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Researchers from Cleveland Clinic’s Global Center for Pathogen Research & Human Health have developed a promising new COVID-19 vaccine candidate that utilizes nanotechnology and has shown strong efficacy in preclinical disease models.
According to new findings published in mBio, the vaccine produced potent neutralizing antibodies among preclinical models and also prevented infection and disease symptoms in the face of exposure to SARS-CoV-2 (the virus that causes COVID-19). An additional reason for the vaccine candidate’s early appeal is that it may be thermostable, which would make it easier to transport and store than currently authorized COVID-19 vaccines.
“Our vaccine candidate delivers antigens to trigger an immune response via nanoparticles engineered from ferritin–a protein found in almost all living organisms,” said Jae Jung, PhD, director of the Global Center for Human Health & Pathogen Research and co-senior author on the study. “This protein is an attractive biomaterial for vaccine and drug delivery for many reasons, including that it does not require strict temperature control.”
Added Dokyun (Leo) Kim, a graduate student in Dr. Jung’s lab and co-first author on the study, “This would dramatically ease shipping and storage constraints, which are challenges we’re currently experiencing in national distribution efforts. It would also be beneficial for distribution to developing countries.”
Other benefits of the protein nanoparticles include minimizing cellular damage and providing stronger immunity at lower doses than traditional protein subunit vaccines against other viruses, like influenza.
The team’s vaccine uses the ferritin nanoparticles to deliver tiny, weakened fragments from the region of the SARS-CoV-2 spike protein that selectively binds to the human entry point for the virus (this fragment is called the receptor-binding domain, or RBD). When the SARS-CoV-2 RBD binds with the human protein called ACE2 (angiotensin-converting enzyme 2), the virus can enter host cells and begin to replicate.
The researchers tested their vaccine candidate on a ferret model of COVID-19, which reflects the human immune response and disease development better than other preclinical models. Dr. Jung, a foremost authority in virology and virus-induced cancers, previously developed the world’s first COVID-19 ferret model–a discovery that has significantly advanced research into SARS-CoV-2 infection and transmission.
A coronavirus variant called B1525 has become one of the most recent additions to the global variant watch list and has been included in the list of variants under investigation by Public Health England.
Scientists are keeping a watchful eye on this variant because it has several mutations in the gene that makes the spike protein – the part of the virus that latches onto human cells. These changes include the presence of the increasingly well-known mutation called E484K, which allows the virus to partly evade the immune system, and is found in the variants first identified in South Africa (B1351) and Brazil (P1).
While there is no information on what this means for B1525, there is growing evidence that E484K may impact how effective COVID vaccines are. But there is no suggestion so far that B1525 is more transmissible or that it leads to more severe disease.
There are other mutations in B1525 that are also noteworthy, such as Q677H. Scientists have repeatedly detected this change – at least six times in different lineages in the US, suggesting that it gives the virus an advantage, although the nature of any benefit has not been identified yet.
The B1525 variant also has several deletions – where “letters” (G, U, A and C) of the virus’s RNA are missing from its genome. These letters are also missing in B117, the variant first detected in Kent, England. Research by Ravindra Gupta, a clinical microbiologist at the University of Cambridge, found that these deletions may increase infectivity twofold in laboratory experiments.
As with many variants, B1525 appears to have emerged quite recently. The earliest example in the shared global database of coronavirus genomes, called Gisaid, dates from 15 December 2020. It was identified in a person in the UK. And like many variants, B1525 had already travelled the world before it came to global attention. A total of 204 sequences of this variant in Gisaid can be traced to 18 countries as of 20 February 2021.
The DxTerity COVID-19 Saliva at-Home Collection Kit detects the presence of the virus but does not confirm immunity or detect antibodies. DxTerity‘s molecular-based PCR test received approval from the Food and Drug Administration last month. The test differs from the quicker and less expensive antigen tests, which use a nasal swab or throat swab to detect the virus.
A single COVID-19 testing kit is listed for $110, and a 10-pack bundle is available for $1,000.
Test takers must spit into a tube provided by the kit. The saliva sample is then inserted into a plastic bag and packed back into the box for shipment to one of DxTerity‘s laboratories certified by the Clinical Laboratory Improvement Amendments. Customers are also granted prepaid express return shipping with the test and should expect to receive results within 24 to 72 hours of sample receipt at the laboratory. DxTerity’s test is currently the only COVID-19 testing kit on Amazon.
“We have demonstrated the reliability and quality of our COVID-19 testing solution with big business and now we want to expand access to customers at home and small businesses,” said Bob Terbrueggen, founder and CEO of DxTerity, when he first announced the collaboration with the company last month. “Amazon is the perfect partner for expanding access to millions of U.S. customers.”
