Virus World

The bivalent vaccine will now form part of the booster campaign to be rolled out this autumn.  Ministers say the vaccine will now form part of the autumn booster campaign. Moderna thinks 13 million doses of its new vaccine will be available this year, but 26 million people are eligible for some form of booster. Health officials say people should take whichever booster they are offered as all jabs provide protection. The original vaccines used in the pandemic were designed to train the body to fight the first form of the virus which emerged in Wuhan, in China, at the end of 2019. The Covid virus has since mutated substantially, with a stream of new variants emerging that can dodge some of our immune defences. They have caused large surges in cases around the world. The original vaccines still provide strong protection against becoming severely ill or dying, but companies are tweaking them to match the virus as it evolves. Cases of coronavirus are currently falling in the UK. In mid-to-late July, around 2.5 million people tested positive for coronavirus.

The likelihood of self-reported long COVID after a first coronavirus (COVID-19) infection compatible with the Omicron BA.1 or BA.2 variants, compared with the Delta variant, using data from the COVID-19 Infection Survey.

• Of triple-vaccinated adults, 4.5%, 4.2% and 5.0% self-reported having long COVID 12 to 16 weeks after a first laboratory-confirmed coronavirus (COVID-19) infection compatible with the Omicron BA.1, Omicron BA.2 or Delta variants, respectively, using data to 27 May 2022.

• There was no statistical evidence of differences in the odds of reporting long COVID between infections compatible with the Omicron BA.1, Omicron BA.2 and Delta variants among adults who were triple vaccinated when infected; this was after statistically adjusting for socio-demographic characteristics for all comparisons, and for time since last vaccine dose when comparing Omicron BA.1 and BA.2.

• Of double-vaccinated adults, 4.0% self-reported long COVID 12 to 16 weeks after a first infection compatible with the Omicron BA.1 variant, compared with 9.2% for those compatible with the Delta variant.

• The odds of reporting long COVID were 48.2% lower for first COVID-19 infections compatible with the Omicron BA.1 variant than those compatible with the Delta variant among adults who were double vaccinated when infected; this was after statistically adjusting for socio-demographic characteristics.

If you are worried about new or ongoing symptoms four or more weeks after having COVID-19, there are resources available to help. See Long-term effects of coronavirus (NHS) and Your COVID Recovery (NHS), which can help you to understand what has happened and what you might expect as part of your recovery. The time it takes to recover from COVID-19 is different for everyone, and the length of your recovery is not necessarily related to the severity of your initial illness or whether you were in hospital.

This briefing is produced to share data useful to other public health investigators and academic partners undertaking related work. Although a detailed clinical case review is also taking place, that data is not shared here as, given the small number of cases, there are some risks to confidentiality.

Cases

As of 3 May 2022, there have been 163 cases of acute non-A-E hepatitis with serum transaminases greater than 500 IU/l identified in children aged under 16 years old in the UK since 1 January 2022. This is the result of an active case finding investigation commencing in April which identified retrospective as well as prospective cases. Eleven cases have received a liver transplant. No cases resident in the UK have died. New cases continue to be identified. Whilst there is some apparent reduction in confirmed cases in the past 2 weeks overall in the UK, there are continued new case reports in Scotland, the number of cases pending classification in England is substantial and the likely reporting lags mean that we cannot yet say there is a decrease in new cases. Cases pending classification are usually those in which laboratory testing to rule out known causes of hepatitis has not been completed.

Working hypotheses

The working hypotheses have been refined. The leading hypotheses remain those which involve adenovirus. However, we continue to investigate the potential role of SARS-CoV-2 and to work on ruling out any toxicological component.

Associated pathogens

Adenovirus remains the most frequently detected potential pathogen. Amongst 163 UK cases, 126 have been tested for adenovirus of which 91 had adenovirus detected (72%). Amongst cases the adenovirus has primarily been detected in blood. On review of some of the adenovirus negative cases it was notable that some had only been tested on respiratory or faecal samples, and some had been tested on serum or plasma rather than whole blood (whole blood being the optimal sample). It is therefore not possible to definitively rule out adenovirus in these cases. SARS-CoV-2 has been detected in 24 cases of 132 with available results (18%). SARS-CoV-2 serological testing is in process. A range of other possible pathogens have been detected in a low proportion of cases and are of uncertain significance, although the inclusive nature of the UKHSA case definition intentionally will pick up some cases of non-A-E hepatitis with recognised causes.

Adenovirus characterisation

Typing by partial hexon gene sequencing consistently shows that the adenovirus present in blood is type 41F (18 of 18 cases with an available result). Whole genome sequencing (WGS) has been attempted on multiple samples from cases but the low viral load in blood samples, and limited clinical material from historic cases, mean that it has not been possible to get a good quality full adenovirus genome from a case as yet.

