Patients under immunosuppressive therapy, who do not respond to primary COVID-19 vaccination, have an increased risk for severe COVID-19 disease courses. Until now, it was not clear whether those patients at risk can benefit from an additional booster vaccination. Recent research findings from MedUni Vienna show that a third vaccination is safe and effective in those patients who were initially unable to produce antibodies after vaccination. The study was recently published in the acclaimed journal Annals of the Rheumatic Diseases.
Even after two vaccinations, patients receiving immunosuppressive treatment for autoimmune diseases often fail to develop an adequate immune response after vaccination to protect them against COVID-19. In particular patients treated with the B-cell depleting drug rituximab, e.g. for rheumatoid arthritis, are considered to be particularly at risk for severe disease courses. Up until now, it had not been established whether these patients can benefit from a third vaccination and whether they should be vaccinated with the same vaccine or a different vaccination strategy.
Booster vaccination essential This question has now been answered by a recently published study conducted by an interdisciplinary research group from MedUni Vienna, coordinated by the Division of Rheumatology of the Department of Medicine III. First author Michael Bonelli and his study team were able to show that even patients under rituximab treatment who did not respond to primary vaccination are able to develop an immune response following a booster vaccination. “Since patients under certain immunosuppressive therapy are at high risk for an insufficient vaccination response and therefore a severe COVID-19 disease, an early booster vaccination should be considered” explains Michael Bonelli.
Included in vaccination recommendations “Our study is the first randomised, blinded trial to show the efficacy and safety of a booster vaccination in patients without an immune response after two vaccinations because of an rituximab treatment. In addition, ongoing studies investigate the efficacy of a forth vaccination in our patients at risk.” points out Daniel Aletaha, Head of the Division of Rheumatology at MedUni Vienna. The results obtained with the chosen study design are considered particularly reliable within the scientific community. Daniel Aletaha says: “Accordingly, our study, which also compared the efficacy and safety of different vaccination strategies, has already been included in the World Health Organization (WHO) and Australian Technical Advisory Group on Immunization (ATAGI) Covid-19 vaccination recommendations for immunosuppressed patients.”
Treatments used to help people with multiple sclerosis (MS) manage their condition can reduce the effectiveness of Covid-19 vaccines, according to research from Cardiff University and Queen Mary University of London.
Disease-modifying therapies (DMTs) are a group of treatments for people with MS and affect the immune system. As vaccines work by triggering the body to produce an immune response, it was suspected that some DMTs could reduce the effectiveness of Covid-19 vaccines. The study, published in the journal Annals of Neurology, provides the largest peer-reviewed, published evidence of the effect of DMTs on immune responses to Covid-19 vaccines.
It is hoped this new information will better equip clinicians to provide guidance to people with MS on treatment options.
The research team studied almost 500 people with MS and used a technique known as dried blood spot sampling to investigate the effects of DMTs on Covid-19 vaccine effectiveness. This approach reduced study costs as well as the need for potentially vulnerable patients to attend the clinic during the pandemic.
The findings show that people with MS taking either of two specific DMTs, fingolimod and ocrelizumab, were less likely to produce antibodies in response to AstraZeneca and Pfizer Covid-19 vaccines than people with MS not taking any DMT. If they did produce antibodies, the levels were lower than those found in people taking other DMTs, or not taking any DMT at all. However, the researchers found that other DMTs, including some that are highly effective for MS treatment, had no detrimental effect on Covid-19 vaccine response.
Immune cells, such as T-cells, are also an important part of our immune response to vaccines or viruses. The researchers studied T-cell responses in a small group of study participants who failed to mount an adequate antibody response to Covid-19 vaccination. They found that overall, 40 per cent of this group were able to produce a strong T-cell response, despite having a poor antibody response.
“People with MS have faced uncertainty during the Covid-19 pandemic as a direct result of their condition and the treatments they take to manage it,” says Dr Ruth Dobson, Clinical Senior Lecturer in Neurology at Queen Mary.
“Our study provides high-quality evidence that will support clinicians to advise people with MS on treatment options considering the Covid-19 pandemic. However, further trials are essential to help us understand how best to balance the risks of potentially suspending or delaying MS treatment with the need to effectively vaccinate people with MS against Covid-19.”
