In a recent study published in the journal Nature, a group of researchers analyzed early cellular response dynamics to severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) in seronegative individuals using single-cell multi-omics profiling, identifying key cellular states and immune responses associated with different infection outcomes.
Summary figure highlighting the key finding from the study. These includes; 1) distinct temporal differences in the cellular dynamics observed between the different infection groups; 2) several novel conserved antiviral responses and higher baseline expression ofHLA-DQA2in participants who were exposed to the virus but who did not go on to develop a sustained infection; 3) novel characteristics of sustained infection, with a rapid relay observed in the blood compared to the site of inoculation, a dynamic local ciliated response occurring early on during infections (pre-symptoms) and a temporally restricted, distinct, SARS-CoV-2 specific activated T cell population which leads to immunological memory; and 4) the identification of public motifs in SARS-CoV-2 specific activated T cells. In addition, our work provides community tools for inference of specific TCR motifs (Cell2TCR) in activated T cells, a detailed publicly available reference database underpinning the detection of future biomarkers and antigen (Ag) targets for therapeutic applications. Schematic created with BioRender.com. Study:Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.
Coronavirus 2019 (COVID-19), caused by SARS-CoV-2, is a potentially fatal disease that has become a severe global health emergency. Severe outcomes are linked to disrupted antiviral and immune responses, including impaired type I interferon responses and altered T lymphocyte (T) and B lymphocyte (B) cell dynamics. Accurate detection of immune responses is challenging due to heterogeneous factors such as viral dose, strain, and clinical features like comorbidities. Understanding the dynamics of SARS-CoV-2 infection, particularly early phases of exposure, is crucial. Studies often miss capturing these early events in natural infections, making pinpointing antigen-responding T cell activation and expansion difficult. Further research is needed to accurately delineate early immune response dynamics to SARS-CoV-2 to better understand and mitigate severe COVID-19 outcomes.
Sixteen healthy adults aged 18-30 years, seronegative for SARS-CoV-2, participated in a human SARS-CoV-2 challenge study for Single-cell RNA sequencing (scRNA-seq) sample processing and analysis. This study, conducted by a government task force, Imperial College London, Royal Free London NHS Foundation Trust, University College London, and hVIVO, took place from June to August 2021. Additionally, 20 healthy adults from earlier cohorts had blood and nasal samples processed for bulk Ribonucleic Acid (RNA)-seq, with 10 receiving pre-emptive remdesivir. Volunteers were screened for anti-SARS-CoV-2 antibodies and excluded if positive. The study followed ethical guidelines, and informed consent was obtained from all volunteers.
a, Illustration of the study design and cohort composition.b,c, Uniform manifold approximation and projection (UMAP) plots of all nasopharyngeal cells (n=234,182), colour coded by their broad cell-type annotation (b), by the infection group (c, top) and by days since inoculation (c, bottom). Only cells from sustained infection cases are shown inc, bottom. Treg, regulatory Tcell;ASDC, AXL+SIGLEC6+dendritic cell.d,e, UMAP plots as inbandc, but showing all PBMCs (n=371,892). CTL, cytotoxic T lymphocyte; DN, double negative.f, Fold changes in abundance of nasopharynx-resident broad immune cell-type categories. Immune cell abundance was scaled to the total amount of detected epithelial cells in every sample before calculating the fold changes over days since inoculation compared with pre-infection (day1) by fitting a GLMM on scaled abundance. Fitted fold changes are colour coded and we used the local true sign rate and BenjaminiHochberg procedure to calculate false-discovery rates (FDRs), which are shown as the size of each dot. The mean cell-type proportions over all cells and samples are shown in the green heatmap to the right of the dot plot to aid the interpretation of changes in cell-type abundance. Illustration inawas created using BioRender (https://www.biorender.com).
Participant 11, who had low pre-inoculation antibody levels, was classified as having an abortive infection, which did not alter the study's conclusions. Participants were followed for one year post-inoculation, with no long-COVID symptoms reported at the final time point. Physiological observations were normal. After discharge, two participants reported receiving a vaccine or a community infection before their day 28 follow-up. Enzyme-Linked ImmunoSpot (ELISpot) tests revealed immune responses in subsequent samples. Participants were intranasally inoculated with a wild-type pre-Alpha SARS-CoV-2 virus, and nasal and throat samples were collected to evaluate viral kinetics. Nasopharyngeal swabs and Peripheral Blood Mononuclear Cells (PBMCs) were processed for single-cell sequencing to analyze immune responses.
In the present study, 16 seronegative young adults were intranasally inoculated with a pre-Alpha SARS-CoV-2 virus strain. Extensive screening excluded participants with severe disease risk factors or comorbidities. Participants received the lowest quantifiable inoculum dose, resulting in no serious adverse events and resolved symptoms.