Metagenomics

Metagenomics undertaken on blood and liver tissue has detected primarily adeno-associated virus 2 (AAV-2) in high quantities. Whilst contamination was originally suspected, AAV-2 is now detected in multiple samples from different hospital sources and tested in more than one sequencing laboratory. This finding is of uncertain significance and may represent a normal reactivation of AAV-2 during an acute viral infection (for example, adenovirus) or during liver injury of another cause. It is not unusual to detect bystander, reactivating or other incidental species during metagenomic sequencing. However, given the presence of AAV-2 in a number of cases, the significance will be further explored through testing of additional sets of controls.

Toxicology

Toxicological investigations continue with no positive findings to date. Detection of paracetamol is likely to be related to appropriate therapeutic use (also noted in the trawling questionnaires) which would not be a concern, however verification work is being undertaken to confirm this.

Host investigations

Host (for example, immunological) investigations require full research consent and are undertaken under the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Clinical Characterisation Protocol. Thirty-seven cases have been recruited to the ISARIC clinical characterisation protocol to date and retrospective and prospective recruitment continues...

Update 2 (May 6, 2022):

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1073704/acute-hepatitis-technical-briefing-2.pdf 

The study involving more than 2,300 people also found that women were 33% less likely to fully recover than men.  Not even 1 in 4 people have completely recovered from the coronavirus a full year after being hospitalized with the disease, a U.K. study indicated Sunday, warning that long COVID-19 could become a common condition. The study involving more than 2,300 people also found that women were 33% less likely to fully recover than men. It also found that obese people were half as likely to fully recover, while those who needed mechanical ventilation were 58% less likely. The study looked at the health of people who were discharged from 39 British hospitals with COVID-19 between March 2020 and April 2021, then assessed the recovery of 807 of them five months and one year later. Just 26% reported a full recovery after five months, and that number rose only slightly to 28.9% after a year, according to the study published in the Lancet Respiratory Medicine journal.

“The limited recovery from five months to one year after hospitalization in our study across symptoms, mental health, exercise capacity, organ impairment and quality-of-life is striking,” said study co-leader Rachel Evans of the National Institute for Health and Care Research. The most common long-COVID-19 symptoms were fatigue, muscle pain, poor sleep, slowing down physically and breathlessness. “Without effective treatments, long-COVID could become a highly prevalent new long-term condition,” said study co-lead Christopher Brightling of the University of Leicester. The study, which will be presented at the European Congress of Clinical Microbiology and Infectious Diseases, is ongoing and will continue to monitor the patients’ health.

Published in The Lancet Respiratory Medicine (April 23, 2022):

https://doi.org/10.1016/S2213-2600(22)00127-8 

A new variant of concern in South Africa has prompted a ban on flights to the U.K. for an undetermined period of time.  The United Kingdom is temporarily suspending flights from six countries as a new Covid variant with more than 30 mutations spreads in South Africa. Sajid Javid, the U.K.’s secretary of state for health and social care, made the announcement hours after the World Health Organization gave a briefing on the new variant. The organization called for a special meeting on Friday to further study the variant, which has been detected in small numbers in South Africa. “More data is needed but we’re taking precautions now. From noon tomorrow six African countries will be added to the red list, flights will be temporarily banned, and UK travellers must quarantine,” Javid wrote on Twitter.

In addition to South Africa, the countries of Namibia, Lesotho, Eswatini, Zimbabwe and Botswana are included in the new restrictions, according to a statement issued by the U.K.’s health, transport and health security agencies. The WHO is holding a special meeting Friday to discuss what the new variant may mean for vaccines and treatments, officials said Thursday. The variant, called B.1.1.529, has been detected in South Africa in small numbers, according to the WHO. The variant has spread rapidly through the Gauteng province, which contains the country’s largest city of Johannesburg. The variant has also been detected in Botswana and Hong Kong, South Africa Minister of Health Joe Phaahla said during the briefing. “We don’t know very much about this yet. What we do know is that this variant has a large number of mutations. And the concern is that when you have so many mutations, it can have an impact on how the virus behaves,” Dr. Maria Van Kerkhove, WHO’s technical lead on Covid-19, said in a Q&A that was livestreamed on the organization’s social media channels.

The newly detected variant arrives as infection levels remain high in countries across the world. In Europe, Austria and Italy announced new restrictions in recent days aimed at slowing the spread of the virus. South African scientists have detected more than 30 mutations in the new variant, raising concern that it could possibly better evade the antibody protection created by vaccines and prior infections. Countries have used restrictions on flights or total travel as a tool to slow the spread of Covid since the early days of the pandemic. The U.S. just lifted its travel ban from 33 countries, including the U.K., earlier this month.

Scientists are studying it to better understand how much of a threat it may pose.  Delta is the UK's dominant variant, but latest official data suggests 6% of Covid cases that have been genetically sequenced are of a new type. AY.4.2, which some are calling "Delta Plus", contains mutations that might give the virus survival advantages. Tests are under way to understand how much of a threat it may pose. Experts say it is unlikely to take off in a big way or escape current vaccines. It is not yet considered a variant of concern, or a variant under investigation - the categories assigned to variants and the level of risk associated with them.

