Coronavirus Research Tracking - 11 June

Data on the Delta, Alpha's escape route, vaccine effectiveness and risks, immune responses

This week quite a bit of new data on the Delta variant. Plus, how the Alpha variant escapes innate immunity, more on the benefits and rare risks of vaccines, old cells and infection risks, research questions about long Covid, and the usefulness of reporting viral loads.

The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre.

Variants of concern name reminder

Alpha = B.1.1.7 (first detected in the UK)

Beta = B.1.351 (first detected in South Africa)

Gamma = P.1 (first detected in Brazil & Japan)

Delta = B.1.617.2 (first detected in India)

The higher transmissibility and severity of the Delta variant

The Delta variant is causing concern because it appears to be more transmissible, can cause more severe symptoms, and may be better able to avoid antibody neutralisation. It appears to be spreading quickly among younger people and the unvaccinated or partially vaccinated.

Public Health England’s latest technical briefing on variants of concern describes that 61% of recently sequenced cases in the UK were of the Delta variant, and the prevalence of this variant is rapidly increasing.

The report notes that the Delta variant appears to be more transmissible than the Alpha. It calculates that the secondary attack rate (probability of a close contact becoming infected) for people who have not travelled is higher for Delta (12.4%), compared to 8.2% for Alpha.

A UK risk assessment for the Delta variant indicates there may be a greater risk of hospitalisation with this variant compared with Alpha. Vaccinations do provide protection, though the effectiveness appears lower than for Alpha.

The Pfizer/BioNTech vaccine is less effective against the Delta variant. Sera from 250 people who had received one or two vaccine doses were tested on five viral strains using a live virus assay. A similar reduced level of neutralising antibody activity was found for Delta as for the Beta variant, and lower than that seen for the Alpha variant. The difference was most marked when comparing variants after one vaccine dose. The authors suggest that delaying the second dose may increase risk of infection with the Beta and Delta variants. The paper was published in The Lancet

Similar results were found in an analysis by Public Health England for incidence of symptomatic infections. While the effectiveness of a single dose of either the AstraZeneca/Oxford or Pfizer/BioNTech vaccine was lower for the Delta than the Alpha variant, after two doses the difference became smaller. The paper has not yet been peer reviewed.

A weekly report on vaccine effectiveness in the UK provides information on other aspects of vaccine effectiveness in the UK

CoronaVac gains emergency use approval from the WHO

The emergency use approval by the WHO of Sinovac’s CoronaVac vaccine is viewed as being particularly important at controlling the pandemic. This is because while less effective (about 51%) than the mRNA vaccines in preventing infection, it is already being given, alongside SinoPharm’s vaccine, in over 70 low income countries. CoronaVac also appears to be very effective in preventing severe Covid-19. The news article was published in Nature.

More evidence for real world effectiveness of mRNA vaccines

A study of nearly 4,000 US healthcare and other essential workers found that the mRNA vaccines were highly effective in preventing infections. None appeared to have been previously infected. Out of 204 infections, only 16 were from partially (between two weeks after first dose and two weeks after second dose) or fully vaccinated (more than two weeks after second dose) participants. Those infected after being vaccinated had lower viral loads, were less likely to report fever, and spent two days fewer in bed than infected unvaccinated participants. The study has not yet been peer reviewed.

Rare cases of heart problems in young men after Pfizer/BioNTech vaccination

Rare cases of heart inflammation in young men vaccinated with the Pfizer/BioNTech vaccine have been reported. Israel’s Ministry of Health  estimated that between one in 3,000 and one in 6,000 men aged 16 to 24 develop this reaction. Most cases are mild and disappear after a few weeks. A news report in Science discusses the issue.

Seven cases of this condition in the US are reported in the journal Pediatrics. The patients (14-19 years old) reported chest pains within four days of receiving their second Pfizer/BioNTech dose. The condition was successfully and quickly treated. A causal relationship between the vaccine and heart inflammation has not yet been proven.

Blood clot risks from AstraZeneca/Oxford vaccine

Analysis of 2.5 million vaccinated Scottish adults (mostly over 40 years old) found slightly increased risks of bleeding or other vascular events for those receiving the AstraZeneca/Oxford vaccine, compared to the Pfizer/BioNTech vaccine.

The study calculated that at 27 days after receiving the first-dose of the AstraZeneca vaccine the estimated frequency of immune thrombocytopenic purpura (which can lead to minor or long term bleeding) was 1.13 cases per 100,000. There was insufficient data to determine if there is an association between the vaccine and blood clots in the brain. No increased risks of bleeding were associated with the Pfizer vaccine. 

The authors’ emphasise that risks of adverse effects from these vaccines are very much less than the risks associated with Covid-19 infection. The paper was published in Nature Medicine.

A second death in Australia has been attributed to blood clots following vaccination with the AstraZeneca vaccine. Forty eight cases of vaccine associated blood clots have been reported there, and the Australian Science Media Centre has produced an Expert Reaction on it.

Correlation between antibody and T cell responses for Pfizer/BioNTech vaccine

A strong correlation has been found between antibody and T cell responses following the first dose of the Pfizer/BioNTech vaccine. The research highlights that not just antibody neutralisation, but other antibody mediated responses and T cell activities are important factors in vaccine effectiveness. With one vaccine dose these immune responses were generally stronger if vaccines had previously had Covid-19. The paper was published in Cell Host & Microbe.

Alpha variant able to escape early innate immune response by suppressing interferon-beta

Mutations outside of the spike protein also have important influences on immune system avoidance. The Alpha variant produces as much as 80 times more copies of its Orf9b protein than other variants. This binds to human proteins associated with interferon production, helping it escape early innate immune system control by reducing the cell's interferon-beta response. This may contribute to its higher transmissibility. The paper has not yet been peer reviewed

The Beta and Delta variants also reduce interferon production, but not by increasing Orf9b according to an article in the New York Times that discusses the paper.

Most people develop neutralising antibodies after infection

A scientific assessment by the World Health Organisation calculated that four weeks after infection 90-99% of people develop detectable neutralising antibodies. Most people appear to have protection from reinfection (or severe symptoms) for at least 6-8 months. However, there is uncertainty over the extent to which some of the variants of concern are able to evade this immune response. 

A correlate of protection

Substantially reduced risk of infection has been found to be associated with the presence of IgG antibodies to the virus’ nucleocapsid protein. The study of staff and residents at long-term care facilities in England found only 14 cases of reinfection in 2,000 people tested. Previous infection was calculated to reduce the risk of reinfection by approximately 85% in residents and 60% in staff members. The paper was published in The Lancet Healthy Longevity.

Natural infection can provide good protection

A study of over 50,000 health care workers in the US found that previously infected employees (about 5% of the workforce) had a low likelihood of becoming reinfected. Vaccinated and unvaccinated participants who had evidence of a previous infection, had similar subsequent risks of reinfection, at least when assessed three months after vaccinations began (with the mRNA vaccines). The authors suggest that this means those who have been previously infected may not need a vaccine. 

However, this does not account for the potential of changed infection risks for new variants, or for possible declining protection over longer periods of time. In addition, most of those with previous infections were younger, under 40. The duration and level of protection from prior infections may differ in older groups. The paper has not yet been peer reviewed.

Similarities and differences between immune responses from natural infection and vaccination

Antibody responses in vaccinated people were similar or better than those seen for those infected with SARS-CoV-2. However, those vaccinated produced a smaller proportion of neutralising antibodies. The study indicates that binding antibodies, not just neutralising antibodies, play an important role in suppressing infection. It also notes that some of the binding antibodies cross react to other coronaviruses, which offers hope for development of a pan-coronavirus vaccine. The paper was published in Cell.

T cell responses remain strong against several variants

Despite poorer neutralising antibody responses, T cell responses to the Beta variant still appear effective. Analysis of 44 South African Covid-19 patients found that while some CD4+ T cells failed to recognise some spike protein epitopes (binding sites) a variety of other CD4 and CD8 cells recognised other regions of the virus, which likely contributes to vaccines still providing a degree of protection. The paper has not yet been peer reviewed.

Old cells may increase risk of infection and severe disease

Senescent (elderly) cells may increase pathogenicity to SARS-CoV-2 by decreasing viral defences and increasing production of inflammatory chemicals. Studies of senescent human cells in culture also found that such cells enhance the expression of SARS-CoV-2 proteins in nearby healthy cells, aiding viral infection. 

Old mice (more than 20 months old) had high levels of mortality when exposed to a mouse coronavirus, while three-month old mice survived infection. Treating old mice with compounds that kill off senescent cells (senolytics) markedly improved their survival after exposure to a range of microbes. While the mouse model doesn’t mimic SARS-CoV-2 infection the authors suggest that reducing the number of senescent cells in older people may help improve Covid-19 outcomes and responses to vaccines. This requires further research. The paper was published in Science.

Double monoclonal antibody therapy may provide good protection against variants of concern

The two antibody therapy REGN-COV can provide protection against all current variants of concern or interest. Research compared the therapy’s effectiveness in lab and animal tests with single, dual or triplet monoclonal antibody combinations. The study also found that Covid-19 patients generally contain a range of viral mutations, which could lead to selective pressures after certain therapies.

The authors suggest the need for ongoing surveillance of mutations and therapies that are designed to target a range of variants to reduce risks of viral resistance. The paper was published in Cell.

A review in another Cell paper describes neutralising monoclonal antibodies that target SARS-CoV-2, and their effectiveness.

Behaviours not just genetics influence transmission

A variant - 20E (EU1) - that rapidly spread from Spain to many parts of Europe in the 2020 European summer appears due to human behaviour rather than viral genetics. Genomic sequencing identified multiple introductions into countries associated with tourists returning from their holidays, rather than greater transmissibility by the virus.

The authors recommend ongoing genetic surveillance and good public health practices, alongside vaccination, to control outbreaks, particularly as countries increasingly open up again. We included this paper as a pre-print in the 4th December Tracker and it has now been published in Nature

Key questions about long Covid

A Nature news feature examines four “urgent questions” about long Covid. These are, “How common is it?”, “What causes it”, “How is it related to other post-infection syndromes”, and “What can be done to help people with it?”

Predicting outbreak trajectory from PCR results

A paper in Science suggests that the cycle threshold (Ct) values from Covid-19 PCR tests can provide a good indication of the epidemic’s trajectory. The Ct value is the number of PCR cycles required to detect the virus in a sample, with a smaller number indicating higher virus levels and so quicker detection.

If the variation in Ct values is assessed across a population this, the authors suggest, will indicate if the epidemic is spreading or contracting because it reflects the effective reproduction rate of the virus. A rapidly expanding epidemic is expected to see a higher proportion of low Ct values in the population. The paper also describes some limitations to this method.

Viral loads peak quickly, regardless of symptoms

Regardless of symptoms, viral loads may peak quickly, at around 3 days after earliest PCR detection. In this study of teams in the National Basketball Association 46 people had acute infections, 33 of whom were asymptomatic. Patients with symptoms cleared the virus on average after 10 days, while asymptomatic cases had quicker clearance (around seven to eight days). Frequent PCR testing of Covid-19 patients can help determine if they are in the infectious stage or clearing the virus, and so inform clinical care. The paper has not yet been peer reviewed.

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