The study analyzed local and systemic immune responses at single-cell resolution. Baseline measurements were taken before inoculation, followed by time series analyses of cellular responses in blood and nasopharynx. Six participants developed sustained infections, defined by consecutive viral load detections and symptoms. Three individuals had sporadic positive polymer chain reaction (PCR) tests and were classified as transient infections. Seven participants remained PCR-negative but showed early innate immune responses, termed abortive infections. The infection rate was comparable to that in a closed household of unvaccinated individuals.
scRNA-seq and single-cell T cell receptor (TCR) and B cell receptor (BCR) sequencing were performed at up to seven time points. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) quantified 123 surface proteins in PBMCs. More than 600,000 single-cell transcriptomes were generated, including 371,892 PBMCs and 234,182 nasopharyngeal cells. Predictive models and marker gene expression annotated 202 cell states, enabling detailed local and systemic response analysis.
Generalized linear mixed models (GLMMs) quantified changes in cell-type abundance over time. Immune cell types infiltrated the inoculation site after SARS-CoV-2 exposure. Sustained infections showed immune infiltration starting at day 5, while transient infections had immediate infiltration at day 1. Abortive infections showed minimal changes except for early Cluster of Differentiation (CD)4+ and CD8+ T cell infiltration.
Gene expression analysis revealed that interferon response genes were the dominant infection-induced module in sustained infections. Interferon signaling was activated in all cell types in both blood and nasopharynx, peaking earlier in blood. This rapid systemic response was validated with bulk RNA-seq data. Myeloid cell redistribution between circulation and tissues was observed during early infection. Mucosal-Associated Invariant T (MAIT) cell activation was detected across all infection groups, indicating rapid viral sensing. Viral RNA peaked at day 7, with hyperinfected ciliated cells identified as major virion producers.
Ciliated cells showed dynamic responses, including acute-phase and interferon-stimulated states. Activated T cells, identified through peptide-Major Histocompatibility Complex (MHC) staining and scRNA-seq, expanded significantly at day 10 after inoculation, resembling a typical antigen-specific adaptive immune response.
The study revealed multiple immune response states that precede clinical symptoms, including MAIT cell activation and a decrease in inflammatory monocytes. These responses emerged even when SARS-CoV-2 exposure did not lead to COVID-19, suggesting their potential as biomarkers of immediate immune response. In sustained infections, a new acute phase response (APR) in ciliated cells and a distinct state for activated T cells with SARS-CoV-2-specific TCRs were identified. Interferon signaling was activated globally in circulating immune cells before the site of infection. These findings provide a detailed time-resolved description of early immune responses to SARS-CoV-2.
You're watching Coronavirus in Context. I'm Dr. John Whyte, Chief Medical Officer at WebMD. Today we're going to talk about the impact of COVID-19 on kids. And my guest is Dr. Burke Harris. She's a pediatrician and surgeon general of the state of California. Dr. Burke Harris, thanks for joining me.
NADINE BURKE HARRIS
JOHN WHYTE
NADINE BURKE HARRIS
And so some of the ways that, um, kids can manifest stress, um, are really, you know, changes in their sleeping patterns. For little kids, changes in their toileting habits. So, you know, a kid who's been potty trained, they can have a little bit of that regression and, uh, you know, go back to wetting or something along those lines.
And then as kids get older, we see, you know, some kids have, uh, they don't necessarily say that, oh, you know, I'm feeling stressed. They may have tummy aches. They may have headaches. And for older kids like teenagers, we-- they may be more irritable or they could even be more withdrawn.
JOHN WHYTE
NADINE BURKE HARRIS
JOHN WHYTE
NADINE BURKE HARRIS
I think for, uh, some kids, asking how are they keeping in touch with their friends, how is so-and-so doing, that is, um, particularly for teenagers who stay in touch with their friends either via social media or through, um, you know, or through text or other technology.
Asking some of these rand-- you know, roundabout questions can help us understand, uh, whether or not our-- our kids are staying connected to their social networks. I think for littler kids, it's-- you can just, you know, really straightforwardly ask if they have any concerns.
Ask-- you know, what have they heard about the coronavirus and if they have any worries. And give them an opportunity to share, in their own language, what they've heard, you know, what they're nervous or scared about, and then correct any misperceptions that may be going on.
JOHN WHYTE
NADINE BURKE HARRIS
So-- so I think that, uh, you know, although of course we want to put limits on kids' screen time. We, at the same time, have to recognize that, you know, it's OK for-- for us to give ourselves a break and give our kids a little bit of a break as well.
JOHN WHYTE
NADINE BURKE HARRIS
Getting out and doing some exercise every day, really important. We make sure that the kids get on their bikes and, you know, go around the-- go around the park and have an opportunity to get some of that energy out. Um, also, even though kids are not going to school every day, I think keeping those regular routines is really important. So going to bed at the same time each night, waking up at the same time each morning, and having some regular routines. Having the kids have an opportunity to-- to share in setting those routines I think is really important. Um, and we have a lot of fun with, you know, nutrition. There's a lot more cooking that goes on during the pandemic time, uh, which is a lot of fun.
But we make sure that the kids are getting healthy meals, because it's very easy for all of us to be, you know, craving some of those high sugar, high fat foods. And that's not just because, you know, we're at home. It's because when we feel stressed, stress hormones like cortisol actually cause our bodies to crave high sugar, high fat foods. And so having good nutrition is actually really important to helping to regulate the stress response.