Researchers in Belgium report on the case of a 90-year-old woman who was simultaneously infected with two different variants of concern (VOCs) of COVID-19, in a Case Report being presented at the European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) held online this year.  On March 3 2021, the woman, whose medical history was unremarkable, was admitted to the OLV Hospital in the Belgian city of Aalst after a spate of falls. She tested positive for COVID-19 on the same day. She lived alone and received nursing care at home, and had not been vaccinated against COVID-19. Initially, there were no signs of respiratory distress and the patient had good oxygen saturation. However, she developed rapidly worsening respiratory symptoms, and died five days later. When the patient's respiratory sample was tested for VOCs with PCR, they discovered that she had been infected by two different strains of the virus—one which originated in the UK, known as B.1.1.7 (Alpha), and another that was first detected in South Africa (B.1.351; Beta). The presence of both strains was confirmed by PCR on a second respiratory sample, by sequencing of the S-gene and by whole genome sequencing.

"This is one of the first documented cases of co-infection with two SARS-CoV-2 variants of concern", says lead author and molecular biologist Dr. Anne Vankeerberghen from the OLV Hospital in Aalst, Belgium. "Both these variants were circulating in Belgium at the time, so it is likely that the lady was co-infected with different viruses from two different people. Unfortunately, we don't know how she became infected." On December 14, 2020, the UK authorities informed WHO that a variant (B.1.1.7; Alpha) had been detected in the south east of England (Kent). Within a few weeks, this variant took over from the viral strains circulating in this region, and has since spread to more than 50 countries, including Belgium. On December 18, 2020, the South African authorities reported that a variant (B.1.351; Beta) had been detected and was spreading rapidly throughout three provinces of South Africa, and has now been identified in at least 40 countries, including Belgium. In January 2021, scientists in Brazil reported that two people had been simultaneously infected with two different strains of the coronavirus—the Brazilian variant known as B.1.1.28 (E484K) and a novel variant VUI-NP13L, which had previously been discovered in Rio Grande do Sul. But the study has yet to be published in a scientific journal [1]. Previous research has reported people infected with different influenza strains [2]. "Whether the co-infection of the two variants of concern played a role in the fast deterioration of the patient is difficult to say", says Vankeerberghen.

"Up to now, there have been no other published cases. However, the global occurrence of this phenomenon is probably underestimated due to limited testing for variants of concern and the lack of a simple way to identify co-infections with whole genome sequencing." She continues, "Since co-infections with variants of concern can only be detected by VOC-analysis of positive samples, we would encourage scientists to perform fast, easy and cheap VOC-analysis by PCR on a large proportion of their positive samples, rather than just whole genome sequencing on a small proportion. Independent of the technique used, being alert to co-infections remains crucial."

See also abstract of the research cited (July 10, 2021):

https://www.olvz.be/sites/default/files/2021-07/04978-90_year_old_double_infection.pdf 

Under-30s to be offered jabs from next week but variant makes decision on easing rules in England ‘more difficult’.  The new Delta variant of coronavirus appears to be about 40% more transmissible than the variant it has largely replaced, Matt Hancock has said, making government decisions about whether to ease restrictions in England on 21 June “more difficult”. Saying that under-30s in England will be called to begin vaccinations from next week, the health secretary confirmed it was still possible the reopening programme could be delayed or some rules kept in place. “We consider all options,” he told Sky News. The transmissibility of the Delta variant, first identified in India, has been seen as a central factor to the decisions over whether to remove most remaining restrictions in England in a fortnight, with the decision due to be made later this week. Estimates have said the Delta variant could be anywhere between 30% and 100% more transmissible than the so-called Alpha variant first identified in Kent. But asked for the latest information, Hancock gave a figure of 40%. “That means that it is more difficult to manage this virus with the new Delta variant,” he said. “But crucially, after two doses of vaccine we are confident that you get the same protection that you did with the old variant. So the good news is that the vaccine still works just as effectively.” It was, he said, still too early to decide what might happen on 21 June: “The prime minister and I and the team will be looking at all of the data over this week … The critical thing is to see whether the four tests we have set have been met.” Saying the Covid vaccination programme had “severed but not broken” the link between infection rates and hospitalisations, Hancock said adults under 30 would be able to seek first injections from next week.

British scientists on Monday launched a trial which will deliberately expose participants who have already had COVID-19 to the coronavirus again to examine immune responses and see if people get reinfected.  In February, Britain became the first country in the world to give the go-ahead for so-called "challenge trials" in humans, in which volunteers are deliberately exposed to COVID-19 to advance research into the disease caused by the coronavirus. read more The study launched on Monday differs from the one announced in February as it seeks to reinfect people who have previously had COVID-19 in an effort to deepen understanding about immunity, rather than infecting people for the first time. "The information from this work will allow us to design better vaccines and treatments, and also to understand if people are protected after having COVID, and for how long," said Helen McShane, a University of Oxford vaccinologist and chief investigator on the study.  She added that the work would help understanding of what immune responses protect against reinfection.

Background: Following a single dose of BNT162b2 mRNA vaccine, higher antibody titres are observed following prior SARS-CoV-2 infection than in infection-naive individuals, but T-cell responses are less well defined.

Methods: We sampled healthcare workers (HCWs) enrolled in the UK PITCH study, before and after BNT162b2 mRNA vaccination. We measured spike-specific antibody, and quantified T-cell responses by IFNγ ELISpot assay and intracellular staining of peripheral blood mononuclear cells (PBMC), comparing SARS-CoV-2-naïve individuals to those with prior infection.

Findings: HCWs aged 22 to 71 years received one (n=216) or two (n=21) vaccine doses. After a single dose, the spike-specific T-cell response was six-fold higher in previously-infected vs. naive individuals (median 340 vs. 58 SFU/106 PBMC, p<0.0001; fresh PBMC, n=99). The T-cell response in previously-infected individuals after one vaccine dose was equivalent to naïve individuals receiving two vaccine doses (median 158 vs. 165 SFU/106 PBMCs, p=0.65; cryopreserved PBMC, n=117). Anti-spike IgG levels following a single dose in those previously infected (median 512.9 antibody units/ml (AU/ml)) were 6.8-fold higher vs. naïve individuals following one dose (median 75.0 AU/ml, p<0.0001) and 2.9-fold higher than naïve individuals given two doses three weeks apart (179.9 AU/ml, p=0.03). Following vaccination, plasma from individuals with prior infection demonstrated higher in vitro neutralisation of the B.1.351 variant of concern compared to naive individuals.

Interpretation: Following a single BNT162b2 dose, HCWs with a prior history of SARS-CoV-2 infection have significantly higher T-cell and antibody responses than naive individuals.Funding UK Department of Health and Social Care and UK Coronavirus Immunology Consortium.

Available as preprint in The Lancet (March 25, 2021):

http://dx.doi.org/10.2139/ssrn.3812375 

New research at Washington University School of Medicine in St. Louis indicates that three new, fast-spreading variants of the virus that cause COVID-19 can evade antibodies that work against the original form of the virus that sparked the pandemic. With few exceptions, whether such antibodies were produced in response to vaccination or natural infection, or were purified antibodies intended for use as drugs, the researchers found more antibody is needed to neutralize the new variants.  The findings, from laboratory-based experiments and published March 4 in Nature Medicine, suggest that COVID-19 drugs and vaccines developed thus far may become less effective as the new variants become dominant, as experts say they inevitably will. The researchers looked at variants from South Africa, the United Kingdom and Brazil. "We're concerned that people whom we'd expect to have a protective level of antibodies because they have had COVID-19 or been vaccinated against it, might not be protected against the new variants," said senior author Michael S. Diamond, MD, Ph.D., the Herbert S. Gasser Professor of Medicine. "There's wide variation in how much antibody a person produces in response to vaccination or natural infection. Some people produce very high levels, and they would still likely be protected against the new, worrisome variants. But some people, especially older and immunocompromised people, may not make such high levels of antibodies. If the level of antibody needed for protection goes up tenfold, as our data indicate it does, they may not have enough. The concern is that the people who need protection the most are the ones least likely to have it."

The virus that causes COVID-19, known as SARS-CoV-2, uses a protein called spike to latch onto and get inside cells. People infected with SARS-CoV-2 generate the most protective antibodies against the spike protein. Consequently, spike became the prime target for COVID-19 drug and vaccine developers. The three vaccines authorized by the Food and Drug Administration (FDA) for emergency use in the U.S.—made by Pfizer/BioNTech, Moderna and Johnson & Johnson—both target spike. And potent anti-spike antibodies were selected for development into antibody-based drugs for COVID-19. Viruses are always mutating, but for nearly a year the mutations that arose in SARS-CoV-2 did not threaten this spike-based strategy. Then, this winter, fast-spreading variants were detected in the United Kingdom, South Africa, Brazil and elsewhere. Sparking concern, the new variants all carry multiple mutations in their spike genes, which could lessen the effectiveness of spike-targeted drugs and vaccines now being used to prevent or treat COVID-19. The most worrisome new variants were given the names of B.1.1.7 (from the U.K.), B.1.135 (South Africa) and B.1.1.248, also known as P.1 (Brazil).

