It looks like you're using an Ad Blocker.
Please white-list or disable AboveTopSecret.com in your ad-blocking tool.
Thank you.
Some features of ATS will be disabled while you continue to use an ad-blocker.
Coronavirus strains are maintained in quasi-species pools circulating in bat populations. (a,b) Traditional SARS-CoV emergence theories posit that host-range mutants (red circle) represent random and rare occurrences that permit infection of alternative hosts.
The secondary-host paradigm (a) argues that a nonhuman host is infected by a bat progenitor virus and, through adaptation, facilitates transmission to humans; subsequent replication in humans leads to the epidemic viral strain.
The direct paradigm (b) suggests that transmission occurs between bats and humans without the requirement of an intermediate host; selection then occurs in the human population with closely related viruses replicating in a secondary host, permitting continued viral persistence and adaptation in both.
(c) The data from chimeric SARS-like viruses argue that the quasi-species pools maintain multiple viruses capable of infecting human cells without the need for mutations (red circles). Although adaptations in secondary or human hosts may be required for epidemic emergence, if SHC014 spike–containing viruses recombined with virulent CoV backbones (circles with green outlines), then epidemic disease may be the result in humans. Existing data support elements of all three paradigms.
RESEARCH ARTICLE
MICROBIOLOGY
On the origin and continuing evolution of SARS-CoV-2
ABSTRACT
The SARS-CoV-2 epidemic started in late December 2019 in Wuhan, China, and has since
impacted a large portion of China and raised major global concern. Herein, we investigated
the extent of molecular divergence between SARS-CoV-2 and other related coronaviruses.
Although we found only 4% variability in genomic nucleotides between SARS-CoV-2 and a bat SARS-related coronavirus (SARSr-CoV; RaTG13), the difference at neutral sites was 17%, suggesting the divergence between the two viruses is much larger than previously estimated.
Our results suggest that the development of new variations in functional sites in the receptor-binding domain (RBD) of the spike seen in SARS-CoV-2 and viruses from pangolin SARSr-CoVs are likely caused by mutations and natural selection besides recombination.
Population genetic analyses of 103 SARS-CoV-2 genomes indicated that these viruses evolved into two major types (designated L and S), that are well defined by two different SNPs that show nearly complete linkage across the viral strains sequenced to date.
Although the L type (~70%) is more prevalent than the S type (~30%), the S type was found to be the ancestral version. Whereas the L type was more prevalent in the early stages of the outbreak in Wuhan, the frequency of the L type decreased after early January 2020.
Human intervention may have placed more severe selective pressure on the L type, which might be
more aggressive and spread more quickly. On the other hand, the S type, which is evolutionarily older and less aggressive, might have increased in relative frequency due to relatively weaker selective pressure.
These findings strongly support an urgent need for
further immediate, comprehensive studies that combine genomic data, epidemiological data,
and chart records of the clinical symptoms of patients with coronavirus disease 2019
(COVID-19).
Keywords: SARS-CoV-2, virus, molecular evolution, population genetics
A replication-incompetent Rift Valley fever vaccine: Chimeric virus-like particles protect mice and rats against lethal challenge
Robert B. Mandell, Ramesh Koukuntla, [...], and Ramon Flick
Abstract
Virus-like particles (VLPs) present viral antigens in a native conformation and are effectively recognized by the immune system and therefore are considered as suitable and safe vaccine candidates against many viral diseases.
Here we demonstrate that chimeric VLPs containing Rift Valley fever virus (RVFV) glycoproteins GN and GC, nucleoprotein N and the gag protein of Moloney murine leukemia virus represent an effective vaccine candidate against Rift Valley fever, a deadly disease in humans and livestock.
RVFV is a member of the Bunyaviridae family, which includes more than 300 viruses grouped into five genera
(Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus, and Tospovirus).
Bunyaviruses are enveloped viruses with a tripartite, single-stranded RNA genome of negative and sometimes ambisense polarity
(Elliott, 1996, Elliott et al., 1991, Schmaljohn and Hooper, 2001).
These promising attempts to generate VLP-based vaccines against many different animal and human pathogens encouraged us to evaluate RVF VLPs as vaccine candidates against RVFV. Here we describe the generation of chimeric RVF VLPs, a novel concept for bunyaviruses, the optimization of VLP production and their successful use as vaccine candidates
RVFV is a prototype of emerging/re-emerging pathogens and is classified as a Category A High Priority Pathogen by the National Institute for Allergy and Infectious Diseases (NIAID)
link from study
, is on the Center for Disease Control (CDC) Bioterrorism Agents
link from study
and is also classified as a Department of Health and Human Services (HHS), United States Department of Agriculture (USDA) overlap select agent (USDA, 2005).