JOHN WHYTE
NADINE BURKE HARRIS
But the other thing that's also really important that we often forget as parents and caregivers is that one of the most important things for children's well-being is our own well-being, right? In scary situations, what kids do is they instinctively look at their parents and caregivers.
And if we're freaking out, that gives them the signal that they-- that they should be freaking out. And so our ability to put our own oxygen mask on and do that self care so that we can be well regulated actually helps our kids be able to regulate themselves.
JOHN WHYTE
NADINE BURKE HARRIS
The tolerable stress response where the body is affected by it, but through the buffering effect of caring relationships, the body returns to that natural biological balance. And there's something that's even called a positive stress responses, which is, you know, a little bit of stress that's self-limited can actually lead to further growth and development.
And so the thing that I'm really optimistic about is that with that safe and nurturing relationships and with that buffering care, I think that there's an opportunity to keep the stress into that positive or tolerable range and out of the toxic range.
And I think there's a lot of, um, growth and connection, a deepening of a sense of empathy, and a-- a level of development that can happen right now that, uh, I think ultimately has an-- an opportunity to be a time of growth.
JOHN WHYTE
NADINE BURKE HARRIS
JOHN WHYTE
Hide Video Transcript
JOHN WHYTE
NADINE BURKE HARRIS
JOHN WHYTE
NADINE BURKE HARRIS
And so some of the ways that, um, kids can manifest stress, um, are really, you know, changes in their sleeping patterns. For little kids, changes in their toileting habits. So, you know, a kid who's been potty trained, they can have a little bit of that regression and, uh, you know, go back to wetting or something along those lines.
And then as kids get older, we see, you know, some kids have, uh, they don't necessarily say that, oh, you know, I'm feeling stressed. They may have tummy aches. They may have headaches. And for older kids like teenagers, we-- they may be more irritable or they could even be more withdrawn.
JOHN WHYTE
NADINE BURKE HARRIS
JOHN WHYTE
NADINE BURKE HARRIS
I think for, uh, some kids, asking how are they keeping in touch with their friends, how is so-and-so doing, that is, um, particularly for teenagers who stay in touch with their friends either via social media or through, um, you know, or through text or other technology.
Asking some of these rand-- you know, roundabout questions can help us understand, uh, whether or not our-- our kids are staying connected to their social networks. I think for littler kids, it's-- you can just, you know, really straightforwardly ask if they have any concerns.
Ask-- you know, what have they heard about the coronavirus and if they have any worries. And give them an opportunity to share, in their own language, what they've heard, you know, what they're nervous or scared about, and then correct any misperceptions that may be going on.
JOHN WHYTE
NADINE BURKE HARRIS
So-- so I think that, uh, you know, although of course we want to put limits on kids' screen time. We, at the same time, have to recognize that, you know, it's OK for-- for us to give ourselves a break and give our kids a little bit of a break as well.
JOHN WHYTE
NADINE BURKE HARRIS
Getting out and doing some exercise every day, really important. We make sure that the kids get on their bikes and, you know, go around the-- go around the park and have an opportunity to get some of that energy out. Um, also, even though kids are not going to school every day, I think keeping those regular routines is really important. So going to bed at the same time each night, waking up at the same time each morning, and having some regular routines. Having the kids have an opportunity to-- to share in setting those routines I think is really important. Um, and we have a lot of fun with, you know, nutrition. There's a lot more cooking that goes on during the pandemic time, uh, which is a lot of fun.
But we make sure that the kids are getting healthy meals, because it's very easy for all of us to be, you know, craving some of those high sugar, high fat foods. And that's not just because, you know, we're at home. It's because when we feel stressed, stress hormones like cortisol actually cause our bodies to crave high sugar, high fat foods. And so having good nutrition is actually really important to helping to regulate the stress response.
JOHN WHYTE
NADINE BURKE HARRIS
But the other thing that's also really important that we often forget as parents and caregivers is that one of the most important things for children's well-being is our own well-being, right? In scary situations, what kids do is they instinctively look at their parents and caregivers.
And if we're freaking out, that gives them the signal that they-- that they should be freaking out. And so our ability to put our own oxygen mask on and do that self care so that we can be well regulated actually helps our kids be able to regulate themselves.
JOHN WHYTE
NADINE BURKE HARRIS
The tolerable stress response where the body is affected by it, but through the buffering effect of caring relationships, the body returns to that natural biological balance. And there's something that's even called a positive stress responses, which is, you know, a little bit of stress that's self-limited can actually lead to further growth and development.
And so the thing that I'm really optimistic about is that with that safe and nurturing relationships and with that buffering care, I think that there's an opportunity to keep the stress into that positive or tolerable range and out of the toxic range.
And I think there's a lot of, um, growth and connection, a deepening of a sense of empathy, and a-- a level of development that can happen right now that, uh, I think ultimately has an-- an opportunity to be a time of growth.
JOHN WHYTE
NADINE BURKE HARRIS
JOHN WHYTE
Finland plans to offer preemptive bird flu vaccination as soon as next week to some workers with exposure to animals, health authorities said on Tuesday, making it the first country in the world to do so.
The Nordic country has bought vaccines for 10,000 people, each consisting of two injections, as part of a jointEU procurementof up to 40 million doses for 15 nations from manufacturer CSL Seqirus.
The Australian company in a statement to Reuters said Finland would be the first country to roll out the vaccine.
The vaccine will be offered to those aged 18 or over who are at increased risk of contracting avian influenza due to their work or other circumstances, the Finnish Institute for Health and Welfare (THL) said in a statement.
The H5N1 strain of bird flu has killed or caused the culling of hundreds of millions of poultry globally in recent years and has increasingly been spreading to mammals,including cowsin the United States and, in some cases, alsoto humans.
Finland has not detected the virus in humans, THL said.
However, the country is eager to roll out vaccinations given transmission risks posed by its fur farms.
The conditions in Finland are very different in that we have fur farms where the animals can end up in contact with wildlife, Chief Physician Hanna Nohynek at the Finnish Institute for Health and Welfare (THL) told Reuters.
Widespreadoutbreaksof bird flu among mink and foxes at Finlands mostly open-air fur farms led to the culling last year of some 485,000 animals to stop the virus from spreading among the animals as well as to humans.
Vaccinations are likely to start as early as next week in at least some parts of Finland, a THL spokesperson told Reuters.
Finland said it procured vaccines for people it deems to be at risk, such as workers at fur and poultry farms, lab technicians who handle bird flu samples and veterinarians who work as animal control officers in regions where fur farms are located.
People working in sanctuaries caring for wild birds, in livestock farms or in the cleaning of premises, such as animal by-products processing plants, will also be offered vaccines, THL said.
If human infection of avian influenza were to occur, close contacts of a suspected or confirmed case would also be offered the vaccine, it added.
U.S. health officials on Wednesday made a stronger endorsement for RSV vaccinations for people 75 and older, but offered a narrower recommendation for people 60 to 74.
The director of the Centers for Disease Control and Prevention accepted the recommendations from a committee of outside advisers, making it the governments updated guidance to doctors.
A year ago, the same advisory group said that people 60 and oldershould simply talk to their doctorsabout whether to get the shots. Physicians have said that kind oflukewarm recommendationis confusing to patients, challenging to explain, and a likely reason that fewer than 25% of older Americans have gotten a shot.
RSV, or respiratory syncytial virus, is a common cause of cold-like symptoms but it can be dangerous for infants and the elderly.
Last year, the U.S. Food and Drug Administration licensedsingle-dose RSV vaccinesmade by two companies, GSK and Pfizer, for older people. At the time, the vaccine advisers refrained from saying all older Americans should get the shots because of questions about possible side effects and the duration of protection.
Some of those questions still exist, and panel members on Wednesday declined a request by vaccine manufacturers to more forcefully recommend the shots for all Americans 60 and older.
Instead, they voted that people 75 and older should get the shots and that those 60 to 74 should do so only if they are higher risk for severe disease. The panel also declined to endorse giving the GSK vaccine to people in their 50s, even though the FDA this month licensed the companys shot for that age group.
A newly approved RSV shot from Moderna will be subject to the same guidance.
Panel members said data has demonstrated that the shots make sense for all people 75 and older, because they are at higher risk for severe RSV cases.
For people who are 60 and older, the conditions that put them at higher risk of severe illness include chronic heart disease, advanced-stage kidney disease, chronic lung illnesses and severe obesity. About 39% of people in that age group would qualify under the strictest interpretation of that guidelines, CDC officials said.
The committee also recommended the vaccine for 60- to 74-year-olds who live in nursing homes or are deemed by their doctors to be frail for other reasons.
Underlying the panels hesitancy are reports of a nervous system disorder, Guillain-Barre syndrome. Though rare, there have beena higher-than-expected numberof Guillain-Barre cases among RSV vaccine recipients, particularly in those who got the Pfizer shot.
FDA officials on Wednesday said there is no clear evidence that the shots are causing the disorder, but some panel members noted research is ongoing.
I do agree with the overall conclusion that the risks of RSV vaccination are greatly outweighed by the overall benefits, said one panel member, Dr. Camille Kotton, an infectious diseases expert at Massachusetts General Hospital. Nonetheless, I remain quite concerned about recurring indicators of Guillain-Barre in vaccination surveillance data, she added.
The Associated Press
The Associated Press
The Center for Disease Control and Prevention (CDC) vaccine advisory group today updated its advice for use of the respiratory syncytial virus (RSV) vaccine in adults, which now recommends that all people ages 75 and older receive a single lifetime dose, and that people ages 60 to 74 who have certain underlying conditions also receive a dose of the vaccine.
The Advisory Committee on Immunization Practices (ACIP) recommendations, which still need to be accepted by the CDC director, represent an evolving RSV vaccine landscape and availability, as well as new scientific findings that the group uses to guide it policy recommendations.
The group voted separately on recommendations for the two different age groups, and both passed unanimously on11 to 0 votes.
Since the CDC first recommended the vaccine for use in ages 60 and older in June 2023, the Food and Drug Administration (FDA) at the end of May approved a third RSV vaccine for use in older adults, an mRNA product made by Moderna. Earlier this month it approved expanded use of Arexvy, made by GSK, for at-risk adults ages 50 to 59.
The updated recommendations come ahead of the second respiratory virus season with the availability of an RSV vaccine for adults, which is thought to hospitalize 60,000 to 160,000 older adults each year, with the biggest burden in those who have chronic heart and lung problems and weakened immune systems.
ACIP has also grappled with the wording of recommendation. When it recommended the vaccine for use in adults ages 60 and older last summer, it did so with a "shared clinical decision making" recommendation, terminology the CDC uses when some uncertainty exists about benefits and risks.
However, the group has acknowledged that shared clinical decision making isn't simple in clinical practice and may contribute to unclear messaging regarding the need to vaccinate.
The group today postponed a recommendation for use of Arexvy in people ages 50 to 59, due to a lack of data that would support a population-based recommendation and lingering concerns about the risk of Guillain-Barre syndrome (GBS) following RSV vaccination.
ACIP members acknowledged that the recommendation for adults ages 60 to 75 was less permissive than last year's advice, which would likely mean those who aren't in risk groups would need to pay out of pocket for the RSV vaccine, which could cost as much as $400. Several said the group's advice typically settles over time when new vaccines enter the market. Matthew Daley, MD, ACIP member and senior investigator with the Institute for Health Research at Kaiser Permanente Colorado, said a shift in recommendations reflects the nature of uncertainty, as scientists gather and analyze more data.
Members also welcomed a list of specific underlying conditions that its RSV vaccine work group pulled together, which they said will help with making clinical decisions for patients ages 60 to 75. Conditions include lung disease, cardiovascular disease, moderate or severe immune compromise, diabetes with end-organ damage, severe obesity, neurologic or neuromuscular conditions, advanced chronic kidney disease, liver disorders, and hematologic disorders.
To add flexibility for doctors treating patients in this age group, the list includes an "other chronic medical conditions" category for when health providers believe other patients are at increased risk of RSV complications.
After the vote, Jamie Loehr, MD, ACIP member and owner of Cayuga Family Medicine in Ithaca, New York, emphasized that the small but real risk of GBS weighed heavily on the group's risk-benefit assessments in the two age groups, given that it is a severe neurological disease that can hospitalized patients for months.
The U.S. Supreme Court declined to hear a case Monday challenging Connecticut legislation that repealed religious exemptions for school vaccine requirements in 2021.
In a lawsuit, three Connecticut parents and two organizations, We the Patriots USA, Inc., and the CT Freedom Alliance, had argued that the state was violating their First Amendment rights with its passage of Public Act 21-6, which eliminated the ability for Connecticut families to apply for a religious exemption to mandated immunizations when a student is enrolling in school. The plaintiffs sued the state departments of education and public health, the Office of Early Childhood Development and three local boards of education.
The decision from the Supreme Court puts an end to a three-year legal battle after decisions by the district court and U.S. Circuit Court of Appeals that ruled in the states favor.
This is the end of the road to a challenge to Connecticuts lifesaving and fully lawful vaccine requirements, said Attorney General William Tong in a news release. We have said all along, and the courts have affirmed the legislature acted responsibly and well within its authority to protect the health of Connecticut families and to stop the spread of preventable disease.
We the Patriots USA, Inc. is a nonprofit that focuses on reclaim[ing] our God-given inalienable rights including but not limited to the rights recorded in the United States Constitution through litigation, education, and advocacy, according to its website.
Brian Festa, co-founder and vice president of the nonprofit, called the Supreme Courts decision disappointing.
Right now, someone might be on one side of the political aisle or on a spectrum when it comes to the issue of vaccinations, but then there might be something else that they object to for religious reasons that theyre not allowed to object to anymore, Festa said. If you keep having rulings like this, what it does is, it sets the precedent that youre not allowed to refuse things for any reason, for personal reasons, religious reasons, anything if the state mandates something, puts something in your body you have to do it.
In April 2021, Connecticut became the fourth state to pass a law ending a religious exemption for school vaccinations, following California in 2015 and New York and Maine in 2019.
By grandfathering any K-12 student who already had an exemption, the Connecticut law initiated a phase-out, not an immediate ban. The grandfather provision did not extend to daycares and preschools.
Senate President Pro Tem Martin M. Looney, D-New Haven, and Senate Majority Leader Bob Duff, D-Norwalk, said the 2021 legislation had closed a loophole for non-medical vaccine exemptions and embraced a common sense vaccination policy that protects the health and safety of all students.
This law has now withstood legal scrutiny at every level of our judicial system, and its perseverance represents a victory for parents and students, who are less likely to be infected by preventable illnesses, the two lawmakers said in a joint statement.
But the battle is not over for Festas organization.
Festa said one claim from the case remains active within the district court regarding students with disabilities and whether special needs children are entitled to receive an education, even if they opt out of vaccinations.
We are not fighting only for children whose parents refuse all vaccinations. It might just be one or two particular vaccinations, Festa said. And to have your child denied education and all services, especially a special needs child, simply because you opted out of one or two vaccinations, is just to me, appalling and really tragic for these children.
Tongs office says theyre confident that the IDEA claim will be dismissed by the District Court on remand.
We the Patriots Inc. has a second case pending on behalf of Milford Christian Church and whether a church can honor religious exemptions in its private day cares and schools.
Two inverse vaccines from Nykode Therapeutics developed to teach the immune system not to respond against its own body worked to reduce disease severity in a mouse model of multiple sclerosis (MS), new data show.
This adds to earlier findings that the companys experimental approach and its TV004 inverse vaccine can prevent the disease from developing in mice by making the immune system unresponsive to a protein involved in MS without fully disrupting the immune response.
These findings represent progress in our ongoing research into inverse vaccines and autoimmune disease treatment, Agnete Fredriksen, PhD, Nykodes chief scientific officer and co-founder, said in a company press release.
A poster detailing the findings, titled Tolerogenic APC-targeted Vaccibody Vaccines Treat Disease in Mouse Models of Experimental Autoimmune Encephalomyelitis and Non-Obese Diabetes, was presented at the Federation of Clinical Immunology Societies (FOCIS) 2024 annual meeting, held June 18-21 in San Francisco.
Michael Engsig, Nykodes CEO, said the company is planning initiatives to advance our efforts in developing an inverse vaccine, also known as a Vaccibody.
We are excited about the progress and promise of Nykodes inverse vaccine platform for the treatment of autoimmune diseases, Engsig said.
In MS, the immune system mistakenly attacks the myelin sheath, a fatty layer that protects nerve fibers in the brain and spinal cord. Such attacks cause inflammation and damage, and result in a range of symptoms that worsen over time.
Nykodes inverse vaccine technology is designed to teach the immune system not to respond against a given target, inducing immune tolerance to that target.
It does that by delivering lab-made DNA molecules to muscles cells with instructions to produce an inverse vaccine, or Vaccibody. The Vaccibody proteins are then secreted by the cells and, once in circulation, they recruit and bind to antigen-presenting cells, called APCs.
APCs are immune cells that present antigens any substance that triggers an immune response to immune T-cells, triggering an immune response against those antigens. But Vaccibody vaccines are instead developed to recruit APCs that present antigens to regulatory T-cells, which limit the activity of other immune cells.
In addition to TV004, the company developed another Vaccibody inverse vaccine called TV036. Both are designed to induce tolerance against myelin oligodendrocyte glycoprotein (MOG), a myelin protein. However, they bind to different targets in APCs.
In experimental autoimmune encephalomyelitis, a widely used model of MS, mice usually develop their first symptoms within one week, and tail paralysis within about two weeks. As the disease progresses, paralysis spreads to the hind legs and then to the forearms.
In the lab, the mice were given an intravenous (into-the-vein) injection of TV004 or TV036 at seven and three days before experimental autoimmune encephalomyelitis was induced. In these animals, disease severity was reduced, and tail and hind paralysis were prevented for up to 28 days.
Similar findings were obtained when the intravenous injections were given at seven and 10 days after experimental autoimmune encephalomyelitis was induced, when some symptoms could have already developed.
[Nykode is] aiming to develop a new class of drugs that are antigen-specific, with the potential to be both long-lasting and have limited side effects. By exploring different targeting units and their impact compared to antigen delivery, Nykode aims to refine therapies that could offer new options for autoimmune conditions.
Using targeting units toward two different receptors on APCs, both Vaccibody inverse vaccines showed potent disease protection in preventive and early therapeutic settings, the researchers wrote in an abstract to the poster presented at FOCIS 2024.
Fredriksen said Nykode is aiming to develop a new class of drugs that are antigen-specific, with the potential to be both long-lasting and have limited side effects.
By exploring different targeting units and their impact compared to antigen delivery, Nykode aims to refine therapies that could offer new options for autoimmune conditions, Fredriksen said.
According to Engsig, Nykode is establishing a subsidiary within the company focused on further progressing the immune tolerance platform.
Makers of RSV vaccines for older adults saw their plans to try to expand usage hit a significant hurdle on Wednesday, when an expert committee that advises the Centers for Disease Control and Prevention on vaccines recommended changes that will likely see fewer older adults qualify for insurance coverage for these products.
In a related move, the Advisory Committee on Immunization Practices opted not to make a recommendation yet on use of GSKs Arexvy vaccine in adults 50 to 59, saying the committee didnt have enough data with which to make such a recommendation. Earlier this month the Food and Drug Administration approved use of the GSK vaccine to include adults in their 50s at high risk of developing severe disease if they contract respiratory syncytial virus, or RSV. When it was initially approved in May 2023, its use was restricted to people 60 and older.
The decision is a blow to GSK, which has been racing to secure market share in a field that now includes two competitors, Pfizer and Moderna. To that end, GSK used a priority review voucher to speed its age extension application through the FDA approval process. The agency is currently reviewing an application from Pfizer to extend the license for its RSV vaccine, Abrysvo, to include adults 18 and older who have health conditions that put them at risk of severe illness from RSV infection.
STAT reached out to GSK for comment but none was forthcoming at the time of publication.