To assess whether the new variants could evade antibodies made for the original form of the virus, Diamond and colleagues, including first author Rita E. Chen, a graduate student in Diamond's lab, tested the ability of antibodies to neutralize three virus variants in the laboratory. The researchers tested the variants against antibodies in the blood of people who had recovered from SARS-CoV-2 infection or were vaccinated with the Pfizer vaccine. They also tested antibodies in the blood of mice, hamsters and monkeys that had been vaccinated with an experimental COVID-19 vaccine, developed at Washington University School of Medicine, that can be given through the nose. The B.1.1.7 (U.K.) variant could be neutralized with similar levels of antibodies as were needed to neutralize the original virus. But the other two variants required from 3.5 to 10 times as much antibody for neutralization. Then, they tested monoclonal antibodies: mass-produced replicas of individual antibodies that are exceptionally good at neutralizing the original virus. When the researchers tested the new viral variants against a panel of monoclonal antibodies, the results ranged from broadly effective to completely ineffective. Since each virus variant carried multiple mutations in the spike gene, the researchers created a panel of viruses with single mutations so they could parse out the effect of each mutation. Most of the variation in antibody effectiveness could be attributed to a single amino acid change in the spike protein. This change, called E484K, was found in the B.1.135 (South Africa) and B.1.1.248 (Brazil) variants, but not B.1.1.7 (U.K.). The B.1.135 variant is widespread in South Africa, which may explain why one of the vaccines tested in people was less effective in South Africa than in the U.S., where the variant is still rare, Diamond said. "We don't exactly know what the consequences of these new variants are going to be yet," said Diamond, also a professor of molecular microbiology and of pathology & immunology. "Antibodies are not the only measure of protection; other elements of the immune system may be able to compensate for increased resistance to antibodies. That's going to be determined over time, epidemiologically, as we see what happens as these variants spread. Will we see reinfections? Will we see vaccines lose efficacy and drug resistance emerge? I hope not. But it's clear that we will need to continually screen antibodies to make sure they're still working as new variants arise and spread and potentially adjust our vaccine and antibody-treatment strategies."

Original Findings Published in Nature Medicine (March 4, 2021):

https://doi.org/10.1038/s41591-021-01294-w

Researchers hope to learn things about how the immune system responds to the coronavirus that would be impossible outside a lab.  In the coming weeks, a small, carefully selected group of volunteers is expected to arrive on the 11th floor of a London hospital to be given what the rest of the world’s 7.8 billion people have been trying to avoid: a coronavirus infection. They will be administered tiny droplets of the virus into their nostrils as part of a plan authorized by British regulators on Wednesday to deliberately infect unvaccinated volunteers with the coronavirus. The scientists hope to eventually expose vaccinated people to the virus as a way of comparing the effectiveness of different vaccines. But before that, the project’s backers have to expose unvaccinated volunteers in order to determine the lowest dose of the virus that will reliably infect them. By controlling the amount of the virus people are subjected to and monitoring them from the moment they are infected, scientists hope to discover things about how the immune system responds to the coronavirus that would be impossible outside a lab — and to develop ways of directly comparing the efficacy of treatments and vaccines. “We are going to learn an awful lot about the immunology of the virus,” Peter Openshaw, an Imperial College London professor involved in the study, said on Wednesday. He added that the study would be able “to accelerate not only understanding of diseases caused by infection, but also to accelerate the discovery of new treatments and of vaccines.”

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes.

A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors. A retrospective analysis of primary care records in the United Kingdom reveals individual symptoms associated with SARS-CoV-2 infections, which persisted for 12 weeks or more after infection, as well as risk factors associated with developing long COVID.

Published in Nature Medicine (July 25, 2022):

https://doi.org/10.1038/s41591-022-01909-w 

Characteristics of people testing positive for COVID-19 from the Coronavirus (COVID-19) Infection Survey. 

The most recent update (May 25, 2022) by the UK Health Security agency shows an increasingly alarming rate of re-infections in the U.K. As compared to the pre-Omicron period, re-infection rates were nearly 8-fold greater in the period from December 20 2021 onwards. A total of 4729 reinfections were reported during the Omicron period, with 75% of the re-infections showing cycle threshold values (Ct) below 30, suggesting high viral loads. People with asymptomatic infections, or with prior infections with lower viral loads (Ct above 30) were more likely to be re-infected. Vaccinated individuals, or older people, were less likely to suffer re-infections. The findings highlight the ability of Omicron, and the newest Omicron sub-lineages, to escape immunity elicited by prior infections.

Health officials in the UK have released new details in their ongoing investigation of an unusual series of hepatitis cases in children. The new report helps explain why they have zeroed in on a possible link to the adenovirus family, the UK Health Security Agency announced Monday.  Since the beginning of the year, at least 111 children have been identified in the UK with acute liver inflammation that does not appear to be caused by the group of hepatitis viruses that would've been a more likely culprit. Many more cases have been announced in the US and other countries around the world. Roughly three-quarters of the 53 children who were tested for adenovirus in the UK came back positive. The virus that causes Covid-19, on the other hand, was found in only a sixth of children who were tested — in line with the levels of community transmission in the UK. 

Study that infected young adults with the coronavirus finds virus may largely be shed from nose

A small trial that involved deliberately infecting volunteers with the virus that causes covid-19 has revealed new details on how it can cause mild to moderate symptoms.  This type of research is known as a human challenge trial, and while similar studies have been conducted for various viruses over the years, this is the first to report findings on the coronavirus. Researchers in the UK gave 36 volunteers aged between 18 and 29 a low dose of the virus via droplets placed in the nose. The virus was taken from a person who became ill with covid-19 very early in the pandemic, before any notable variants had emerged.  Eighteen of the volunteers became infected with the virus, and 16 of them developed cold-like symptoms, such as a runny rose, sore throat, cough, fever or headache. Many of these symptoms were not included on symptom lists published by health authorities early in the pandemic. Thirteen of the volunteers also temporarily lost their sense of taste and smell.  Among those who became infected, the virus could be detected, and symptoms began to develop, within 42 hours. This incubation period is significantly shorter than estimates at the time, which put the incubation period between two and 14 days.

The virus could be detected in the throat at 40 hours, before it could be detected in the nose at around 58 hours. Peak levels of the virus were found to be higher in the nose, suggesting that more virus may spread this way – and highlighting the importance of ensuring face coverings shield the nose as well as the mouth. Other findings from the study support the use of lateral flow tests in picking up infectious cases of the disease. “We found that overall, lateral flow tests correlate very well with the presence of infectious virus,” Christopher Chiu at Imperial College London, the trial’s chief investigator, said in a statement. “Even though in the first day or two they may be less sensitive, if you use them correctly and repeatedly, and act on them if they read positive, this will have a major impact on interrupting viral spread.” None of the volunteers developed any serious symptoms and no damage was seen in their lungs. 

The UK Medicines and Healthcare Products Regulatory Agency said Thursday it had authorized Merck and Ridgeback Biotherapeutics' oral antiviral, molnupiravir, to treat mild-to-moderate Covid-19 in adults at risk for severe illness. It is the world's first oral antiviral to be authorized anywhere for the treatment of Covid-19. The drug comes in capsule form and will be known as Lagevrio. The companies have sought US Food and Drug Administration emergency use authorization for the drug, and the FDA said it will convene its Antimicrobial Drugs Advisory Committee on November 30 to discuss molnupiravir's ability to treat mild-to-moderate Covid-19 in adults who are at high risk for severe disease, including hospitalization or death. Merck and Ridgeback also say the European Medicines Agency has initiated a rolling review of its marketing application.  Merck announced last month that the capsule reduced the risk of hospitalization or death from Covid-19 by half. "At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization (28/385), compared with 14.1% of placebo treated patients (53,377)," the company said in a news release in October. "Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo." The data has not yet been peer-reviewed or published, but spurred excitement about a potentially easy, accessible treatment for Covid-19.

ONS figures show 51,281 Covid deaths between January and July, with 458 dying at least 21 days after second dose.  People who were fully vaccinated accounted for just 1.2% of all deaths involving Covid-19 in England in the first seven months of this year. The figures, published by the Office for National Statistics (ONS), have been seized on as proof of the success of the vaccine programme. The figures show a total of 51,281 deaths involving Covid-19 in England between 2 January and 2 July, of which 38,964 were of unvaccinated people.  Of the total Covid-related deaths, 458 (about 0.9%) were of people who died at least 21 days after their second vaccine dose. Just 256 deaths (0.5%) were of people who were fully vaccinated and had their first positive PCR test at least 14 days after their second dose. No vaccine is 100% effective against Covid-19, and health authorities have made it clear that some deaths of vaccinated individuals are to be expected. Public Health England (PHE) has estimated that two-dose effectiveness against hospital admission with infections from the Delta variant – which is now the UK’s dominant strain – has been around 94%.  However, the figures on Monday underlined that the risk of death involving Covid-19 is consistently lower for people who have received two doses compared with one dose or no vaccination at all.

A detailed breakdown of data was made available for 252 of the 256 people who died after having received both jabs and who first tested positive at least 14 days after the second dose. They are what the ONS describes as “breakthrough” deaths. It shows that just over three-quarters of these deaths (76.6%) occurred in those who were clinically extremely vulnerable – a slightly higher proportion than for other Covid-19 deaths (74.5%) and deaths not involving Covid-19 (69.7%). Of the breakthrough deaths, 61.1% occurred in males, which is higher than for other Covid-19 deaths (52.2%) and deaths not involving Covid-19 (48.5%), while 13% were among people who were immunocompromised. Experts emphasised the importance of context in terms of the data, which covered a period when the seven-day average daily UK deaths varied between six and more than 1,200 per day. Trends were increasing at the end of the ONS study period, when rates were about 25 per day, while daily death rates are now consistently over 100 per day.  Dr Duncan Robertson, a data analyst at Loughborough University who has been focusing on Covid-19 modelling and analysis, said: “By definition, as the proportion of vaccinated people increases, fewer remain in the unvaccinated category. In the extreme, if everyone were vaccinated, 100% of deaths would be of vaccinated people, just as before the vaccine rollout, 0% of deaths would be of vaccinated people.” But he added: “What is clear from the ONS data is the significance of being fully vaccinated – full vaccination offers very high – but not perfect - protection against death, where only having a first dose offers significantly less protection.”

Background

The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear.

Methods

We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike (S) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status.

Results

Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant.

Conclusions

Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.)

Published in NEJM (July 21, 2021):

https://doi.org/10.1056/NEJMoa2108891 

Vaccination and Household Transmission of SARS-CoV-2 In this study involving household contacts of persons with laboratory-confirmed Covid-19, the risk of household transmission was 40 to 50 lower in households of index patients who had been vaccinated 21 days or more before testing positive than in households of unvaccinated index patients.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevents infection and reduces the severity of coronavirus disease 2019 (Covid-19) in vaccinated persons.1,2 We investigated whether vaccination would reduce transmission in the household setting in the context of postvaccination infection. We analyzed data from the Household Transmission Evaluation Dataset (HOSTED), which has information on all laboratory-confirmed cases of Covid-19 in England and in which data on all persons sharing the same address are linked.3 We then linked to individual-level data on all Covid-19 vaccinations in England (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We compared the risk of secondary infection (defined as a positive SARS-CoV-2 test 2 to 14 days after the positive test for the index case) among unvaccinated household contacts of persons with SARS-CoV-2 infection who had received at least one dose of the ChAdOx1 nCoV-19 or BNT162b2 vaccine 21 days or more before testing positive with the risk among unvaccinated household contacts of unvaccinated persons with infection. We fitted logistic-regression models with adjustment for the age and sex of the person with the index case of Covid-19 (index patient) and the household contact, geographic region, calendar week of the index case, deprivation (a composite score of socioeconomic and other factors), and household type and size. We also considered the timing of effects among index patients who had been vaccinated at any time up to the date of the positive test.

Between January 4 and February 28, 2021, there were 960,765 household contacts of unvaccinated index patients, and there were 96,898 secondary cases of Covid-19 (10.1%). (Descriptive data regarding the index patients and their household contacts are provided in the Summary Results section.) The numbers of secondary cases according to the vaccination status of the index patient, and the results of logistic-regression models, are shown in Table 1. Overall, the likelihood of household transmission was approximately 40 to 50% lower in households of index patients who had been vaccinated 21 days or more before testing positive than in households of unvaccinated index patients; the findings were similar for the two vaccines. Most of the vaccinated index patients in our data set (93%) had received only the first dose of vaccine. Assessment of infection risks among household contacts according to the timing of vaccination of the index patient showed protective effects when the vaccine had been administered at least 14 days before the positive test (Figs. S1 and S2 in the Supplementary Appendix)....

Published in NEJM (June 23, 2021):

https://doi.org/10.1056/NEJMc2107717 

A single dose of the COVID-19 vaccine made by either Pfizer or AstraZeneca cuts a person’s risk of transmitting SARS-CoV-2 to their closest contacts by as much as half, according to an analysis of more than 365,000 households in the United Kingdom. Although the vaccines have been shown to reduce COVID-19 symptoms and serious illness, their ability to prevent coronavirus transmission has been unclear. Kevin Dunbar, Gavin Dabrera and their colleagues at Public Health England in London looked for cases in which someone became infected with SARS-CoV-2 after receiving a dose of either vaccine (R. J. Harris et al. Preprint at Knowledge Hub https://go.nature.com/3e3iu1i; 2021). They then assessed how often those individuals transmitted the virus to household contacts. The team found that people who had been vaccinated for at least 21 days could still test positive for the virus. But viral transmission from these individuals to others in their households was 40–50% lower than transmission in households in which the first person to test positive had not been vaccinated. Results for the two vaccines were similar. The findings have not yet been peer reviewed.

Sage says majority were likely infected shortly before or soon after jab, before immunity had time to develop.  One in 25 people hospitalised with Covid-19 since December have had at least one dose of vaccine, with the majority infected shortly before or soon after vaccination – before immunity would have had time to develop. However, few of those who developed symptoms, did so more than 2 weeks after receiving a first dose – indicating that the vaccines do help to prevent serious disease once they’ve had time to take effect. The data, presented to the government’s Scientific Advisory Group for Emergencies (Sage), could be a further indication that people are dropping their guard once they’ve received a jab, wrongly assuming that they are immediately protected. Alternative explanations include the possibility that they were infected shortly before vaccination, during the vaccine appointment itself, or that vaccination triggered symptoms in infected people who were previously asymptomatic. In minutes from its 83rd meeting on 11 March Sage said:“The observation that a significant number of people developing symptoms within a few days of a first dose may suggest some behaviour change following vaccination. It is important therefore that communications around vaccination reinforce the need for safe behaviours to be maintained.” Almost 29 million people in the UK have received at least one dose of a coronavirus vaccine so far, with some degree of immune protection thought to develop around two weeks after receiving the first jab – although a second dose is needed to achieve the highest levels of protection.