The test may not be valid for all travel purposes because sample collection is unsupervised, according to the product description. The Centers for Disease Control and Prevention recommends saliva specimens should be collected under supervision.
Amazon joins other retail giants in offering at-home COVID-19 saliva tests. Costco offers both regular and those approved for travel requirements to Hawaii, Bermuda and some other destinations for $129.99 and $139.99, respectively. However, the test has several dozen one-star reviews, with most complaining about delayed shipping and poor customer service from provider AZOVA.
COVID-19 Vaccine AstraZeneca confirms 100% protection against severe disease, hospitalisation and death
The primary analysis of the Phase III clinical trials from the UK, Brazil and South Africa, published as a preprint in The Lancet confirmed COVID-19 Vaccine AstraZeneca is safe and effective at preventing COVID-19, with no severe cases and no hospitalisations, more than 22 days after the first dose.
Results demonstrated vaccine efficacy of 76% (CI: 59% to 86%) after a first dose, with protection maintained to the second dose. With an inter-dose interval of 12 weeks or more, vaccine efficacy increased to 82% (CI: 63%, 92%).
The analysis also showed the potential for the vaccine to reduce asymptomatic transmission of the virus, based on weekly swabs obtained from volunteers in the UK trial. The data showed that PCR positive readings were reduced by 67% (CI: 49%, 78%) after a single dose, and 50% (CI: 38% to 59%) after the two dose regimen, supporting a substantial impact on transmission of the virus.
The primary analysis for efficacy was based on 17,177 participants accruing 332 symptomatic cases from the Phase III UK (COV002), Brazil (COV003) and South Africa (COV005) trials led by Oxford University and AstraZeneca, a further 201 cases than previously reported.
“This primary analysis reconfirms that our vaccine prevents severe disease and keeps people out of hospital. In addition, extending the dosing interval not only boosts the vaccine’s efficacy, but also enables more people to be vaccinated upfront. Together with the new findings on reduced transmission, we believe this vaccine will have a real impact on the pandemic,”said Sir Mene Pangalos, Executive Vice President BioPharmaceuticals R&D.
“These new data provide an important verification of the interim data that has helped regulators such as the MHRA in the UK and elsewhere around the world to grant the vaccine emergency use authorisation. It also helps to support the policy recommendation made by the Joint Committee on Vaccination and Immunisation for a 12-week prime-boost interval, as they look for the optimal approach to roll out, and reassures us that people are protected 22 days after a single dose of the vaccine,” explained Professor Andrew Pollard, Chief Investigator of the Oxford Vaccine Trial, and co-author of the paper.
Data will continue to be analysed and shared with regulators around the world to support their ongoing rolling reviews for emergency supply or conditional approval during the health crisis. AstraZeneca is also seeking Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries.
The vaccine can be stored, transported and handled at normal refrigerated conditions (two-eight degrees Celsius/36-46 degrees Fahrenheit) for at least six months and administered within existing healthcare settings.
Evidence increasingly indicates that male sex is a risk factor for more severe disease and death from COVID-19. Male bias in COVID-19 mortality is observed in nearly all countries with available sex-disaggregated data, and the risk of death in males is ∼1.7 times higher than in females. Aging is strongly associated with higher risk of death in both sexes, but at all ages above 30 years, males have a significantly higher mortality risk, rendering older males the most vulnerable group. Sex differences are intertwined with differences in gender roles socially and with behavioral factors, which also influence COVID-19 incidence and outcomes. However, there are also possible biological mechanisms of male sex bias that affect the severity of COVID-19, particularly with respect to immune responses.
Sex differences beyond sex organs are present across species and extend to physiological systems, including the immune system. Infection by different pathogens results in differential immune responses and disease outcomes by sex, and although the pattern depends on age and other host factors, male sex is more often associated with lower immune responses and higher susceptibility and/or vulnerability to infections in animals. This is generally also the case in humans: Male patients have higher viral loads for hepatitis B virus (HBV) and HIV. Conversely, females generally mount a more robust immune response to vaccines, such as influenza vaccines. However, the heightened immune responses in females can also lead to detrimental immunopathology in infections.
The physiological response to virus infection is initiated when virus replication is detected by pattern recognition receptors. This leads to two antiviral programs by the infected cells.
Scientists in the UK have just recruited the first participants in the world to be part of a new long-acting antibody study. If the treatment is effective, it could give those who have already been exposed to SARS-CoV-2 protection from developing COVID-19.
“We know that this antibody combination can neutralise the virus,” explains University College London Hospitals (UCLH) virologist Catherine Houlihan. “So we hope to find that giving this treatment via injection can lead to immediate protection against the development of COVID-19 in people who have been exposed – when it would be too late to offer a vaccine.”
This might not be the first antibody treatment for COVID-19 you’ve heard of. Outgoing US President Donald Trump was given monoclonal antibodies when he came down with the disease, and in the US two different antibody treatments – casirivimab and imdevimab – received emergency approval back in November. But those antibody treatments are given to patients with mild or moderate COVID-19, who risk progressing to a severe version of the disease.
“In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalisation or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo,” the FDA explained in a press statement when the drugs were approved. This new antibody therapy, called AZD7442 and developed by UCLH and AstraZeneca, is a little different. AZD7442 is a combination of two monoclonal antibodies AZD8895 and AZD1061, which both target the receptor binding domain of the SARS-CoV-2 spike protein.
“By targeting this region of the virus’s spike protein, antibodies can block the virus’s attachment to human cells, and, therefore, is expected to block infection,” the team wrote on the US ClinicalTrials.gov website. “Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector functionin order to decrease the potential risk of antibody-dependent enhancement of disease.”
Antibodies are little Y-shaped proteins that lock on to a particular section – called an antigen – of a virus, bacterium or other pathogen, and either ‘tag‘ it to be attacked by the immune system, or directly block the pathogen from invading our cells. Normal antibodies are produced by your body after an infection, while monoclonal antibodies are cloned in a lab and can be injected into a person already infected, to give the immune system a hand in the fight.
The researchers are hoping that AZD7442 – which is just starting the Storm Chaser study (the name for its phase 3 trial) – provides protection for those that have been exposed to the virus but do not yet have symptoms. Effectively, they’re trying to stop COVID-19 happening in the first place. “If you are dealing with outbreaks in settings such as care homes, or if you have got patients who are particularly at risk of getting severe COVID, such as the elderly, then this could well save a lot of lives,” said University of East Anglia infectious disease expert Paul Hunter.
For epidemiologists, the COVID-19 pandemic has greatly intensified their long-standing nightmare about another virus: the emergence of a new and deadly strain of flu. A universal flu vaccine, effective against any strain of the influenza virus that can infect humans, could protect us from this peril, but progress has been slow. A novel concept for one universal vaccine candidate has now passed its first test in a small clinical trial, its developers report today in Nature Medicine.
Seasonal flu vaccines induce antibodies against the “head” (slate) of the influenza surface protein hemagglutinin, but a new universal vaccine triggers antibodies (fragments of them shown in gray) that bind to the stalk (light blue) portion
“This is an important paper,” says Aubree Gordon, an epidemiologist at the University of Michigan School of Public Health who studies influenza transmission and vaccines.
The influenza virus rapidly accumulates mutations and easily “reassorts,” or swaps, genes between strains, creating variants that can dodge any past immunity people had acquired naturally or from vaccines. That’s why a new flu vaccine must be developed each year. Existing flu vaccines contain weakened or inactivated influenza viruses with a mix of hemagglutinins (HAs), the proteins that stud their surfaces. These vaccines primarily aim to trigger antibody responses against HA’s top part, or head. Genetic changes in flu viruses rarely alter most of the head. But a small part of the head does reassort, or mutate, frequently, which allows new viral strains to dodge any immune memory and forces flu vaccinemakers to prepare new formulations each year, with updated HAs.
In the trial, 51 participants received the various vaccines and their antibodies were compared with those of 15 people who received placebos. A single shot of vaccine with chimeric HA inactivated viruses, the researchers report, “induced remarkably high antistalk antibody titers.”
As the COVID-19 pandemic continues to spread across the world, testing remains a key strategy for tracking and containing the virus. Bioengineering graduate student, Maha Alafeef, has co-developed a rapid, ultrasensitive test using a paper-based electrochemical sensor that can detect the presence of the virus in less than five minutes. The team led by professor Dipanjan Pan reported their findings in ACS Nano.
“Currently, we are experiencing a once-in-a-century life-changing event,” said Alafeef. “We are responding to this global need from a holistic approach by developing multidisciplinary tools for early detection and diagnosis and treatment for SARS-CoV-2.”
There are two broad categories of COVID-19 tests on the market. The first category uses reverse transcriptase real-time polymerase chain reaction (RT-PCR) and nucleic acid hybridization strategies to identify viral RNA. Current FDA-approved diagnostic tests use this technique. Some drawbacks include the amount of time it takes to complete the test, the need for specialized personnel and the availability of equipment and reagents. The second category of tests focuses on the detection of antibodies. However, there could be a delay of a few days to a few weeks after a person has been exposed to the virus for them to produce detectable antibodies.
n recent years, researchers have had some success with creating point-of-care biosensors using 2D nanomaterials such as graphene to detect diseases. The main advantages of graphene-based biosensors are their sensitivity, low cost of production and rapid detection turnaround. “The discovery of graphene opened up a new era of sensor development due to its properties. Graphene exhibits unique mechanical and electrochemical properties that make it ideal for the development of sensitive electrochemical sensors,” said Alafeef. The team created a graphene-based electrochemical biosensor with an electrical read-out setup to selectively detect the presence of SARS-CoV-2 genetic material.