A formalin-inactivated RVFV vaccine, TSI-GSD-200, has been developed; however, it is not licensed and not commercially available (Pittman et al., 1999). TSI-GSD-200 is only provided to veterinarians working in endemic areas, high containment laboratory workers and others at high risk for contracting RVFV (Pittman et al., 1999). Unfortunately, th
Unfortunately, this vaccine is (i) expensive, (ii) difficult to produce, (iii) in short supply, (iv) requires larger dose relative to an attenuated vaccine and three initial inoculations followed by a 6-month booster (v) and requires continued annual boosters to maintain protective immunity (Frank-Peterside, 2000, Kark et al., 1982, Kark et al., 1985, Niklasson et al., 1985).
The use of virus-like particles (VLPs) is a promising approach for the development of a safe and efficient RVFV vaccine.
Expression of structural proteins of many non-enveloped and enveloped viruses leads to the formation of VLPs (Garcea and Gissmann, 2004, Grgacic and Anderson, 2006a, Grgacic and Anderson, 2006b, Noad and Roy, 2003).
Such VLPs frequently exhibit a morphology very similar to that of wild-type (wt) viruses (Johnson and Chiu, 2000).
Developing the vaccine
Since clinical trials are always the final stage in demonstrating that a vaccine is safe to use in humans, my colleagues and I started by using a technique that has extensively been shown to be safe for human vaccination against a host of diseases, including influenza, malaria, and Ebola.
The technique uses a chimpanzee respiratory (adenovirus) virus to expose individuals to just a small part of the Rift Valley Fever virus – enough for the immune system to recognise a future infection, but not enough to cause an infection in itself.
As this incomplete virus is markedly different to the full virus, the technique allows animal health practitioners to accurately test whether an animal is vaccinated, or an infected but symptomless carrier.
This is crucial during outbreaks, as false positives can lead to unnecessary culling of livestock, increased costs, and reduced cooperation of farmers in the fight to control the disease
Rapid development of vaccines against emerging pathogens: The replication-deficient simian adenovirus platform technology
Upon coexpression of M, S, and E by using the vaccinia virus T7 system (20), virus-like particles (VLPs) containing these three viral membrane proteins were assembled in and released from cells.
However, only M and E were required for particle formation. The S protein was dispensable but was incorporated when present (6, 73).
The envelope particles produced by this system were shown to form a homogeneous population of spherical particles indistinguishable from authentic virions in size and shape (73).
One of our main interests is to understand the process of coronavirus assembly.
We are particularly interested in the interactions and the mechanisms that drive the formation of the viral particles. With the VLP assembly system, we have developed an ideal tool for the study of coronavirus envelope formation and for the analysis of the interactions between the viral membrane proteins in molecular detail
The past 48 hours or so have seen a huge revelation: COVID-19 causes prolonged and progressive hypoxia (starving your body of oxygen) by binding to the heme groups in hemoglobin in your red blood cells
. People are simply desaturating (losing o2 in their blood), and that’s what eventually leads to organ failures that kill them, not any form of ARDS or pneumonia. All the damage to the lungs you see in CT scans are from the release of oxidative iron from the hemes, this overwhelms the natural defenses against pulmonary oxidative stress and causes that nice, always-bilateral ground glass opacity in the lungs.
Patients returning for re-hospitalization days or weeks after recovery suffering from apparent delayed post-hypoxic leukoencephalopathy strengthen the notion COVID-19 patients are suffering from hypoxia despite no signs of respiratory ‘tire out’ or fatigue.
A formalin-inactivated RVFV vaccine, TSI-GSD-200, has been developed; however, it is not licensed and not commercially available (Pittman et al., 1999). TSI-GSD-200 is only provided to veterinarians working in endemic areas, high containment laboratory workers and others at high risk for contracting RVFV (Pittman et al., 1999). Unfortunately, th
Unfortunately, this vaccine is (i) expensive, (ii) difficult to produce, (iii) in short supply, (iv) requires larger dose relative to an attenuated vaccine and three initial inoculations followed by a 6-month booster (v) and requires continued annual boosters to maintain protective immunity (Frank-Peterside, 2000, Kark et al., 1982, Kark et al., 1985, Niklasson et al., 1985).
The use of virus-like particles (VLPs) is a promising approach for the development of a safe and efficient RVFV vaccine.
Expression of structural proteins of many non-enveloped and enveloped viruses leads to the formation of VLPs (Garcea and Gissmann, 2004, Grgacic and Anderson, 2006a, Grgacic and Anderson, 2006b, Noad and Roy, 2003).