Dr Emma Tallantyre, Clinical Senior Lecturer in Neurology at Cardiff University, adds: “Questions about the Covid vaccine are among the most common we are currently facing from people with MS in our clinics. Highlighting groups who have mounted an inadequate Covid vaccine response has already been helpful in guiding who should receive additional doses of the vaccine, and who may need to continue to take additional infection-prevention precautions over the winter. We hope further work will allow us to individualise our management, to protect people with MS from Covid, while keeping their MS under control.”
Jo Welton, 38 was diagnosed with relapsing MS in 2009. She is a medical writer from South Wales. Day-to-day Jo mainly experiences fatigue, weakness, and pain in her left leg. She has been on disease modifying treatment (DMT) Gilenya for nearly eight years. She joined the study after being told about it by her MS team. Since, despite having two AstraZeneca vaccinations she has been told she has reduced immunity to COVID-19 and is waiting to find out if her booster vaccination has worked.
Jo says: “I have a scientific background so was interested in the study as soon as I heard about it. It was also important for me to know how much immunity I had as this impacts my day-to-day living. I’ve followed the guidelines about DMTs and MS right from the start, so this has meant I’ve been shielding for over 20 months. It’s been so difficult seeing everyone getting back to some sort of normality and not feeling like I was able to. I feel vulnerable and, although it’s not deliberate, left behind.
“Ignorance is bliss for some people, but it’s not a risk I want to take. I lost my Grandma to the virus earlier this year – this has made it even more important for me to take the necessary steps to mitigate the risk. Knowing I don’t have immunity means I can continue working remotely, socially distance, and ask friends and family to get their booster vaccine and do lateral flow tests when we meet. Having MS is hard enough without getting COVID-19 as well.”
Dr Clare Walton, Head of Research at the MS Society, says: “This is the largest published study looking at the relationship between certain high intensity disease modifying treatments (DMTs) and the AstraZeneca and Pfizer Covid-19 vaccines. It found some people with MS on these DMTs had a significantly reduced immune response to the vaccine compared to people not taking any.
“While this doesn’t mean these patients are necessarily at higher risk of severe illness if they catch COVID-19, it will be worrying for some. It’s vital that people with weakened immune systems are better supported to protect themselves from the virus, including a right to work from home and feeling assured that the general public are doing everything they can to help keep them safe. We also advise people with MS on these DMTs not to alter their treatment without speaking to someone from their MS healthcare team.”
New research presented this week at ACR Convergence, the American College of Rheumatology’s annual meeting, shows that in Alabama, one in 10 racial or ethnic minority patients with a rheumatic disease in a large rheumatology clinic said they were unlikely to get vaccinated against COVID-19 (Abstract #0617). COVID-19 is the disease caused by the novel SARS-CoV-2 coronavirus.
Research presented at ACR Convergence 2020 showed that people of color with rheumatic disease have worse health outcomes from COVID-19 infection, are more likely to be hospitalized to treat their coronavirus infection and are more likely to require invasive ventilator treatment. While COVID-19 vaccines are now available in the U.S., hesitancy to receive them persists. Alabama lags behind other U.S. states in COVID-19 vaccine uptake. According to researchers, people in racial and ethnic minority groups also face disparities in access to the vaccines.
In addition, many in Alabama’s large Black population mistrust the medical establishment due to past abuses like the Tuskegee Syphilis study. Researchers at the University of Alabama at Birmingham (UAB) launched this new study to find out more about vaccine hesitancy and uptake among racial and ethnic minority patients at a large academic center’s rheumatology clinic. “Many patients seen in rheumatology clinics are immunosuppressed or have comorbidities that put them at risk for higher morbidity and mortality due to COVID-19,” says Maria I. Danila, MD, MSc, MSPH, Associate Professor of Medicine, Division of Clinical Immunology and Rheumatology at UAB and the study’s corresponding author. “Early during the rollout of the COVID-19 vaccination program in our region, it became apparent that vaccination among some minority communities was lagging. We conducted this study to take ‘the pulse’ of vaccine uptake in our area and to understand the top reasons why some patients had not been vaccinated. Our goal was to inform the development of communication strategies to ensure equitable access to vaccination among our patients.”
Between April 19 and May 6, 2021, researchers invited patients from racial and ethnic minority communities in Alabama to complete a survey during their in-person visits to the rheumatology clinic. They assessed patients’ vaccination confidence using a standard psychological scale. They analyzed patients’ attitudes and beliefs about COVID-19 vaccines and determined the potential factors associated with getting a vaccine: such as age, sex, education level, vaccine confidence, safety concerns about the vaccine, medical mistrust and receipt of a flu vaccine in the past. There were 150 patients who agreed to complete the survey. They had a mean age of 54, 86.9% were women, 94% identified as Black or African American, 69% had some college, and 22% said they believed that they would get better medical care if they belonged to a different racial or ethnic group. Although 81% of people who completed the survey had received the flu vaccine in the past, only two-thirds said they had received a COVID-19 vaccine. Of 50 people who remained unvaccinated, only half said they had been offered a COVID-19 shot. One third said they did not plan to be vaccinated.
The participants who did not plan on receiving a vaccine listed several reasons why. More than half said they had concerns about vaccine side effects, 53% feared a rheumatic disease flare, 32% said they knew someone who had a bad experience with the vaccine, 21% said they worried about getting COVID-19 from the vaccine, and 18% were concerned that the vaccine would “modify my DNA.” Unvaccinated patients also expressed their desire to have more information about the safety and efficacy of the vaccine in people with a rheumatic disease. After multivariable adjustment, researchers found that patients of an older age, not having safety concerns about the new vaccine, having gotten a flu shot in the past, and having higher vaccine confidence overall were associated with receipt of a COVID-19 vaccine. There was no association between reporting medical mistrust and vaccine receipt.
“Our findings suggest that a one-size-fits-all approach is not a viable solution to help inform COVID-19 vaccine decisions among people with rheumatic disease,” says Dr. Danila. “To build trust, it is important to listen to understand why people may be reluctant to become vaccinated, and to address their specific concerns in an empathic and non-judgmental.
With around 256 million cases and more than 5 million deaths worldwide, the COVID-19 pandemic has challenged scientists and those in the medical field. Researchers are working to find effective vaccines and therapies, as well as understand the long-term effects of the infection.
While the vaccines have been critical in pandemic control, researchers are still learning how and how well they work. This is especially true with the emergence of new viral variants and the rare vaccine side effects like allergic reactions, heart inflammation (myocarditis) and blood-clotting (thrombosis).
Critical questions about the infection itself also remain. Approximately one in four COVID-19 patients have lingering symptoms, even after recovering from the virus. These symptoms, known as “long COVID,” and the vaccines’ off-target side effects are thought to be due to a patient’s immune response.
Drawing upon classic immunological concepts, Murphy and Longo suggest that the Network Hypothesis by Nobel Laureate Niels Jerne might offer insights.
Jerne’s hypothesis details a means for the immune system to regulate antibodies. It describes a cascade in which the immune system initially launches protective antibody responses to an antigen (like a virus). These same protective antibodies later can trigger a new antibody response toward themselves, leading to their disappearance over time.
These secondary antibodies, called anti-idiotype antibodies, can bind to and deplete the initial protective antibody responses. They have the potential to mirror or act like the original antigen itself. This may result in adverse effects.
Coronavirus and the immune system
When SARS-CoV-2, the virus causing COVID-19, enters the body, its spike protein binds with the ACE2 receptor, gaining entry to the cell. The immune system responds by producing protective antibodies that bind to the invading virus, blocking or neutralizing its effects.
As a form of down-regulation, these protective antibodies can also cause immune responses with anti-idiotype antibodies. Over time, these anti-idiotype responses can clear the initial protective antibodies and potentially result in limited efficacy of antibody-based therapies.
“A fascinating aspect of the newly formed anti-idiotype antibodies is that some of their structures can be a mirror image of the original antigen and act like it in binding to the same receptors that the viral antigen binds. This binding can potentially lead to unwanted actions and pathology, particularly in the long term,” Murphy said.
The authors suggest that the anti-idiotype antibodies can potentially target the same ACE2 receptors. In blocking or triggering these receptors, they could affect various normal ACE2 functions.
“Given the critical functions and wide distribution of ACE2 receptors on numerous cell types, it would be important to determine if these regulatory immune responses could be responsible for some of the off-target or long-lasting effects being reported,” Murphy commented. “These responses may also explain why such long-term effects can occur long after the viral infection has passed.”
As for COVID-19 vaccines, the primary antigen used is the SARS-CoV-2 spike protein. According to Murphy and Longo, current research studies on antibody responses to these vaccines mainly focus on the initial protective responses and virus-neutralizing efficacy, rather than other long-term aspects.
“With the incredible impact of the pandemic and our reliance on vaccines as our primary weapon, there is an immense need for more basic science research to understand the complex immunological pathways at play. This need follows to what it takes to keep the protective responses going, as well as to the potential unwanted side effects of both the infection and the different SARS-CoV-2 vaccine types, especially as boosting is now applied,” Murphy said. “The good news is that these are testable questions that can be partially addressed in the laboratory, and in fact, have been used with other viral models.”
A long-term history of glycemic control better predicts risk of severe COVID-19 among type 2 diabetics than shorter-term measurements. CREDIT Rensselaer Polytechnic Institute
People with type 2 diabetes who contract COVID-19 are nearly 50% more likely to wind up in intensive care if they have poorly managed their blood sugar levels over the long-term than those with better long-term glycemic control, according to a study using anonymized health care data. The study, which looked at several potential impacts to COVID-19 severity among diabetics, also calculated a lower risk for patients using the common diabetes-control medication metformin, or a combination of metformin and insulin, or corticosteroids.
“We find that two- to three-year longitudinal glycemic levels better indicate the risk of COVID-19 severity than measurements which look at a shorter period of time,” said Deepak Vashishth, corresponding author, professor of biomedical engineering, and director of the Center for Biotechnology and Interdisciplinary Studies at Rensselaer Polytechnic Institute. “We hope these insights aid physicians in better treating and managing high-risk patients.”
Type 2 diabetes patients are unable to regulate the amount of the sugar glucose in their bloodstream without medication and managing their diet. Chronic high blood-sugar levels, typically tracked as the percentage of hemoglobin A1c (HbA1c) found in the blood, can damage a variety of functions, including the circulatory, nervous, and immune systems.
Poor glycemic control creates a reaction that causes molecules known as advanced glycation end-products (AGEs) to accumulate, deteriorating the quality of bone over time, and Vashishth, an expert in bone, researches the impact of diabetes on bone. At the time the SARS-CoV-2 pandemic began, his research team was investigating whether measurements of longitudinal glycemic control – measures of blood-sugar levels averaged over two to three years – could provide a more accurate predictor of bone fracture risk among diabetics than the current standard predictor, which relies on measurements of bone mineral density.
AGEs are known to contribute to increased oxidant stress and inflammation, which are risk factors in COVID-19 and other respiratory illnesses. The team reasoned that the same longitudinal glycemic control measurement they were testing as a predictor of bone fracture risk might be useful in predicting the severity of COVID-19, said Bowen Wang, first author and a doctoral student in Vashishth’s lab.
Wang divided the records of type 2 diabetic patients in the study into two groups, those with “adequate” longitudinal glycemic control ranging from 6 to 9%, and those with “poor” glycemic control of 9% or above over two to three years. His analysis of the two groups revealed that those with poor glycemic control were 48% more likely to require treatment in an intensive care unit. By another measure, a 1% increase in longitudinal HbA1c is directly associated with a 12% increase in the risk of landing in the ICU.
Other statistically significant findings showed that diabetics who were taking metformin when they contract COVID-19 face a 12% lower risk of visiting the ICU, those on metformin and insulin have an 18% lower risk, and those prescribed corticosteroids have a 29% lower risk.
“People knew that diabetes was a risk factor for COVID-19-related outcomes, but not all diabetic patients are the same. Some people have a longer history of diabetes, some have more severe diabetes, and that has to be accounted for,” said Wang. “What this study does is to better stratify the level of diabetes within the population, so diabetic patients aren’t treated as a single population without any differences among them.”
Vashishth and Wang were joined on the research by Benjamin S. Glicksberg and Girish N. Nadkarni at the Icahn School of Medicine at Mount Sinai. Their work was supported by a grant from the National Institutes of Health.
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