There are two components to this biosensor: a platform to measure an electrical read-out and probes to detect the presence of viral RNA. To create the platform, researchers first coated filter paper with a layer of graphene nanoplatelets to create a conductive film. Then, they placed a gold electrode with a predefined design on top of the graphene as a contact pad for electrical readout. Both gold and graphene have high sensitivity and conductivity which makes this platform ultrasensitive to detect changes in electrical signals.
Denmark set off alarm bells this week with its announcement that it is culling the nation’s entire mink herd — the largest in the world — to stop spread of the SARS-CoV-2 virus in the prized fur species because of potentially dangerous mutations. Inter-species jumps of viruses make scientists nervous — as do suggestions of potentially significant mutations that result from those jumps. In this case, Danish authorities say they’ve found some genetic changes that might undermine the effectiveness of Covid-19 vaccines currently in development. But is this latest twist in the Covid-19 saga reason to be deeply concerned?
“This hits all the scary buttons,” noted Carl Bergstrom, an evolutionary biologist at the University of Washington. But Bergstrom and others argued that while the virus’s penchant for infecting mink bears watching, it isn’t likely to lead to a nightmare strain that is more effective at infecting peoplethan the current human virus.
“I don’t believe that a strain which gets adapted to mink poses a higher risk to humans,” said Francois Balloux, director of University College London’s Genetics Institute. “We can never rule out anything, but in principle it shouldn’t. It should definitely not increase transmission. I don’t see any good reason why it should make the virus more severe,” he said.
Let’s take a look at what’s known about the Danish situation, why inter-species jumps make scientists nervous, whether the mutations are likely to affect vaccine effectiveness, and why Balloux thinks this situation is “fantastically interesting.” Denmark is the world’s largest producer of mink — by some estimates 40%. Unfortunately, mink are susceptible to the SARS-2 virus, a fact that came to light in April when the Netherlands reported outbreaks on mink farms there. Infected humans who work in the farms transmit the virus to captive minks, which are housed in close quarters ideal for rapid transmission from mink to mink.
Occasionally, the mink infect people — a phenomenon recorded in both the Netherlands and in Denmark. In a statement, the Danish Ministry of Environment and Food said the country would cull its entire herd — estimated to be about 17 million animals — after finding mutations in the viruses from the mink that it believes would allow those viruses to evade the immune protection generated by Covid-19 vaccines.
Tiny artificial lungs grown in a lab from adult stem cells have allowed scientists to watch how coronavirus infects the lungs in a new ‘major breakthrough‘. Researchers from Duke University and Cambridge University produced artificial lungs in two independent and separate studies to examine the spread of Covid-19. The ‘living lung‘ models minimic the tiny air sacs that take up the oxygen we breathe, known to be where most serious lung damage from the deadly virus takes place. Having access to the models to test the spread of SAS-CoV-2, the virus responsible for Covid-19, will allow researchers to test potential drugs and gain a better understanding of why some people suffer from the disease worse than others.
In both studies the 3D min-lung models were grown from stem cells that repair the deepest portions of the lungs when SARS-CoV-2 attacks – known as alveolar cells. To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. The main target tissues of SARS-CoV-2, especially in patients that develop pneumonia, appear to be alveoli, according to the Cambridge team. They extracted the alveoli cells from donated tissue and reprogrammed them back to their earlier ‘stem cell‘ stage and forced them to grow into self-organising alveolar-like 3D structures that mimic the behaviour of key lung tissue. Dr Joo-Hyeon Lee, co-senior author of the Cambridge paper, said we still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease.
Representative image of three – dimensional human lung alveolar organoid produced by the Cambridge and Korean researchers to better understand SARS-CoV-2
‘Our approach has allowed us to grow 3D models of key lung tissue – in a sense, “mini-lungs” – in the lab and study what happens when they become infected.’
Duke researchers took a similar approach. The team, led by Duke cell biologist Purushothama Rao Tata, say their model will allow for hundreds of experiments to be run simultaneously to screen for new drug candidates. ‘This is a versatile model system that allows us to study not only SARS-CoV-2, but any respiratory virus that targets these cells, including influenza,‘ Tata said.
Both teams infected models with a strain of SARS-CoV-2 to better understand who the virus spreads and what happens in the lung cells in response to the disease. The Cambridge team worked with researchers from South Korea to take a sample of the virus from a patient who was infected in January after travelling to Wuhan. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.
When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue, explained the Cambridge research team. Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection. Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.