LIVE BLOG: R&D response to COVID-19 pandemic (archived)

A UK study investigating the immune response to a fourth dose of COVID-19 vaccine has shown immunity to SARS-CoV-2 is boosted.

The latest results from the COV-BOOST trial, show that a fourth dose of an mRNA vaccine is safe and increases antibodies to higher levels than seen after a third dose.    

This is the first data from a randomised clinical study looking at the safety and efficacy of a second booster dose.

Countries including the US, Germany,  Israel and the UK have been offering fourth doses to the most vulnerable, as a precautionary strategy to maintain high levels of immunity prior to data being available.

However, on 6 April the European Medicines Agency and the European Centre for Disease Control and Prevention concluded it was too early to consider using a fourth dose of COVID-19 vaccine in the general population, saying there was currently no clear evidence in the EU that vaccine protection against severe disease is waning substantially in adults with normal immune systems aged 60 to 79 years. 

The COV-BOOST findings, published in Lancet Infectious Diseases, now show that a fourth dose mRNA booster is well-tolerated in people who received Pfizer as a third dose. It is also effective at increasing both antibody and cellular immunity up to and above baseline and peak levels observed following third dose boosters.

Saul Faust, professor of paediatric immunology at Southampton University, and lead of the COV-BOOST study said, “These results underline the benefits of the most vulnerable people receiving current spring boosters and gives confidence for any prospective autumn booster programme in the UK.”

In December 2021, COV-BOOST provided the world’s first data on the safety, immune responses and side effects of third dose in mix and match schedules.

In the fourth dose study, 166 people who had received a third dose of Pfizer, following Pfizer or AstraZeneca initial doses in June 2021, were randomised to receive full dose Pfizer or half dose Moderna as a fourth dose. These were approximately seven months after their third dose.    

Pain at the vaccination site and fatigue were the most common side effects. There were no vaccine-related serious adverse events, and fourth doses were safe and well tolerated.

Andrew Ustianowski, National Institute of Health Research clinical lead for the COVID-19 vaccination programme said, “We knew that it was important to offer a fourth dose to those most vulnerable earlier in the year. These new study findings support that decision and provides the public with the confidence that fourth doses are both safe and even more effective than third doses at boosting immunity against COVID-19.”

Adults with severe obesity generate a significantly weaker immune response to COVID-19 vaccination compared to those of normal weight, according to a study by Volkan Demirhan Yumuk, professor of medicine at Istanbul University.

This is significant because obesity is a risk factor for getting more severe disease if infected with SARS-CoV-2.

The study, presented the European Congress on Obesity in Maastricht, Netherlands last week,  also found that people with severe obesity (BMI of more than 40kg/m2) vaccinated with Pfizer/BioNTech’s mRNA vaccine generated significantly more antibodies than those vaccinated with the whole inactivated SARS-CoV-2 vaccine CoronaVac, which was developed by the Chinese vaccines manufacturer Sinovac Biotech. That suggests the Pfizer vaccine might be a better choice for this vulnerable population.

Vaccines against influenza, hepatitis B and rabies, have shown similar reduced responses in people with obesity.

The researchers investigated antibody responses following Pfizer/BioNTech and CoronaVac vaccination in 124 adults (average age 42-63 years) with severe obesity who visited the Obesity Centre at Istanbul University-Cerrahpasa, Cerrahpaşa Medical Faculty Hospitals, between August and November 2021.

They also recruited a control group of 166 normal weight adults (BMI less than 25kg/m2, average age 39-47 years) who were visiting the Cerrahpasa Hospitals Vaccination Unit.

In those without previous SARS-CoV-2 infection and vaccinated with Pfizer/BioNTech, patients with severe obesity had antibody levels more than three times lower than normal weight controls.

Similarly, in participants with no prior SARS-CoV-2 infection and vaccinated with CoronaVac, patients with severe obesity had antibody levels 27 times lower than normal weight controls.

However, in those with previous SARS-CoV-2 infection, antibody levels in patients with severe obesity and vaccinated with Pfizer/BioNTech or CoronaVac were not significantly different.

“These results provide new information on the antibody response to SARS-CoV-2 vaccines in people with severe obesity and reinforce the importance of prioritising and increasing vaccine uptake in this vulnerable group,” said Yumuk.

Cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age, and is the equivalent to losing 10 IQ points, according to a study by researchers at Cambridge University and Imperial College London.

The results suggest the effects are still detectable more than six months after the acute illness, and that any recovery is at best gradual.

There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, ‘brain fog’, problems recalling words, sleep disturbances, anxiety and post-traumatic stress disorder, months after infection.

Between a third and three-quarters of hospitalised patients report still suffering cognitive symptoms three to six months later.

To explore this link in greater detail, researchers analysed data from 46 individuals who received in-hospital care, of whom 16 were put on mechanical ventilation, at Addenbrooke’s Hospital, Cambridge.

They underwent detailed computerised cognitive tests an average of six months after their acute illness. COVID-19 survivors were less accurate and had slower response times than the matched control population.

The effects were strongest for those who required mechanical ventilation. By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that seen over 20 years ageing, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.

David Menon of the division of anaesthesia at Cambridge University said, “Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine ageing, but the patterns we saw – the cognitive 'fingerprint' of COVID-19 – was distinct from all of these.”

The patients’ scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual.

There are several factors that could cause the cognitive deficits, say the researchers. Direct viral infection is possible, but unlikely to be a major cause. Instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds.

However, emerging evidence suggests that the most important mechanism may be damage caused by the body’s own inflammatory response and immune system.

By combining data from 110 COVID-19 studies, researchers at Queen Mary University London have found that unvaccinated individuals who contract the virus when they already have high blood pressure, diabetes or major heart damage are up to nine times more likely to suffer serious outcomes, including death, lung failure, admission to intensive care and kidney problems.

The study looked at almost 49,000 unvaccinated patients in total, and identified multiple predictors of more severe COVID-19 and worse outcomes compared to people who were vaccinated.

It found that evidence of heart muscle damage at the time of admission to hospital was associated with a nine-fold increase in likelihood of death. These patients also had higher chances of developing other complications, including severe lung failure and acute kidney injury, and to require intensive care and mechanical ventilation.

Ajay Gupta, study author and senior clinical lecturer at Queen Mary said, “These findings present a strong case for these at-risk groups to be prioritised for vaccinations and other preventative measures.”

Online misinformation had a negative impact on the US COVID-19 vaccination campaign, according to an EU-funded study by Francesco Pierri, researcher at the Politecnico di Milano, carried out in collaboration with Indiana University.

The objective of the study, which was part of the EU’s €9.9 million Periscope project, was to determine whether or not there are statistically significant associations between the quality of information consumed online and “anti-vax” sentiment in the US, with consequent repercussions on the vaccination campaign.

The study confirmed a statistically significant association between the amount of misinformation shared online and the tendency to refuse or delay vaccination. In the states and counties where the most online misinformation is consumed, there is greater vaccination hesitancy and, consequently, lower vaccination coverage.

Since the beginning of 2021, researchers at the Politecnico di Milano have collected millions of posts shared on Twitter related to vaccines, with the aim of studying the effects of unreliable and/or inaccurate information on the US vaccination campaign, which began at the end of 2020.

Using a list of news sites tagged by journalists, fact-checkers, and other academics as portals spreading false and unreliable news, the researchers identified millions of posts with potentially harmful content, for example articles claiming that vaccines don't work or cause death, shared by millions of Twitter users in early 2021 across the US.

In order to measure people's willingness or not to get vaccinated, the researchers used millions of responses to daily polls administered on Facebook in which they asked users in the US whether or not they intended to get vaccinated.

Pierri said the results, “show that the proportion of misinformation shared on average by users in a given area is positively correlated with the proportion of people who declare they have no intention of getting vaccinated and, similarly, negatively correlated with the number of vaccine doses administered.”

Periscope is a €9.9 million project involving a consortium of 32 European institutions, which is investigating the implications of COVID-19 in a broad way, including the socio-economic impacts, health impacts and the impacts on health systems.

In a controversial approach, Sweden was the only country in Europe not to have a lockdown during the first wave of the COVID-19 pandemic in 2020. Now, a new study by Xiaoqin Wang and colleagues at the University of Gävle has shown that the country’s public health agency had data on hand which if analysed at the time, would have led to stricter control measures.

One of the main criticisms of the COVID-19 Commission, which was set up to look at Sweden’s response to the pandemic, was that early protective measures were belated and failed to prevent or even significantly reduce the spread of the infection in the country.

The new analysis shows that if public health agency data which was available early had been used and analysed, it would very likely have resulted in a more restrictive strategy with tougher infection control measures.

“The opportunity was not taken to use available data to determine the outcome of Sweden’s strategy. As a result, COVID-19 mortality rates in Sweden are exceptionally high compared to our Nordic neighbours,” Wang said.

Decisions during the earliest period of the pandemic were based on subjective judgements and later, when more data became available, mathematical analyses were only focused on achieving herd immunity, the researchers note.

“Due to dubious interpretations, only less invasive infection control measures were introduced in Sweden, even at the arrival of the second wave, leading to significantly higher mortality rates compared to the other Nordic countries,” the researchers conclude.

As the pandemic progresses the number of people living with Long COVID is increasing, but it remains unclear how and why Long COVID develops, whether it can be prevented, and how it is best treated.

Now a team of scientists at the University of Zurich’s Epidemiology, Biostatistics and Prevention Institute has joined forces with representatives of two patients’ groups, Long COVID Switzerland and the Long COVID Network, to form the Long COVID citizen science board.

The aim is to amplify the voice of people with Long COVID in order to get greater understanding of the condition and drive research to improve healthcare and the development of treatments.

“Collaborative projects that bring together different stakeholders allow us to grasp the impact of such a new disease and hopefully effectively tackle the challenges for people living with Long COVID,” said Milo Puhan, professor of epidemiology and public health at the university.

The research team recruited the Long COVID citizen science board, whose members met online to discuss their needs and identify the most relevant research areas, acting as citizen scientists in co-shaping the study’s direction, analysis and findings.

The study found that people affected by Long COVID and their families need answers to a long list of 68 questions, which fall into four areas: medical, for example, risk factors, diagnosis and treatment; healthcare services; socio-economic factors, such as the impact on work and finances;  and disease burden.

Through an online survey, the research team asked the citizen scientists and 241 other people affected by Long COVID to rate and prioritise these 68 questions.

“The scientists empowered us to define those research topics which have the largest impact on our health and lives. Not surprisingly the results reflect our top concern, which is that we still lack effective therapies,” said Chantal Britt, founder and president of Long COVID Switzerland.

The researchers hope this study will guide funding of future Long COVID research, and say that given the limited resources it is important to prioritise the areas of most relevance to those who are affected by the condition. Contacts

A study in eight European countries has shown that public health information on the benefits of vaccines has in some cases reduced the willingness to get immunised against COVID-19.

Taken overall, COVID-19 vaccination campaigns in Europe did not live up to the hopes of the public health authorities. However, earlier studies in various countries have yielded a mixed picture as to which communication strategies increase vaccine uptake and which factors undermine certain messages.

A team of the Technical University of Munich (TUM), the University of Trento and the London School of Economics explored these questions in Bulgaria, France, Germany, Italy, Poland, Spain, Sweden and the UK.

During the intensive phase of the vaccination campaigns, April - June 2021, more than 10,000 unvaccinated adults were initially provided online with general information on the available vaccines. Then they received one of three messages combining text and images, or were assigned to a control group.

Message 1 highlighted the efficacy of the available vaccines in reducing the risk of serious illness and death through COVID-19.

Message 2 stressed the advantages of having a vaccination certificate, especially for travel.

Message 3 presented the prospect of leisure-time activities without restrictions, for example restaurant and cinema visits, access to fitness studios and attendance at concerts.

The participants were then asked whether they intended to be vaccinated against COVID-19 if given the opportunity during the following week.

The study, published in Science Advances, shows that the text messages would be effective in boosting vaccination quotas only in Germany and, to a lesser extent, in the UK. In Germany vaccination willingness was significantly higher in the three groups than in the control group. In the UK, the readiness was higher only when the message stressed the benefits of a vaccination certificate.

In all other countries the messages were ineffective, or even produced results opposite to those intended: people in Spain and Italy, when informed of the reduced risk of illness through vaccines, were less likely to seek vaccination than the corresponding control groups.

Using data mining methods, the researchers carried out detailed analysis of various associations between the message effectiveness and sociodemographic characteristics, as well as the following factors: citizens’ trust in their government; health literacy; and the share of the population who believe in certain conspiracy theories.

For all messages, the likelihood of achieving the desired effect was reduced in countries where the health literacy of the population was low. “This result surprised us,” said Matteo Galizzi, professor of behavioural science at the London School of Economics. “We had thought that understandable and clearly visualised information on COVID-19 would lead to an improved understanding of the disease among people with little prior knowledge and thus to a greater vaccination willingness.”

In contrast, the study confirmed conjecture that citizens’ trust in their own government would have a positive effect on vaccination intention.

“During the pandemic, people often looked at other countries to see what was working better or worse. Our study showed that such comparisons have limited usefulness,” said professor Tim Büthe, chair of International Relations at TUM. “A more promising approach is to investigate the existing conditions in every country and then adapt the policy measures and communication strategies accordingly. Policy makers can use our findings to inform messaging for upcoming COVID-19 booster campaigns.”

DOI

10.1126/sciadv.abm9825

Researchers at Birmingham University have worked with patients experiencing Long COVID to develop a tool that can capture symptoms and assess the impact on quality of life.

More than 200 symptoms are associated with Long COVID, which in many cases is affecting people for months after the original SARS-CoV-2 infection has gone. The symptoms can involve many organs in the body and include breathlessness, fatigue and brain fog. It is estimated Long COVID affects more than 100 million people worldwide.

Reliable ways of measuring these symptoms are needed to inform the development of new therapies and ensure patients get the best possible care.

To address this, a team from the Centre for Patient-Reported Outcomes Research at Birmingham University has designed the Symptom Burden Questionnaire for Long COVID. Patients can use it to report symptoms and the data can be used to help identify current drugs that are potential treatments and to test whether new drugs are safe and effective.

“People living with Long COVID say they experience a huge range of symptoms, but getting these recognised by healthcare practitioners and policy-makers has been a struggle,” said one of the researchers, Sarah Hughes. “We designed and tested this tool with our patient partners to ensure it is as comprehensive as possible, while also not being burdensome for patients to complete.”

The resulting questionnaire measures different symptoms of Long COVID and the impact of these symptoms on daily life.  It was developed with extensive patient input following regulatory guidance, meaning its scores may be used to support regulatory decisions around the approval of new therapies for Long COVID and by policymakers.

Shielding those vulnerable to COVID-19, while allowing the virus to spread through the rest of the population, would have failed according to a new modelling paper by scientists at Bath University.

The economic and social costs of COVID-19 control measures, especially lockdowns, have been high. An alternative and widely discussed public health strategy was to ‘shield’ those most vulnerable to COVID-19, minimising their contacts with others while allowing infection to spread among lower risk individuals, with the aim of reaching herd immunity.

Shielding strategies or “focused protection” would have been impossible to implement in practice and would have likely led to far worse outcomes, according to the research. Even if implemented perfectly, the modelling reveals that allowing the infection to spread through less vulnerable groups prior to vaccination would have overwhelmed health care capacity in the UK and led to tens of thousands of unnecessary deaths.

In reality, practical considerations would have meant that large numbers of vulnerable people who were supposed to be protected would also have died.

The researchers assessed a hypothetical large city in England with a population of one million inhabitants. They compared the outcomes from no shielding, with imperfect and perfect shielding, with shielding restrictions lifted when cases fall below a given threshold.

The research concludes that while shielding may have protected the vulnerable in theory, it required extremely restrictive conditions that were impossible to achieve in practice.

For example, because shielding in real populations would have been imperfect, infections in the lower-risk population would have leaked through to vulnerable people who were shielding. In addition, if lower-risk individuals reduced social contact to avoid infection it may have been impossible to achieve herd immunity, meaning a second wave of infections would have occurred after shielding had ended.

There is would also be an even greater healthcare burden associated with the large number of cases of Long COVID. Waning immunity, and new variants would only have served to make a shielding-only strategy even more untenable.

The researchers say that although vaccines are now available and have been successfully rolled out in many countries, modelling studies are critical to determine whether shielding would have been a viable strategy for dealing with COVID-19, or, indeed, the next pandemic. Many countries have poor vaccine coverage and so the choice between shielding and measures that are more restrictive at a population level is likely to remain for some time. In future, new variants may continue to emerge that are able to escape immunity, which may require a renewed choice between lockdowns and shielding.

Despite the success of vaccination programmes, the recent omicron wave shows that we are not out of the woods yet,” said one of the authors Ben Ashby. “If in future a new variant emerges that substantially escapes existing immunity, then it’s possible we may have to choose between lockdowns and shielding once again (or indeed, in future pandemics). Although lockdowns are costly for many reasons, attempting to shield the vulnerable while letting the virus spread through the rest of the population is far worse.”