mutations affect T cell-linked immunity
However, a paper, not yet peer reviewed, reports that two recent mutations enable the virus to escape from human leukocyte antigen-restricted cellular immunity. This is a T cell-associated response, different from antibody-mediated (or humoral) immunity that most studies of variants have focussed on.
The mutations are L452R (seen in variant B.1.427/429) and Y453F (in B.1.298). The L452R mutation increases protein stability, viral infectivity, and potentially enhances viral replication. The experiments used pseudoviruses and cell lines. The effects of these mutations on transmissibility and pathogenicity are unknown.
Antibodies can persist for at least 12 months
A study of nearly 900 infected people in Wuhan found that IgG antibodies against the virus persisted for at least 12 months in more than 70% of the people. The research, not yet peer reviewed, reports that antibody levels at 12 months were around 30% of the level recorded one month after infection, with antibody levels stabilizing at the nine month mark.
IgG levels were positively correlated with neutralising antibody titers (or concentrations). There was also a positive correlation between antibody levels and age for infected people aged between 18 and 55.
Covid-19 may evade immune response after a few years
A study of another human coronavirus, 229E which causes the common cold, found that its spike protein evolves, allowing it to escape previous immunity. This suggests that Covid-19 will probably do the same.
The research, published in PLOS Pathogens, found that sera collected in the 1980s and 1990s could inhibit older 229E strains but not more recent ones. More recent strains were neutralised by recently collected sera
Viral evolution
A preprint paper that the Tracker covered in the 1st March edition has now been published in PLOS Pathogens. This study used sensitive genome sequencing to identify the emergence of mutations during infection within individuals and reported that the rate of production of mutations within a person is higher than expected. Of relevance too is a paper in Science, cited in the 12th March Tracker, that reported that variants tend to disappear quickly.
Long Covid
A review of Long Covid, published in Nature Medicine, notes the multiple symptoms that are associated with it. It also highlights potential clinical actions for those considered at risk for developing ong Covid.
A detailed international study, not yet peer reviewed, concluded that the morbidity of Covid-19 illness has been greatly underappreciated. It involved over 3,000 people and found that Long Covid patients experience symptoms affecting a range of organs that often last for over 7 months. Of those with confirmed or suspected Covid symptoms for at least 28 days 96% still had symptoms after 90 days.
There were significant impacts on lives and livelihoods. The most frequent symptoms reported after six months were fatigue, post-exertional malaise, and cognitive dysfunction. Most of the respondents were women and of European ancestry.
A paper, not yet peer reviewed, discusses the challenges in defining Long Covid. This is due to differences in the literature, and lack of standardisation of health records.
Increased risks of neurological or psychiatric problems
A review of medical records of over 230,000 people recovering from Covid-19 found that 33% were diagnosed with neurological or psychiatric problems six months after being infected. The research, published in The Lancet Psychiatry, reports that risks were greatest for those who had severe Covid-19, with 46% of those who were in ICU developing a neuropsychiatric illness.
Overall, 17% had a diagnosed anxiety disorder, 2% an ischaemic stroke, 1.4% a psychotic disorder, 0.7% dementia, and 0.6% an intracranial haemorrhage. The authors highlight that services need to be resourced to meet these needs.
Coagulation proteins help the virus infect cells
A study, not yet peer reviewed, found that two proteases involved in blood clotting are involved in helping the virus enter cells. These results suggest that anticoagulants may reduce infection or disease progression if provided early after infection. However, further research is needed to assess the feasibility and effectiveness of anticoagulants.
Most infections asymptomatic
A serological study in the Netherlands, not yet peer reviewed, estimated that about 70% of infections were asymptomatic. Incidence of asymptomatic cases varies with age. The proportion was higher in those under 20 (80%), and lowest (around 55%) in those seventy or older.
The global mass of SARS-CoV-2
A study, not yet peer reviewed, estimated that each infected person may carry one to 100 billion copies of the viral genome, and 100,000 to 10 million infectious viral particles. This leads to the calculation that the total mass of SARS-CoV-2 in people is only between 0.1 and 10 kg.
The study also estimated the rate of emergence of new variants, concluding that globally up to one million mutations are produced each day. However, a variety of factors result in only very few of these mutations persisting.
Risk assessment of the pandemic potential of hundreds of animal viruses
A paper published in the Proceedings of the National Academy of Sciences assesses the risks of 887 novel animal viruses infecting humans. Fifty potential risk factors are used to rank risks that assess virus, host and environmental features. Lassa virus has the highest risk rank at the moment, and severa; newly discovered viruses have higher rankings than known zoonotic pathogens. The authors have created a living interactive database, called SpillOver, for policy makers and health researchers.
Assessing policy trade-offs
A Covid-19 Pandemic Trade-offs tool has been developed by Australian researchers. It’s purpose is to help policy makers explore how policy responses (such as restrictions, vaccination roll-out, and border opening) impact future infection rates, health impacts and economic impacts.