Such VLPs frequently exhibit a morphology very similar to that of wild-type (wt) viruses (Johnson and Chiu, 2000).
Medicago Announces Production of a Viable Vaccine Candidate for COVID-19
Published: Mar 12, 2020
The biopharma successfully produced Virus-Like Particles (VLP) of the coronavirus in just 20 days using proprietary plant-based technology
Medicago’s platform can produce both vaccine and antibody candidates against COVID-19 disease
The company uses a proprietary plant-based technology to develop protein-based therapeutics. Unlike traditional vaccination development, Medicago does not use animal products or live viruses to create its products. Instead, it uses Virus-Like Particles (VLPs) that mimic the shape and dimensions of a virus, which allows the body to recognize them and create an immune response in a non-infectious way.
QUEBEC CITY, Quebec--(BUSINESS WIRE)--Medicago, Inc., a biopharmaceutical company headquartered in Quebec City, announced today that they have successfully produced a Virus-Like Particle (VLP) of the coronavirus just 20 days after obtaining the SARS-CoV-2 (virus causing the COVID-19 disease) gene.
Medicago is also using its technology platform to develop antibodies against SARS-CoV-2 in collaboration with the Laval University’s Infectious Disease Research Centre headed by Dr. Gary Kobinger, who helped develop a vaccine and treatment for Ebola. These SARS-CoV-2 antibodies could potentially be used to treat people infected by the virus. This research is being funded, in part, by the Canadian Institutes for Health Research (CIHR).
Delivery of self-amplifying RNA vaccines in in vitro reconstituted virus-like particles
Many mRNA-based vaccines have been investigated for their specific potential to activate dendritic cells (DCs), the highly-specialized antigen-presenting cells of the immune system that play a key role in inducing effective CD4+ and CD8+ T-cell responses. In this paper we report a new vaccine/gene delivery platform that demonstrates the benefits of using a self-amplifying (“replicon”) mRNA that is protected in a viral-protein capsid.
In vitro evolution of enhanced RNA replicons for immunotherapy
Scientific Reports volume 9, Article number: 6932 (2019) Cite this article
3619 Accesses
2 Altmetric
Metricsdetails
Abstract
Self-replicating (replicon) RNA is a promising new platform for gene therapy, but applications are still limited by short persistence of expression in most cell types and low levels of transgene expression in vivo.
To address these shortcomings, we developed an in vitro evolution strategy and identified six mutations in nonstructural proteins (nsPs) of Venezuelan equine encephalitis (VEE) replicon that promoted subgenome expression in cells.
.... a self replicating lipid structure with imbeded Viron RNA...
.... harvesting from bacteria....
RT-PCR is the workhorse of viral diagnosis and has been invaluable in COVID-19 case confirmation and isolation guidance.
However, while fast and sensitive, PCR suffers from some inherent drawbacks that limit it to diagnosis during the acute phase of infection.
To better understand the transmission dynamics of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and develop effective countermeasures against it, antigen- and antibody-based immunoassays will be essential.
In this blog, we explain the key differences between PCR and immunoassays for COVID-19 diagnosis, and present our growing pipeline of coronavirus reagents for the development of highly accurate diagnostic kits
However, the biggest advantage of immunoassays is their ability to detect past infections.
Once a patient has recovered from COVID-19 and virus is cleared from the body, viral RNA is no longer available for detection in the respiratory tract, leaving only a short window during the acute stage of infection in which SARS-CoV-2 can be detected.
While this works well for the diagnosis of ongoing infections, it gives no indication of whether a patient has had the infection historically, and what their immune status is (i.e. if they are immune to COVID-19 or still susceptible to infection).
Unlike RNA, antibodies are long-lasting and can persist in the bloodstream for many years after infection. As such, immunoassays enable us to identify patients that have had COVID-19, retrospectively.
The type of antibody and its relative levels could also be used to indicate the stage of infection and estimate time since exposure for contact tracing.
However, antibody tests have their limitations too. As immunological data continues to emerge, it is becoming apparent that the body’s antibody response to COVID-19 is slow – considerably slower than we might expect.
While data at this point is still limited, it appears that the initial IgM antibody response doesn’t peak until ~9 days after initial infection and the IgG antibody response doesn’t peak until day ~11 [8][9].
As a disease, COVID-19 shows considerable symptomatic variation. Individuals may present with no symptoms at all, while some may have a mild cough and fever, and an unlucky few may experience severe pneumonia and respiratory failure [1]. To complicate matters, COVID-19’s most common symptoms strongly overlap with those presented by other co-circulating respiratory illnesses: