At the beginning of the pandemic, many people hoped that infections with SARS-CoV-2, the virus that causes COVID-19 or vaccines against the virus would providedurable lifetime immunity, as is the case with diseases likemeaslesor mumps. Instead, the COVID virus is more akin to the influenza virus, which mutates constantly and confers only short-term immunity. Both COVID and the flu require new and different vaccine formulas aimed at defeating newly circulating variants of the viruses. The inevitable result of this has been, for most of us, increasing vaccine fatigue.
But what if it were possible to protect against COVID and the flu, and other unknown viruses that haven't yet emerged, with just one shot? If that became reality, seasonal or annual boosters would be part of the past. And what if such vaccinations didn't even require a needle?
While those possibilities may sound far in the future, scientists at the University of California, Riverside, believe they could become reality relatively soon perhaps within the next five to 10 years. As illustrated in a paper justpublished in the Proceedings of the National Academy of Sciences, a new, RNA-based vaccine strategy could be effective against any viral strain to emerge in the future. This next generation of vaccines would theoretically offer protection against viruses we arent even aware of yet, and could be used safely on infants and people with compromised immune systems, who today must often opt out of vaccination to protect their health.
This new RNA-based technology, the research paper reports, would target a part of the viral genome that is common to all strains of any virus and would depend on a second immune system response.
We have a very strong reason to believe that all these other human viruses, like dengue virus and COVID-19, produce a protein that we can target to make a vaccine, Shouwei Ding, distinguished professor of microbiology at UC Riverside and lead author of the paper, told Salon in a phone interview. With any future virus, "all we need to do is to identify the protein that can suppress RNAi.
Here's what Ding was talking about. Traditional vaccines work by training the body to recognize and combat specific molecules found on a particular pathogen. For example, live-attenuated vaccines often use a weakened form of a virus to train the immune system. Once the weakened form of the virus is in the body, the immune system learns to recognize the antigen and develop immunity to it.
Another type of vaccine, based on "viral vectors," uses DNA and RNA to give cells a blueprint, rather than a piece of the pathogen itself, to build immunity. MRNA vaccines, like the best-known vaccines against COVID-19, use a synthetic version of single-stranded RNA to create a bespoke version of the mRNA within the body. This creates cells that can produce proteins like those found in a virus, and which then train the immune system to fight a disease before it enters a persons bloodstream.
The new vaccine technology proposed in this paper would still use a live, modified version of a virus. But its effectiveness would not depend on the body's traditional immune response, which produces T-cells and memory B-cells. Instead, it would produce proteins that block a pathogens RNAi response, which is something all viruses create.
Researchers tested their theory in mice with a virus called Nodamura. The mice lacked T and B cells, but after one injection with the test vaccine, the mice were protected against the virus for at least 90 days.
This new vaccine tech could be key to fighting bird flu, researchers say: "We are actively seeking funding to do just that.
In 2013, this same group of researchers at UC Riverside published a paper showing that flu infections also cause people to produce RNAi molecules. Ding said their next step will be to generate a universal, one-time-use influenza vaccine that would be safe for very young infants. Current flu vaccines are only recommended for infants over the age of six months. Furthermore, this new vaccine would likely be delivered as a spray. As Salon has previously reported, vaccines that dont require needles may one day become standard.
This intriguing report arrives at a moment when the bird flu virus, known as H5N1, has reportedly begun to spread among cattle. There has also been at least one confirmed human case. As Salon has reported, infectious disease experts do not expect bird flu to become a pandemic this year, that's a definite possibility in the future. One virologist told Salon she would recommend public vaccination against bird flu right now. No avian flu vaccines have yet been approved for use in humans, however, although several areunder development, none have been approved for use in humans yet.
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Ding said the vaccine his team is developing could be a contender:That's what we're aiming for. We are actively seeking funding to do just that.
Among the additional implications of this new vaccine technology, Ding said, could be more rapid protection than is now typical. What we find is that two days after the shot, you are already fully protected, he said. With current vaccines, "it will often take two weeks or more to be effective, and that's not very good for an emerging infection.
Ding said his team anticipates having a vaccine candidate ready for human clinical trials in about a year. After that, the traditional regulatory would likely take 5 to 10 years although a new public health emergency, like the COVID pandemic, could speed that up considerably.
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about vaccines and viruses
A 72-year-old from the Netherlands was infected with COVID-19 for 613 days, the longest period of infection ever recorded.
Dutch researchers have reported the case of an immunocompromised man, who was infected with the virus for so long, a new variant evolved inside his body.
The man sadly died of a blood disorder relapse while still infected with COVID-19, the researchers said.
READ MORE: Two charged months after alleged kidnapping plot
"The case is the longest-known COVID-19 infection to date", PhD candidate Magda Vergouwe said.
Several COVID-19 cases lasting hundreds of days have been previously recorded.
The patient was admitted to Amsterdam University Medical Center in February 2022 with a SARS-CoV-2 infection.
The man's immune system had become compromised after a stem cell transplant, which depleted the immune cells that usually fight COVID-19.
Vaccinations and treatments failed to prevent or cure his case of the virus.
Where healthy patients can clear the virus within days, immunocompromised people can develop persistent infections.
DNA sequencing of the virus showed it had become resistant to one form of treatment called sotrovimab.
The man died after "a relapse of his haematological condition", but had retained a high viral load for 613 days.
The man did not pass on the new, drug-resistant variant of COVID-19 to anyone else before he died.
The scientists said "the case highlights the potential for new COVID-19 variants to arise in immunocompromised patients with very long infections".
"We emphasise the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections given the potential public health threat of possibly introducing viral escape variants into the community," they said.
"The duration of SARS-CoV-2 infection in this described case is extreme, but prolonged infections in immunocompromised patients are much more common compared to the general community".
The number of pupils suspended from school has reached a record high as experts warn that bad behaviour has increased since lockdown school closures.
Data from the Department for Education (DfE) found that there were 263,904 suspensions in the spring term during the 2022/23 academic year, an increase from 201,090 during the period the year before.
In the same term, there were 3,039 permanent exclusions, an increase from 2,179.
Academics warned that the deeply concerning increase was a result of pupils losing the habitof going to school during the Covid-19 pandemic.
A spokesman for the DfE said: The most common reason for suspensions and permanent exclusions was persistent disruptive behaviour. This is in line with previous terms and years where this reason was the most commonly recorded.
Suspensions are typically higher in autumn term than in spring and summer, so spring 2022/23 is a change from that trend and the highest recorded number of termly suspensions.
The figures showed a 31 per cent increase in suspensions compared to the previous year, the highest outside of Covid restrictions.
The rise was particularly high among secondary children, with cases increasing from 174,522 to 232,635 - a 33 per cent jump and the equivalent of one in sixteen pupils.
Prof Alan Smithers, director of the Centre for Education and Employment Research at the University of Buckingham, said: The huge increases in suspensions and exclusions from school for disruptive behaviour is deeply concerning.
It seems that far too many pupils lost the habit of regularly attending school during the pandemic and on being forced to return are taking it out on the teachers.
Being thrown out of school not only harms the learning and future prospects of the pupils themselves, but also the behaviour leading to these drastic steps lowers the quality of education of other pupils.
Disruptive pupil behaviour is the major reason given by teachers for quitting the profession. The Government must urgently address the decline in pupil behaviour.
It comes as Englands exam regulator, Ofqual, published figures showing that the number of contested GCSE and A-level results increased in the year when grading returned to pre-pandemic levels in England.
Figures show that 2,570 GCSE, AS and A-level grades were challenged in 2022/23, compared to 2,430 in 2021/22.
Of these grades, 710 were changed as part of an upheld appeal in 2022/23 - which is a 15.8 per cent rise on the previous year, when 610 grades were changed.
Overall, 6.3 million grades were issued for GCSEs, AS and A-levels in 2022/23.
Last summer, the proportion of GCSE and A-level entries awarded top grades fell from the previous year when efforts were made in England to return grading to pre-pandemic levels.
It came after the pandemic led to an increase in top grades in 2020 and 2021, with results based on teacher assessments instead of exams.
A DfE spokesman said: The Government is very clear it backs head teachers to use exclusions where required, so they can provide calm, safe, and supportive environments for children to learn in.
We are providing targeted support to schools to help improve behaviour, attendance and reduce the risk of exclusions with an investment of 10 million in our Behaviour Hubs programme, and our mental health teams who will reach at least 50 per cent of pupils by 2025.
We are continuing to deliver on our plan to give every child a world-class education and standards have risen sharply across the country, with 90 per cent of schools now rated good or outstanding by Ofsted, up from just 68 per cent in 2010.
Early death and poor health from HIV/AIDS and diarrhea cut in half
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Rates of early death and poor health caused by HIV/AIDS and diarrhea have been cut in half since 2010, and the rate of disease burden caused by injuries has dropped by a quarter in the same time period, after accounting for differences in age and population size across countries, based on a new study published in The Lancet. The study measures the burden of disease in years lost to early death and poor health. The findings indicate that total rates of global disease burden dropped by 14.2% between 2010 and 2019. However, the researchers found that the COVID-19 pandemic interrupted these downward trends: rates of disease burden increased overall since 2019 by 4.1% in 2020 and by 7.2% in 2021. This is the first study to measure premature death and disability due to the COVID-19 pandemic globally and compare it to other diseases and injuries.
The study reveals how healthy life expectancy, which is the number of years a person can expect to live in good health, rose from 61.3 years in 2010 to 62.2 years in 2021. Pinpointing the factors driving these trends, the researchers point to rapid improvements within the three different categories of disease burden: communicable, maternal, neonatal, and nutritional diseases; non-communicable diseases; and injuries. Among communicable, maternal, neonatal, and nutritional diseases, the burden of disease declined for neonatal disorders (diseases and injuries that appear uniquely in the first month of life), lower respiratory infections, diarrhea, malaria, tuberculosis, and HIV/AIDS between 2010 and 2021, ranging from reductions of 17.1% for neonatal disorders to 47.8% for HIV/AIDS. In the category of non-communicable diseases, disease burden from stroke dropped by 16.9%, while disease burden from ischemic heart disease fell by 12.0% during this period.
"The world made huge strides in expanding treatment for HIV/AIDS and combatting vaccine-preventable diseases and deaths among children under 5."
For injuries, the years of healthy life lost due to road injuries was slashed by nearly a quarter (22.9%), while disease burden from falls was reduced by 6.9%. Progress in reducing disease burden varied by countries Socio-demographic Index a measure of income, fertility, and education underscoring inequities. For example, the burden of disease due to stroke dropped by 9.6% from 2010 to 2021 in countries with the lowest Socio-demographic Index, but it declined faster by 24.9% among countries with higher Socio-demographic Index.
Our study illuminates both the worlds successes and failures, said Dr. Alize Ferrari, Affiliate Associate Professor at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Honorary Associate Professor at the School of Public Health at the University of Queensland, and co-first author of the study. It demonstrates how the world made huge strides in expanding treatment for HIV/AIDS and combatting vaccine-preventable diseases and deaths among children under 5. At the same time, it shows how COVID-19 exacerbated inequities, causing the greatest disease burden in countries with the fewest resources, where health systems were strained and vaccines were difficult to secure. Governments should prioritize equitable pandemic preparedness planning and work to preserve the momentum that weve seen in improving childrens health.
With low back pain, the leading cause of poor health globally, we see that the existing treatments arent working well to address it.
The research presents updated estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. The GBD 2021 study analyzes incidence, prevalence, years lived with disability (years lived in less-than-ideal health), and disability-adjusted life years (lost years of healthy life) at global, regional, national, and subnational levels. It presents estimates of health and health loss in age-adjusted rates and total rates per 100,000 people. The study provides globally comparable measures of healthy life expectancy and is the first study to fully evaluate burden of disease amid the first two years of the COVID-19 pandemic. COVID-19 was the single leading cause of disease burden worldwide in 2021, accounting for 7.4% of total disease burden globally.
The study also examined how the COVID-19 pandemic affected males and females differently. The researchers found that males were more likely than females to die of COVID-19; the age-standardized disease burden rate for COVID-19 among males was nearly twice that of females. However, the secondary effects of the COVID-19 pandemic, including long COVID and mental disorders, hit females hardest. For example, females were twice as likely as males to develop long COVID. Depression, which increased sharply during the pandemic, was most likely to affect females between ages 15 and 65. Looking at differences between age groups, COVID-19 caused the most disease burden in older adults. For COVID-19, adults 70 years and older had more than double the levels of disease burden compared to adults between the ages of 50 and 69.
The study highlights not only the diseases and injuries that cut life short and cause poor health, and how the burden of disease from different causes has changed over time, but also examines how these patterns differ across countries and regions. In essence, the authors write, the study provides a comprehensive toolkit to inform and enhance decision-making processes across various levels of governance and practice.
GBD 2021 shines a light on the different causes of disease burden, showing which ones have improved and which are stagnating or worsening. It also tallies the number of years that people are living healthy lives. Healthy life expectancy rose significantly in 59 countries and territories between 2010 and 2021, with the greatest improvements in countries ranking lowest on the Socio-demographic Index, jumping from 52.2 years in 2010 to 54.4 years in 2021. In contrast, healthy life expectancy showed minimal change among countries in the highest levels of the Socio-demographic Index, decreasing slightly from 68.9 years in 2010 to 68.5 years in 2021. The findings on healthy life expectancy demonstrate that even though people are living longer lives all over the world, they arent spending all those years in good health. The researchers found that the main causes of poor health were low back pain, depressive disorders, and headache disorders.
With low back pain, the leading cause of poor health globally, we see that the existing treatments arent working well to address it, said Dr. Damian Santomauro, Affiliate Assistant Professor of Health Metrics Sciences at IHME; Stream Lead at Queensland Centre for Mental Health Research; Adjunct Fellow at the School of Public Health at the University of Queensland; and co-first author of the study. We need better tools to manage this major cause of global disease burden.
In contrast, for depressive disorders, we know what can work: therapy, medication, or both in combination for an adequate period of time. However, most people in the world have little or no access to treatment, unfortunately, he said. Considering how depression increased dramatically during the COVID-19 pandemic, its urgent to ensure that everyone with this disorder can get treatment.
Another way to understand what is making people ill is by looking at which diseases are growing fastest. GBD 2021 reveals that diabetes experienced the most rapid growth among the different causes of poor health, what the researchers call years lived with disability. Age-adjusted years lived with disability due to diabetes rose by 25.9% between 2010 and 2021. Poor health from diabetes increased in every country and territory that the researchers studied.
Diabetes is a major contributor to stroke and ischemic heart disease, which are among the top three causes of disease burden worldwide, said Dr. Theo Vos, Professor Emeritus at IHME and one of the studys senior authors. Without intervention, more than 1.3 billion people in the world will be living with diabetes by 2050. To counter the threat of diabetes, we must ensure that people in all countries can access preventive care and treatment, including to anti-obesity medications, which can lower a persons risk of developing diabetes.
For interview requests, journalists may contact [emailprotected].
The Institute for Health Metrics and Evaluation (IHME) is an independent research organization at the University of Washington (UW). Its mission is to deliver to the world timely, relevant, and scientifically valid evidence to improve health policy and practice. IHME carries out its mission through a range of projects within different research areas including the Global Burden of Diseases (GBD), Injuries, and Risk Factors; Future Health Scenarios; Cost Effectiveness and Efficiency; Resource Tracking; and Impact Evaluations.
IHME is committed to providing the evidence base necessary to help solve the worlds most important health problems. This requires creativity and innovation, which are cultivated by an inclusive, diverse, and equitable environment that respects and appreciates differences, embraces collaboration, and invites the voices of all IHME team members.
The Global Burden of Disease Study (GBD) is the largest and most comprehensive effort to quantify health loss across places and over time. It draws on the work of more than 11,000 collaborators across more than 160 countries and territories. GBD 2021 the newly published most recent round of GBD results includes more than 607 billion estimates of 371 diseases and injuries and 88 risk factors in 204 countries and territories. The Institute for Health Metrics and Evaluation coordinates the study.