Without a recommendation for use from the ACIP and the CDC, insurance companies are unlikely to cover the cost of the GSK vaccine for people in their 50s. And at nearly $300 a dose not including administration fees those individuals may be reluctant to pay out of pocket.
The final decision on vaccination use policy rests with the CDC director, Mandy Cohen. Late Wednesday the CDC issued a statement adopting the recommendations the ACIP had approved about an hour before.
The CDC has updated its RSV vaccination recommendation for older adults to prioritize those at highest risk for serious illness from RSV, Cohen said in the statement.
In particular, the work group suggested it needs information on how adults in their 50s who have immunocompromising conditions react to the vaccine what kind of antibody responses it generates more data on whether additional shots will boost protection that has waned. Some of the data to date suggest the reaction to booster shots is not as powerful as the response to the initial vaccine. ACIP member Sarah Long, a pediatrics professor at Drexel University College of Medicine in Philadelphia, worried that if boosting isnt effective, giving the RSV vaccine too soon might squander a tool that could be more needed later in life. Long and others on the committee worried that given the possible link to GBS, the risk-benefit ratio for people in their 50s may not favor vaccination in the way it does in older adults.
RSV vaccines for older adults are new. The first two, from GSK and Pfizer, were approved last spring and were rolled out for the first time in the autumn. Initially licensed only for adults 60 and older, the ACIP opted last June not to make a universal recommendation for their use, in the way that everyone is urged to get an annual flu shot. Instead, it suggested people who were eligible could get one of the vaccines, but should first talk to a health care provider to weigh the risks and benefits of getting vaccinated.
That approach, called shared decision-making, made sense to a committee that was reluctant to urge everyone 60 and older to get a shot, given that there are concerns that a small number of people who get the Pfizer and GSK vaccines particularly the former may develop Guillain-Barr syndrome, a form of progressive paralysis from which people normally recover, but after an extended period of hospitalization. There were no reports of Guillain-Barr syndrome among people in the clinical trials that led to the approval of Modernas RSV vaccine, mResvia, which was just approved by the FDA at the end of May.
Doctors and pharmacists complained about the shared decision-making recommendation, indicating they didnt always know how to advise patients. There are concerns that the recommendation may have depressed uptake of the vaccine.
So the ACIPs RSV work group proposed changing the recommendation in two ways, both of which were unanimously accepted by the full committee. In a vote of 11 to 0, the committee recommended that people aged 75 and older should get an RSV shot, if they have not yet had one. While its known the protection of these vaccines wanes with time, its not yet clear what the optimal cadence for revaccination is. So at present there is no recommendation for people who were vaccinated already to get another RSV shot.
In the second vote, the committee recommended that people aged 60 to 74 who have health conditions that put them at high risk of severe illness from RSV should also get the vaccine. People aged 60 to 74 who do not have one of the health conditions named could still get the vaccine, if they wish. But without an ACIP/CDC recommendation, they would have to pay out-of-pocket, committee chair Helen Keipp Talbot noted.
The health conditions listed include lung disease, cardiovascular disease, diabetes with end organ damage, severe obesity, neurological or neuromuscular conditions, advanced chronic kidney disease, liver disorder, or blood disorders. Adults aged 60 to 74 who live in long-term care facilities or who are deemed frail would also qualify, as would people who aremoderately or severely immunocompromised.
While a couple of members of the public raised concerns about the effect the new recommendation may have on vaccine uptake in people aged 60 to 74, committee members noted that the science on use of these products is evolving, and policy on their use will as well. ACIP member Matthew Daley noted after the votes that the panel perhaps should have added the words at this time to the wording of the votes, to make that point clear.
All adults ages 75 years and older should receive a single dose of any respiratory syncytial virus (RSV) vaccine, and adults ages 60 to 74 years who are at increased risk of severe RSV disease should receive a vaccine, according to a unanimous 11-0 vote by the CDC's Advisory Committee on Immunization Practices (ACIP).
Also, people who have already received the RSV vaccine are not recommended to receive a booster, based on data that showed another dose did not improve outcomes.
These recommendations supplant the current recommendation that adults ages 60 and older may receive RSV vaccination after engaging in shared clinical decision-making with their healthcare provider.
There are currently three RSV vaccines available for use in older adults -- GSK's adjuvanted RSV prefusion F protein-based vaccine (Arexvy), Pfizer's unadjuvanted, bivalent RSV prefusion F protein vaccine (Abrysvo), and Moderna's mRNA-1345 vaccine (mRESVIA).
Since the ACIP issued the first RSV vaccine recommendation for adults in 2023, the shared decision-making recommendation has proven problematic in clinical practice, Camille Kotton, MD, chair of the ACIP's Adult RSV Work Group, told the committee. "We have learned from feedback from healthcare providers that having shared decision-making conversations is not simple," she said. "Unlike a universal recommendation where there's a clear call to vaccinate, with shared clinical decision-making the call to action is to discuss with a healthcare provider -- a less clear message."
The recommendation also clarified that although the vaccine is universally recommended for those 75 and older, adults 60 to 74 who are not at increased risk of severe disease do not need to receive an RSV vaccine.
Who exactly is at high-risk for severe disease? The committee offered a list of chronic medical conditions associated with risk for severe RSV disease -- such as lung disease, cardiovascular disease, moderate or severe immune compromise, diabetes mellitus with end-organ damage, severe obesity, and other systemic diseases -- that will be provided by the CDC.
Benefits Still Outweigh Risks?
The benefits of the RSV vaccine in older adults continue to outweigh the small documented risk of Guillain-Barre syndrome that was linked with the vaccine, Michael Melgar, MD, co-lead of the Adult RSV Work Group, said in a presentation. "Bottom line, preventable outcomes far exceed potential cases of Guillain-Barre syndrome for both [GSK and Pfizer] vaccine products," Melgar commented during an overview of vaccine benefits and risks.
Earlier in the day, James Donahue, PhD, DVM, MPH, of the Marshfield Clinic Research Institute in Wisconsin, presented recent surveillance data from Vaccine Safety Datalink that revealed a small statistical signal for immune thrombocytopenic purpura (ITP) with the GSK vaccine. Upon review, most cases were determined to not be new cases that emerged after RSV vaccination. However, ongoing chart review is planned.
No Recommendations for RSV Vaccination in Adults Ages 50-59
The committee decided there was not enough data on benefits versus risks to recommend for or against the use of GSK's Arexvy vaccine in people ages 50 to 59 years at risk for severe RSV-associated disease, according to Amadea Britton, MD, co-lead of the Adult RSV Vaccine Work Group. On June 10, the FDA expanded the approval of Arexvy to include at-risk adults in this age group.
"This does not mean that the Work Group feels that RSV disease in this age group is unimportant," she said. "This opinion is also not a recommendation against the use of the RSV vaccine in adults aged 50 to 59 years. Rather, the Work Group believes more information is needed to make a population-level policy."
In other meeting news, the ACIP also voted unanimously to recommend that the combined diphtheria and tetanus toxoids and acellular pertussis, inactivated poliovirus, Haemophilus influenza type b conjugate and hepatitis type B vaccine (DTaP-IPV-Hib-HepB) (Vaxelis) should be included with PRP-OMP (PedvaxHIB) in the preferential recommendation for American Indian and Alaska Native infants based on the Haemophilus influenzae type b (Hib)Hib component.
Previously, Vaxelis did not have a preferential recommendation for these infants because it contains PRP-OMP in a lower amount than PedvaxHIB, and post-dose 1 immunogenicity data were not previously available, Melgar explained.
Katherine Kahn is a staff writer at MedPage Today, covering the infectious diseases beat. She has been a medical writer for over 15 years.
Disclosures
Kotton, Melgar, and Britton reported no ties to industry.
Why Is Moderna Stock Trading Lower On Wednesday?
The Centers for Disease Control and Preventions Advisory Committee on Immunization Practice will meet this week to consider and recommend who should get respiratory syncytial virus (RSV), influenza, and COVID-19 vaccines.
In the presentation slides to the U.S. agency, Moderna Inc (NASDAQ:MRNA) shared safety set data, with a cut-off date of March 8, 2024, based on the median of 18.8 months of follow-up.
The data showed that vaccine efficacy fell to around 50% after 18 months on participants aged 60 years and above.
Vaccine efficacy in the infection with more than two symptoms was 50.3% and 49.9% in disease with three or more symptoms.
After a median of 3.7 months of follow-up, vaccine efficacy stood at 78.7% and 80.9%, respectively, falling to 62.5% and 61.1% after a median of 8.6 months.
Efficacy of a single dose of GSK Plcs (NYSE:GSK) Arexvy over two calendar years showed vaccine efficacy of 73.3% (W/o season covariate) and 78.6% in severe infection.
Pfizer Incs (NYSE:PFE) Abrysvo demonstrated an overall efficacy of 77.8% in the second season and 81.5% across two seasons.
Last year, GSKs Arexvy and Pfizers Abrysvo went head to head for adults over 60.
Reuters notes that GSK won two-thirds of the market, mostly due to its contracts with retail pharmacies, including CVS Health Inc (NYSE:CVS).
Last month, Moderna Inc. (NASDAQ:MRNA) received FDA approval for its shot, mRESVIA, to protect adults aged 60 and older.
Earlier this year, Modernas longer-term trial analysis revealed a faster decline in the effectiveness of its RSV vaccine.
Follow-up data from Phase 3 mRNA-1345 Trial ReSViNET suggests the vaccine efficacy is declining faster than RSV vaccines fromGSK and Pfizer.
Read Next: Pfizer Seeks Expanded Use Of Abrysvo As Vaccine Shows Potential In 18+ Patients.
Pfizer secured a major contract with the U.K. to supply millions of doses of its Abrysvo respiratory syncytial virus (RSV) vaccine, edging out local pharmaceutical giantGSK.
This agreement includes over 3.5 million doses for older adults and more than 1.4 million doses for pregnant mothers in England and Northern Ireland over the next two years.
Price Action: MRNA shares are down 6.98% at $128.08 at the last check on Wednesday.
Photo by Lutsenko_Oleksandr on Shutterstock
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