Omicron variant papers

Emerging information on severity of Omicron variant

A news article in Nature discusses the currently limited information about the severity of Omicron variant infections.

A report, not yet peer reviewed, from Imperial College, London, analysed 6,000 Omicron variant cases in the UK. It concluded that current data does not indicate that disease severity from Omicron infections are less than those seen for the Delta variant. Although it notes that hospitalisation data are still limited. Omicron was associated with a 5.41-fold higher risk of reinfection compared with Delta.

Early analyses from South Africa suggest people there infected with the Omicron variant have an 80% lower risk of being hospitalised than those infected during the same period with other variants. The former also had a 70% lower risk of developing severe Covid-19 than those infected with the Delta variant.

The authors attribute this lower level of severity to high levels of population immunity due to previous infections and/or vaccination, though this is not yet proven. The level of severity may change as more people become infected, and the results from South Africa may not be applicable to other countries. The paper has not yet been peer reviewed.

A Press Release (on 14 December) from a South African health care company reported that risk of hospitalisation for adults from an Omicron infection was 29% lower than in the first infection wave in 2020. However, hospitalisation risk was 20% higher for children with the Omicron variant. Over 200,000 infection records from the first three weeks of Omicron infections were analysed.

The overall seropositivity rate in the Gauteng Province of South Africa prior to the Omicron variant was high (73%), while only 20% of those over 12 in the Province have had two vaccine doses. Seropositivity varied according to age group and locality, ranging from 56% in children under 12 to 80% in those over 50.

With the Omicron wave there has been an uncoupling of infection and hospitalisation & death rates, in contrast with earlier infection waves. The paper has not yet been peer reviewed.

Vaccine effectiveness against Omicron

A Danish study found that the mRNA vaccines provided some protection against infection from the Omicron variant soon after the second dose, but the effectiveness then rapidly declined. One month after the second dose vaccine effectiveness was 55% for Pfizer/BioNTech and 37% for Moderna. After three months effectiveness was around 0%.

For those who had a third dose of the Pfizer vaccine two to six weeks earlier effectiveness against infection increased back up to around 55%. The confidence intervals for the effectiveness estimates were broad. The paper has not yet been peer reviewed.

Enhanced cell entry by Omicron …

The Omicron variant is not only able to evade antibody neutralisation, but can more readily enter cells. The latter was assessed using pseudoviruses, and Omicron exhibited much higher infectivity than an early D614G, the Beta, and the Delta variants. The paper was published in Signal Transduction & Targeted Therapy.

… But may be harder for it to spread within the body

Another study has shown reduced neutralisation of the Omicron variant after two vaccine doses for both the Pfizer/BioNTech and Moderna vaccines.

However, while infectivity is high for this variant, the study also found that cell-cell fusion efficiency is lower than for other variants. This may contribute to lower virulence. The authors suggest that lower cell-cell fusion may be the result of a trade-off resulting from mutations that enhance immune avoidance. The research is based on infections of cell cultures with pseudoviruses. The paper has not yet been peer reviewed.

That conclusion is supported by another study. While the spike protein of the Omicron variant can more readily infect upper respiratory tract cells, it shows lower infectivity of lung cells. The spike protein is also poorly cleaved compared with the Delta variant, and this reduces its ability to spread within the body by cell-cell fusion. The paper has not yet been peer reviewed.

Omicron doesn’t escape from T cell responses

T cells appear relatively unaffected by the Omicron mutations. An analysis of the binding sites for several hundred spike-specific CD4+ and CD8+ T cells predicts only 10 will not bind to the variant. At least 97% of other T cells were predicted to bind to other parts of the variant. The study did not test the actual binding of the T cells. The paper has not yet been peer reviewed.

Omicron origins and selection

One paper suggests that mutations in the spike protein of the Omicron variant support an origin in mice. Analyses of the Omicron genome with other SARS-CoV-2 variants indicated that the very rapid accumulation of mutations seen in Omicron appears to be unlikely if humans were the only host. It proposes the virus moved from humans to mice and back to humans. This hasn’t been proven yet. The paper has not yet been peer reviewed.  [See last week’s tracker about the ability of Omicron to naturally infect mouse cells]

The potential origins of the Omicron variant were discussed at the beginning of December in Science and in StatNews.

An analysis of 87,000 SARS-CoV-2 genomes emphasises the unusual mutation rate in the Omicron variant. The predominance of mutations in the spike protein in Omicron suggest very strong selective pressure on this part of the genome. The cause(s) of this pressure is unknown at the moment. The paper has not yet been peer reviewed.

Vaccine-related papers

Waning levels of protection against infection from Delta

A US study found that protection from Delta variant infection among all ages waned with increasing time since vaccination for several vaccines. Deaths among older adults also increased somewhat as time since vaccination lengthened. The rates of waning were similar for the Pfizer and Moderna vaccines, although protection against death was more durable.  Infections were assessed in August-September.

Infection levels were higher for the Johnson & Johnson/Janssen vaccine, and its effectiveness showed a bimodal pattern over time, rather than a consistent waning. The analysis was published in the New England Journal of Medicine.

Waning effectiveness against infection of the Moderna vaccine

Like the Pfizer/BioNTech vaccine, the effectiveness against infection also wanes for the Moderna vaccine. In this Qatari study, three months after the second dose effectiveness was about 90% but declined from four months onwards, falling to around 50% seven months after the second dose. Effectiveness against severe disease and death remained around 100% over that time. The paper has not yet been peer reviewed.

Unvaccinated more likely to become infected

A US study of over 1 million who had Covid tests found unvaccinated people were up to four times more likely to be infected than vaccinated people. Testing was done between May and August this year at retail locations, rather than healthcare centres. The results therefore reflect less severe infections.

Vaccination status was largely self-reported. People vaccinated with the Moderna, Pfizer or Johnson & Johnson vaccines were included in the study, with the J&J vaccine showing lower effectiveness than the mRNA vaccines. Waning vaccine effectiveness over time was also observed. The paper was published in JAMA Network Open.

Non-vaccine-related papers

Ultrapotent monoclonal antibodies

Ultra-potent monoclonal antibodies that can neutralise a range of variants, and other coronaviruses, have been identified. They were identified from 10 people who were classed as “elite neutralisers”, based on testing of plasma from 963 people with Covid infections. The paper was published in Cell Host & Microbe.

T cells provide good protection against variants

A South African study found that T cell recognition of the Beta variant was largely unaffected despite reduced antibody neutralising activity. Some CD4 T cells did not recognise the Beta variant but most CD4, and CD8, T cells did. This resulted in a T cell response similar to that seen for the original SARS-CoV-2 virus.

The findings support initial observations of T cell responses to the Omicron variant. The paper was published in Science Translational Medicine.

Assessing the fitness of different variants requires the use of several models

A study shows that several different infection models are needed to understand the differences in fitness of different SARS-CoV-2 variants. The Alpha variant is able to outcompete the Beta variant in infection experiments of cell cultures. The Alpha variant also outcompetes a wild type strain in infection competitions in mice (with the human ACE2 receptor) and ferrets, but in hamsters (where replication is higher) the two variants had similar fitness.

Despite the Beta variant having a stronger binding ability to the ACE2 receptor than the wild type virus, the latter (along with the Alpha variant) outcompeted the Beta variant in mice and hamsters. The results support the observed infection and transmission results in people. The paper was published in Nature.

Several factors may explain why children have less severe Covid-19

Less severe Covid-19 symptoms in children may be due to several factors, a detailed study of epithelial and blood cells reports. Children have higher innate interferon responses, which limits viral replication. Higher levels of cytotoxic immune responses in adults may create more tissue and organ damage. Children have a higher level of T cell receptor diversity, which may lead to more rapid and effective recognition of the virus in children. And inflammation-inducing factors are more common in adult blood that, combined with cytotoxic factors, could create more damage. The paper was published in Nature.

Covid-19 may be an immune disease not just a respiratory disease

A paper proposes that mitochondrial dysfunction is a key consequence of Covid-19, and so it shouldn’t just be considered a respiratory disease. Following infection mitochondrial gene expression can be significantly reduced in cells that are part of the immune system.

This disruption can lead to increased production of type I interferons and a consequent cytokine storm. The authors suggest that drugs that target mitochondria may benefit patients with more severe Covid-19. The paper was published in iScience.

SARS-CoV-2 likely to become endemic

A model predicts that SARS-CoV-2 will become endemic, even with high levels of vaccination. A slower lifting of restrictions may result in lower levels of infection according to some model settings. The paper has not yet been peer reviewed.

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