Age-standardized rate per 100,000 (2010)
Lower respiratory infections
Chronic obstructive pulmonary disease
Congenital birth defects
Cirrhosis and other chronic liver diseases
Tracheal, bronchus, and lung cancer
Age-related and other hearing loss
Other musculoskeletal disorders
Dietary iron deficiency
Alzheimers disease and other dementias
Age-standardized rate per 100,000 (2020)
Lower respiratory infections
Chronic obstructive pulmonary disease
Congenital birth defects
Cirrhosis and other chronic liver diseases
Tracheal, bronchus, and lung cancer
Other musculoskeletal disorders
Age-related and other hearing loss
Alzheimers disease and other dementias
Dietary iron deficiency
Age-standardized rate per 100,000 (2021)
Lower respiratory infections
Chronic obstructive pulmonary disease
Congenital birth defects
Cirrhosis and other chronic liver diseases
Other musculoskeletal disorders
Tracheal, bronchus, and lung cancer
Age-related and other hearing loss
Alzheimers disease and other dementias
Dietary iron deficiency
Study design
This was a prospective, multicenter, open-label, randomized phase 2 seamlessly followed by a phase 3 study to evaluate the safety, tolerability and immunogenicity of GEMCOVAC-OM as a booster in participants 18years of age and older. In this seamless study, phase 2 safety data till day 7 were analyzed and presented to an independent DSMB. The DSMB evaluated these data and provided their approval to initiate the phase 3 part of the study. The phase 3 study was conducted at 20 hospitals in 13 cities across India in compliance with the principles defined in the Declaration of Helsinki, International Conference for Harmonisation Good Clinical Practice Guideline. The study protocol was approved by the local ethics committee at each study site and Central Drugs Standard Control Organisation, the central licensing authority in India. This clinical trial is registered with the Clinical Trial Registry India, CTRI/2022/10/046475. Details on the sites and Ethics Committees can be found in Supplementary Information.
An interim analysis was planned at day 29 of phase 3 where the immunogenicity and safety of the participants was assessed and presented to the Central Drugs Standard Control Organisation for Emergency Use Authorization.
In phase 2, the safety and immunogenicity of GEMCOVAC-OM as a booster was compared with the prototype vaccine GEMCOVAC-19 designed against the spike protein of the D614G strain of SARS-CoV-2 (n=140). Participants were randomized to receive the vaccines in a 1:1 ratio.
The phase 3 study comprised a safety and an immunogenicity cohort. The safety cohort consisted of 3,140 participants of whom 3,000 were enrolled into the GEMCOVAC-OM arm and 140 were enrolled into the ChAdOx1 nCoV-19 arm. Within the safety cohort, the immunogenicity cohort consisted of 420 participants of whom 280 were enrolled into the GEMCOVAC-OM arm and 140 were enrolled into the ChAdOx1 nCoV-19 arm. Participants were healthy adults (male or female participants reported by self), 18years of age or older, who have received two doses of either BBV152 or ChAdOx1 nCoV-19, 4months before the screening visit. Additionally, the participants should have had no known COVID-19 infection at least 3months before the screening visit. Key exclusion criteria included pregnant or lactating mothers, individuals with illnesses that in the opinion of the investigator may affect safety, and the immunocompromised. Detailed inclusion and exclusion criteria are provided in the protocol (Supplementary Information). Participants were screened on the basis of medical history, vital signs and physical examination before enrollment. Eligible participants provided signed informed consent forms at enrollment. Participants were compensated at every visit for their time and cost of travel.
Participants who met the inclusion criteria and successfully completed all screening procedures were randomized in the study by using the interactive web response system (IWRS). Unique randomization codes were assigned to the participants and remained unchanged until the completion of the trial. The randomization codes were generated through Proc Plan using SAS version 9.4 or higher (SAS Institute) by an independent biostatistician. The final randomization list was filed securely by the independent biostatistician and accessible to authorized persons only. Participants were enrolled by investigators with the help of the IWRS.
In phase 3, consecutive 420 in the immunogenicity cohort were randomized in a 2:1 ratio into GEMCOVAC-OM and ChAdOx1 nCoV-19 by stratified block randomization through the IWRS. A randomization code was assigned to each participant in sequence in the order of enrollment, and then the participants received the investigational products labeled with the same code. This was an open-label study, and no masking was performed.
GEMCOVAC-OM consists of an in vitro transcribed mRNA encoding for the spike protein of the Omicron variant of the SARS-CoV-2 virus and cationic lipid nano-emulsion in a buffer containing 10% sucrose in 10mM sodium citrate, pH 6.5 (ref. 45). The complete antigenic sequence that was used has been published in the DDBJ database (accession no. LC769018). GEMCOVAC-OM, 10g in 0.1ml, was administered intradermally using a Tropis needle-free injection system (PharmaJet). More information on the vaccine, mRNA platform and development can be found in Supplementary Information.
ChAdOx1 nCoV-19 (COVISHIELD), the comparator vaccine in phase 3, consisted of Corona Virus Vaccine (Recombinant) 51010 viral particles. This vaccine is based on recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein, produced in genetically modified human embryonic kidney 293 cells. ChAdOx1 nCoV-19 was administered intramuscularly.
GEMCOVAC-19 consists of an in vitro transcribed mRNA encoding for the spike protein of the D614G variant of the SARS-CoV-2 virus and cationic lipid nano-emulsion in a buffer containing 10% sucrose in 10mM sodium citrate, pH 6.5. The complete antigenic sequence that was used has been published in the DDBJ database (accession no. LC776732.1). GEMCOVAC-19, 10g in 0.5ml, was administered intramuscularly.
The participants were screened on visit 1 (day 1), which included a validated reverse transcription polymerase chain reaction (RTPCR) for SARS-CoV-2. Regardless of the outcome of the RTPCR, the participants who fit the inclusion criteria were enrolled and the vaccine was administered on the same day. Those found to be RTPCR positive would be excluded from the immunogenicity analysis to avoid confounding. Importantly, during the trial, in India, a third dose of BBV152 or ChAdOx1 nCoV-19 (precautionary dose) was approved for participants who had received primary doses of BBV152 or ChAdOx1 nCoV-19, respectively. However, individuals who had taken two doses of BBV152 as their primary vaccination were not eligible for a third dose of ChAdOx1 nCoV-19. Keeping in line with these vaccination guidelines, participants with ChAdOx1 nCoV-19 as their primary vaccination were randomized to get ChAdOx1 nCoV-19 or GEMCOVAC-OM, whereas participants with BBV152 as their primary vaccination received GEMCOVAC-OM only in the clinical trial.
Participants were provided an e-diary or a paper diary to record the solicited AEs till day 7 and unsolicited AEs as well as concomitant medication taken, if any, till the end of the study. A telephone call was placed to all the participants at day 7 to record any additional AEs, if any. Participants visited the study site for visit 2 (day 29+7), visit 3 (day 90+14) and visit 4 (day 180+14). Blood for assessing immunogenicity was drawn at visit 1 before vaccination (baseline), day 29 and day 90. Safety was assessed throughout the duration of the study.
In phase 2, the primary endpoints were to compare the safety and anti-spike IgG antibodies between the two vaccinated arms at day 29. Secondary endpoints included comparison of seroconversion as assessed by 2-fold rise in anti-spike IgG antibody titers from baseline, percentage neutralization by a surrogate neutralization (cPass) assay and cellular immune responses at day 29. Exploratory endpoints included comparison of anti-spike IgG antibodies, percentage neutralization by cPass assay and cellular immune responses at day 90.
In phase 3, the primary endpoint was the demonstration of noninferiority of neutralizing antibody GMT assessed by a plaque reduction neutralization test (PRNT50) assay in terms of LSGMR at day 29 and difference in seroconversion (2-fold rise in antibody titers at day 29 from baseline) between GEMCOVAC-OM and ChAdOx1 nCoV-19. Secondary endpoints included comparison of safety, LSGMR and seroconversion in terms of anti-spike IgG antibody titers, percentage neutralization by a surrogate virus neutralization assay (cPass assay, GenScript) and cell-mediated immunity assessment by intracellular cytokine expression at day 29. Exploratory endpoints included humoral and cellular immune response assessment at day 90.
Although the trial was open-label, laboratory analysis was conducted in a blinded manner. Measurements were taken from distinct samples. Information on the materials used is provided in detail in Supplementary Information.
Neutralizing antibody titers were assessed by the PRNT50 assay at the Interactive Research School for Health Affairs (IRSHA, Bharati Vidyapeeth, Deemed to be University, Pune) that was previously developed46 and then optimized for the BA.1 Omicron variant of SARS-CoV-2 (SARS-CoV-2-IND/0005/2022; B.1.1.529.1 lineage). In brief, Vero E6 cells were initially seeded at a density of 1105 cellsml1 in 24-well plates using Minimum Essential Medium (MEM) containing 10% fetal bovine serum (FBS) and antibiotics and allowed to incubate overnight at 37C with 5% CO2. Serum samples, initially diluted at 1:5 ratios, were subjected to heat inactivation for 30min at 56C. Subsequently, a fourfold serial dilution was executed, and these serum dilutions were mixed in equal proportions with the SARS-CoV-2 virus with a titer ranging from 600 to 1,000 plaque-forming units (pfu) per milliliter. The serumvirus mix was then incubated for 1h at 37C within a humidified incubator with 5% CO2. Following incubation, 100l of the resultant mixture was introduced into duplicate wells of the seeded 24-well plate and subjected to an additional 3-h incubation at 37C in a humidified incubator with 5% CO2. Then, 1ml of an overlay medium, constituting MEM, Aquacide-II, 2% FBS and antibiotics, was added to the Vero cell monolayer. Plates were then incubated for 6days at 37C within a humidified incubator with 5% CO2. At the end of this incubation period, the overlay medium was removed, and cells were fixed through the application of 3.7% formaldehyde. After washing with phosphate-buffered saline, cells were stained using 1% crystal violet. Plates were washed once more and air-dried. Viral plaques were counted using the C.T.L. ImmunoSpot platform. PRNT50 titers were determined using standard logistic regression model. Neutralization was also assessed using a semi-quantitative surrogate virus neutralization assay (cPass, GenScript)47 for the BA.1 variant.
Anti-IgG responses against the spike glycoprotein of B.1.1.529 Omicron variant of SARS-CoV-2 was assessed by an in-house developed indirect ELISA. In brief, 96-well ELISA plates (Nunc Maxisorp) coated with spike protein (full length from Sino Biologicals, 40589-V08H26) were washed thrice with phosphate-buffered saline-Tween (PBS-T). Plates were blocked with 3% nonfat dried milk. Diluted sera samples were added to the blocked plates and incubated at room temperature for 2h. Plates were then washed thrice with PBS-T and incubated at room temperature with detection antibody (1:5,000), anti-human IgG (Fc region specific from Sigma A0170) for 1h at room temperature. After secondary antibody incubation, plates were washed thrice with PBS-T before addition of TMB substrate. Color development was quenched with 3M HCl after 20min of incubation at room temperature. Plates were read at 450nm using a plate reader. The assay background was calculated from the 10s.d. added to the average of the readouts where there was no sample but diluent in the wells. For all samples, IgG titers were an interpolation of previously calculated assay background in 5 parameter logistic fit of sample dilution versus absorbance.
PBMCs were isolated using BD Vacutainer CPT with sodium citrate tubes following the manufacturers guidelines and subsequently cryopreserved in liquid nitrogen. For immune-phenotyping purposes, frozen PBMCs were thawed and allowed to rest in complete RPMI 1640 culture medium (CRPMI) supplemented with 10% FBS, 100Uml1 penicillin and 0.1mgml1 streptomycin (1 pen-strep) for 1822h. Gating strategies for both T cell and B cell experiments are given in Extended Data Fig. 3. In T cell response analysis, intracellular cytokine staining (ICS) was performed using 0.5 million PBMCs in 100l CRPMI medium per well in a V-bottom plate. These cells were stimulated with a 1gml1 epitope mapping 15-mer peptide pool derived from the Omicron B.1.1.529/BA.1 spike glycoprotein peptides, specifically the PepTivator SARS-CoV-2 Prot S B.1.1.529/BA.1 Mutation Pool. Stimulation was carried out in the presence of 1gml1 BD FastImmune (anti-CD28/49d antibody)48 for 6h, with the addition of 1l of Brefeldin-A during the final 4h of stimulation. After stimulation, PBMCs were washed and subjected to surface and ICS staining using antibodies targeting CD3 PE-Cy7 (BD 557851, clone SK7, 1:20), CD4 BV480 (BD 566104, clone SK3, 1:20), CD8 FITC (BD 555366, clone RPA-T8, 1:5), IFN PE (BD 559327, clone B27, 1:5), TNF APC (BD 551384, clone MAb11, 1:5), IL-2 BV421 (BD 562914, clone 5344.111, 1:20), IL-2 BV786 (BD 564113, clone MP4-25D2, 1:10), IL-13 BV711 (BD 564288, clone JES10-5A2, 1:10) and CD19 PerCP-Cy5.5 (BD 561295, clone HIB19, 1:20) markers. ICS was executed utilizing the BD cytofix/cytoperm kit following the manufacturers instructions. Antibody incubation was carried out for 30min at 4C. Phorbol myristate acetate (PMA)ionomycin was used as positive control. To assess the B cell population specific to the B.1.1.529 spike protein, PBMCs were initially labeled with biotinylated spike protein specific to Omicron B.1.1.529. Subsequently, surface staining was performed with common surface markers CD3 BV605 (BD 563219, clone SK7, 1:20), CD19 PerCP-Cy5.5 (BD 561295, clone HIB19, 1:20), CD20 APC-H7 (BD 560734, clone 2H7, 1:20). Following staining and washing steps, PBMCs were resuspended in fluorescence-activated cell sorting buffer, acquired using the FACSLyric system (BD Biosciences), and analyzed using FlowJo software version 10.8.1 (FlowJo LLC, BD Biosciences).
Solicited events data were captured up to 7days after booster vaccine administration through an electronic or paper diary. Local solicited events included pain, redness, swelling, warmth, pruritus and bruising. Systemic solicited events included fever, headache, myalgia, arthralgia, fatigue, malaise, nausea and chills. Unsolicited events were assessed throughout the duration of the study. AE terms were coded using Medical Dictionary for Regulatory Activities. These AEs were graded on the basis of the Division of AIDS criteria49. Myocarditis was considered as an AE of special interest; site investigators were asked to thoroughly evaluate participants with any symptoms of chest pain, breathlessness or palpitations.
No formal sample size calculations were performed for phase 2. Phase 3 consisted of a safety and an immunogenicity cohort. The safety cohort consisted of 3,140 participants of whom 3,000 were included in the GEMCOVAC-OM arm. The immunogenicity cohort was analyzed for two primary endpoints based on World Health Organization guidelines50, with individuals randomized to GEMCOVAC-OM and ChAdOx1 nCoV-19 in a 2:1 ratio. A sample size of 420 (280 in GEMCOVAC-OM and 140 in ChAdOx1 nCoV-19) was found adequate for assessing noninferiority of neutralizing antibody titers if the lower limit of the two-sided 95% CI of the LSGMR (GMTGEMCOVAC-OM/GMTChAdOx1 nCoV-19) was >0.67 considering a standard deviation of 1.82, alpha error of 5%, power of 90% and dropout rate of 20%. A sample size of 381 (254 in GEMCOVAC-OM and 127 in ChAdOx1 nCoV-19) was found adequate for assessing the noninferiority of seroconversion difference considering a margin of 10%, alpha error of 5%, power of 90% and dropout rate of 20%. The sample size of 420 (280 in GEMCOVAC-OM and 140 in ChAdOx1 nCoV-19 arm) was considered in this study to provide adequate numbers for the statistical analysis of both the primary endpoints.
All immunogenicity analysis was performed in the full analysis set (intention to treat) population. The observed GMT and associated 95% CIs (ClopperPearson method) were calculated on the basis of log-transformed antibody titers. The rise in neutralizing antibody titers from baseline to day 29 was compared using a paired t-test. The LSGMR of neutralizing antibody titers in both the arms at day 29 from the PRNT50 (BA.1 strain of SARS-CoV-2) assay was calculated using ANCOVA with baseline titers as covariates. If the lower limit of the two-sided 95% CI of the LSGMR was >0.67, GEMCOVAC-OM would be considered noninferior to ChAdOx1 nCoV-19. Seroconversion in terms of neutralizing antibody titers from PRNT50 assay was defined as a 2-fold rise in titers at day 29 from baseline. The difference in seroconversion was determined using the MeitinenNurminen method. If the lower bound of the two-sided 95% CI for seroconversion difference was >10%, GEMCOVAC-OM would be considered noninferior to ChAdOx1 nCoV-19.
Similarly, for the secondary endpoint, LSGMR of anti-Spike IgG antibody titers from ELISA at day 29 was assessed using ANCOVA, with baseline titers as covariates. The 95% CI was calculated for percentage by using the ClopperPearson method. The difference in seroconversion at day 29 for anti-spike IgG antibodies from ELISA were calculated using the MeitinenNurminen method. The difference in the change in mean percentage neutralization from baseline to day 29, assessed by the cPass assay, was analyzed using ANCOVA with baseline neutralization considered as a covariate. In cell-mediated immunity, change in expression from baseline to day 29 was assessed by either a two-sided paired t-test or Wilcoxon signed-rank test depending on normality of the data. Expression at day 29 was compared using a two-sided t-test or Wilcoxon rank sum base based on normality. The normality of the data was assessed using a ShapiroWilk test. This was also performed for subgroups based on their primary vaccination of either BBV152 or ChAdOx1 nCoV-19.
Sex-disaggregated analysis was conducted for humoral and safety data from phase 3. For humoral immunogenicity, ANCOVA was used to compare the differences in neutralizing antibody and anti-spike IgG between men and women at days 29 and 90, using baseline titers as covariates. For safety, unadjusted OR was calculated along with the 95% CI.
Data were collected using Clinion (version 3.1). Statistical analysis for humoral immunogenicity was performed using Statistical software SAS version 9.4 (SAS Institute). Figures were generated using GraphPad Prism (Version 9.5.1). The Spearman rank correlation coefficient (denoted as r) was computed for all pairs of parameters utilizing the corrplot package (version 0.92) within RStudio (version 2022.12.0.0). To complement the correlogram, two-tailed P values associated with Spearman rank correlations were calculated through the corr.mtest function and visualized using the corrplot function.
Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
Saturday, April 20, or 4/20, is known to many as a day for celebrating cannabis and its consumption. It is also the first 4/20 since recreational cannabis use was legalized in Minnesota, going into effect last August. With this in mind, we looked at recently published research into cannabis use in Minnesota.
According to a study from the University of Minnesota School of Public Health published this past January, pre-legalization cannabis use among Minnesotans is relatively on par with the national average. The study uses 2018-2019 data from the National Survey on Drug Use and Health, the latest state-level data available, and found:
Among Minnesotans age 12 and older, roughly half reported using cannabis once in their life.
Only 10 percent reported recent use within the past 30 days, only slightly lower than the nationwide rate of 10.8 percent.
Minnesotans reported cannabis dependence rate is virtually identical to the national average, 1.8 percent compared to 1.7 percent.
4.4 percent of Minnesotans admit to driving under the influence of cannabis, virtually identical to the 4.5 percent who do so nationally.
It remains to be seen how these cannabis rates shift in Minnesota once we have data from after its legalization. But a reminder to remain vigilant with cannabis, especially around children.
As we have reported, over 50 children age 10 or younger, and another 100 in the 11-14 age range, ended up in U.S. emergency rooms every week, as of 2022, due to intentional and unintentional cannabis consumption.
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The Centers for Disease Control and Prevention reports that one-quarter of all U.S. adults have seasonal allergies. A quick perusal of AccuWeather forecasts show tree pollen in the high range everywhere from Fargo and Duluth to Worthington and Rochester.
Infectious respiratory diseases, however, continue to wane in Minnesota.
Hospital admissions due to influenza are finally dropping in Minnesota. After averaging nearly 250 hospital admissions per week since mid-December, the count fell to 212 in the week ending March 23 and then 163 for the final week of March.
Hospitalizations due to respiratory syncytial virus (RSV) and COVID-19 leveled off a bit in the most recent week or two after steady declines ever since their recent peaks in late December.
The Minnesota Department of Health has not reported any new cases of measles in the state since the third case this year was reported back in February.
Nationally, however, the CDC is reporting 24 new cases of the highly infectious disease since just two weeks ago, bringing the yearly total to 121 and already tying 2024 with 2022 as the highest year of U.S. measles infection since 2019, when 1,274 cases were identified.
This months COVID-19 vaccination data update, released by the Minnesota Department of Health on Thursday, shows that only three percent of those most vulnerable to hospitalization due to COVID-19, those age 65 or older, are up to date on their COVID-19 vaccinations.
This is an increase of two percentage points from last month, when the vaccination data first reflected a new definition of up to date, factoring in the CDCs latest recommendation that older adults (and those with compromised immune systems) seek a second dose of the newest COVID-19 vaccine formula.
COVID-19 levels in Minnesota wastewater increased 15 percent statewide over the prior week, as of April 10, according to the latest data from the University of Minnesotas on-going Wastewater Surveillance Study.
Recent increases in statewide wastewater levels reverse the decline we had seen since mid-March, but the current level is still a 10 percent decrease from the statewide level recorded one month ago.
Over the last two weeks, the studys South Central and South West regions have seen the largest increases in wastewater levels.
As of April 3, the south central region had a weekly increase of 141 percent, and the south west region had a weekly increase of 86 percent. Those increases were followed by upticks of 59 and 60 percent, respectively.
Looking back four weeks, the north west region had an increase of 111 percent and COVID levels increased in the south west region by 103 percent. Both regions, however, have seen longer-term decreases.
While these recent increases in COVID-19 as measured in wastewater are still relatively minor, it is worthwhile to keep watching.
Dr. Eric Topol, founder and director of Scripps Research Triangle Institute, acknowledges in his most recent Substack article that newly arriving variants have some researchers forecasting an uptick in COVID-19 activity in coming months.
He does not think there is a high risk in the short term, but does conclude with the reminder, High-risk people should continue to take precautions, keeping up with boosters, and all forms of protection.
FILE -{ }Top-line estimates of COVID-19 aid fraud are now at $1 trillion, according to LexisNexis Risk Management, making it the largest public fraud in history. (TND){p}{/p}
WASHINGTON (TND)
Top-line estimates of COVID-19 aid fraud are now at $1 trillion, according to LexisNexis Risk Management, making it the largest public fraud in history.
Top-line%20estimates%20of%20COVID-19%20aid%20fraud%20are%20now%20at%20$1%20trillion,%20according%20to%20LexisNexis%20Risk%20Management,%20making%20it%20the%20largest%20public%20fraud%20in%20history.%20(TND)
CEO of Open the Books Adam Andrezejewski joined The National Desks Jan Jeffcoat to discuss the issue.
Its been four years since the pandemic started and still the federal government hasn't given us a top-line estimate. Their estimate of the total fraud, he said. So that's left it to third-party organizations like LexisNexis to come up with an estimate.
Not much has been done to get it back and prosecute the criminals who stole the money.
Andrzejewski argues that the issue couldve been prevented by the use of facial recognition which the federal government is now working on.
There is a stunning $1 trillion and here's how they come to that. They took the admitted improper payments and the unemployment COVID aid program and the government admits to about $200 billion in that program. It's about $0.22 on every dollar. That was paid out, the government says was fraud and so on. $5 trillion of pandemic aid, Andrzejewski said. That's where LexisNexis gets to $1 trillion. It's such a big number.
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Mayor Scott says 'White-ran' arts orgs are overfunded, unveils COVID diversity grant
by JULIAN BARON | The National Desk
Baltimore Mayor Brandon Scott speaking to a crowd on Tuesday, April 16, 2024. (CharmTV)
BALTIMORE (TND)
Baltimore City Mayor Brandon Scott shared his disappointment Tuesday that too much public money has gone to arts organizations that "just happen to be White-ran."
The comment came during the announcement of a $3.6 million "Diversity in Arts" grant funded by COVID-19 relief dollars. Capital grant recipients include the The National Great Blacks In Wax Museum on North Avenue and the Reginald F. Lewis Museum.
The mayor went on the thank President Biden and Maryland's congressional delegation for helping ensure the availability of federal funding to promote his efforts.
Baltimore%20Mayor%20Brandon%20Scott%20speaking%20to%20a%20crowd%20on%20Tuesday,%20April%2016,%202024.%20(CharmTV)
Grant funding will also be provided to a list of 24 "project" recipients, including $200,000 for Baltimore Center Stage and $100,000 for Creative Nomads, which brings "African drumming" and "mindfulness" to its partners, according to its website.
Mayor Scott is engaged in a tense Democratic primary race against former Mayor Sheila Dixon. Recent polling shows Mayor Scott holds just a three-point lead on Dixon, who has criticized Scott on a myriad of issues, including his alleged shortcomings on public safety.
A spokesperson for Mayor Scott did not immediately respond to a request for comment from The National Desk and local affiliate FOX45 News on Friday.
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West Virginia will not face a clawback of $465 million in COVID-19 money from the federal government, alleviating concerns raised by state lawmakers during the legislative session in March
By
LEAH WILLINGHAM Associated Press
April 19, 2024, 6:43 PM ET
3 min read
CHARLESTON, W.Va. -- Gov. Jim Justice announced Friday that West Virginia will not face a clawback of $465 million in COVID-19 money from the U.S. Department of Education, alleviating concerns raised by state lawmakers during the final days of the legislative session in March.
The Republican governor said in a statement that federal officials approved the state's application for a waiver for the money, which was a portion of the more than a billion dollars in federal aid the state received to help support students during the COVID-19 pandemic.
In order to receive the money, the state needed to keep funding education at the same or a higher level than before the pandemic. In other words, the federal money could supplement existing state investment in education but not replace it.
For federal spending packages passed in 2020 and 2021, that meant a dollar-for-dollar match. For 2022 and 2023, the federal government examined the percentage of each states total budget being spent on education.
Those regulations were waived for West Virginia in 2022. As lawmakers worked to finish the state budget in March at the close of the session, the state had not been approved for a waiver for 2023.
The question threw the states budget process into disarray and caused uncertainty in the days before the 60-day legislative session, with lawmakers saying they would pass a skinny budget and reconvene to address unfinished business in May, when the financial situation is clearer.
Justice said then that his office was negotiating with the federal government and that he expected a positive resolution, citing funds dedicated to school service and teacher pay raises each year since 2018 when school employees went on strike over conditions in schools.
On Friday, he praised the federal government's decision, and he said he was never concerned the waiver wouldnt be approved.
This announcement came as no surprise and was never a real issue, Justice said.
He also said the state has dedicated money to building projects and putting teaching aides in classrooms to improve math and reading skills. The state said it spent $8,464 per K-12 pupil in 2024, compared with $7,510 during Justices first year as governor in 2017, according to documents submitted to the federal government.
But because state spending increased overall from $4.9 billion in 2017 to $6.2 billion in 2023 the percentage marked for education decreased. The key metric eliciting pause from the federal government was an 8% decrease in the education piece of the budget pie from 51% in 2017 to 43% last year.
Justice said the state's investment in education speaks for itself: State leaders also approved $150 million for the state's School Building Authority in the state budget for the fiscal year starting in July.
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