According to data submitted to Sage by the Covid-19 Clinical Information Network (CO-CIN), there were 1,802 recorded cases of vaccinated patients hospitalised with Covid-19 in the UK as of 5 March. This accounted for 4.2% (1,802/42,788) of all Covid-related hospital admissions since 8 December – the date when the first people in the UK were vaccinated. The median time between vaccination and symptom onset for these patients was five days, indicating that most of them were infected shortly before or around the time of vaccination, with the remainder infected after vaccination but before immunity had developed. “Elderly and vulnerable people who had been shielding, may have inadvertently been exposed and infected either through the end-to-end process of vaccination, or shortly after vaccination through behavioural changes where they wrongly assume they are immune,” the CO-CIN report said.  Data from previous vaccine rollouts, national surveys and evidence from Israel have also indicated that people may be less likely to abide by social distancing rules once they’ve been vaccinated. In its 11 March meeting, Sage emphasised the need for better government communication about how long it takes for the jab to work, and that although the Covid-19 vaccines in use in the UK are highly effective, no vaccine is 100% effective. Minutes from the meeting said: “Some people will be hospitalised with Covid-19 even after completing their full vaccination schedule. It will be particularly important to monitor the prevalence of different variants present in this group by sequencing to understand any potential immune escape. This is under way by Public Health England.” A separate document released by Sage on Friday suggested there has been a four-fold increase in confirmed cases of the Brazilian P1 variant during the fortnight of 10 March to 24 March from 5 to 21, while cases of the South African variant have increased from 190 to 305.

Novavax Inc's COVID-19 vaccine was 96% effective in preventing cases caused by the original version of the coronavirus in a late-stage trial conducted in the United Kingdom, the company said on Thursday, moving it a step closer to regulatory approval.  There were no cases of severe illness or deaths among those who got the vaccine, the company said, in a sign that it could stop the worse effects of new variants that have cropped up. The vaccine was 86% effective in protecting against the more contagious virus variant first discovered and now prevalent in the United Kingdom, for a combined 90% effectiveness rate overall based on data from infections of both versions of the coronavirus. Novavax shares jumped 22% in after-hours trading to $229. They were trading below $10 on Jan. 21, 2020, when the company announced it was developing a coronavirus vaccine. In a smaller trial conducted in South Africa - where volunteers were primarily exposed to another newer, more contagious variant widely circulating there and spreading around the world - the Novavax vaccine was 55% effective, based on people without HIV, but still fully prevented severe illness.  Novavax Chief Medical Officer Filip Dubovsky said the performance in South Africa suggests there may still be a case for using it in areas where the South African variant is dominant.

Novavax is also developing new formulations of its vaccine to protect against emerging variants and plans to initiate clinical testing of these shots in the second quarter of this year. Results from the final analysis of the UK trial were largely in line with interim data released in January. The company expects to use the data to submit for regulatory authorization in various countries. It is not clear when it will seek U.S. authorization or if regulators will require it to complete an ongoing trial in the United States. Novavax expects data from a 30,000-person trial in the United States and Mexico by early April. Dubovsky said that Novavax is still planning to file for authorization from UK regulators early in the second quarter of 2021.  The UK trial, which enrolled more than 15,000 people aged 18 to 84, assessed efficacy of the vaccine during a period with high transmission of the UK virus variant now circulating widely.

The shot’s effectiveness in the South Africa trial declined to around 49% when the analysis included data from HIV-positive participants. The vaccine could be cleared for use in the United States as soon as May if U.S. regulators decide the UK data is enough to make a decision. It could take a couple months longer if they insist on first seeing data from the U.S. trial, its chief executive told Reuters earlier this month. “Ultimately, they have to decide whether the data we can bring to the table is adequate or whether they would prefer to wait on data from our U.S. study,” Dubovsky said on Thursday. Novavax’s vaccine production plants should all be fully functional by April, executives said on a March investor call. The drugmaker expects to have tens of millions of doses stockpiled and ready to ship in the United States when it receives authorization, CEO Stanley Erck told Reuters.  Novavax plans to produce its two-shot vaccine at eight manufacturing locations, including the Serum Institute of India. If authorized, it would follow three COVID-19 vaccines previously approved for use in Britain from Pfizer and partner BioNTech, Moderna Inc and the AstraZeneca shot developed with Oxford University. The Maryland-based company has received $1.6 billion from the U.S. government in funding for the vaccine trial and to secure 100 million doses.

Rapid approval without lengthy tests can happen if new vaccines are needed to fight variants, say regulators.  Current vaccines may not work as well against some variants and scientists are working on updating them now. But manufacturers will not need to seek brand new approval or do lengthy clinical studies. However they will need proof that the shots trigger protective antibodies in the blood. The aim is to shorten the process, where possible, so that vaccine approval could happen in weeks and months, not years. A similar fast-track method is already used for annual flu vaccines which regularly need updating to keep up with a virus that is constantly changing by mutating. The MHRA has issued guidance, along with authorities in Australia, Canada, Singapore and Switzerland, on what checks and measures would be necessary. The coalition of regulators - the ACCESS Consortium - insist no corners will be cut, with safety paramount.