Feeds:
Posts
Comments

Archive for the ‘COVID-19’ Category


Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis

Author: Meg Baker, PhD

 

N-Glycosylation and COVID19

Glycobiology

N-linked glycosylation (NLG) is a complex biosynthetic process that regulates proper folding of proteins through and intracellular transport of proteins to the secretory pathway. This co- and post-translational modification occurs by a series of enzymatic reactions, which results in the transfer of a core glycan from the lipid carrier to a protein substrate and the possibility for further remodeling of the glycan. The enzymes are located in the cytosolic and the luminal side of the ER membrane. The study of NLG and related effects of glycans is called glycobiology.

NLG takes place at sites specified in the protein sequence itself. N-linked oligosaccharides are attached via a GlcNAc linked to the side chain nitrogen of Asn found in the consensus sequence NXT/S (X ≠ P) known as the ‘glycosylation sequon’. Formation of a precursor branched carbohydrate chain, the lipid-linked oligosaccharide (LLO) structure, takes place in the endoplasmic reticulum. The LLO consists of a Glc3Man9GlcNAc2 molecule (three glucose, nine mannose, and two N-acetylglucosamine sugars) linked to a dolichol pyrophosphate. The enzyme oligosaccharyltransferase then moves it to an Asn in the polypeptide.

The removal of the three glucose sugars from the new N-linked glycan signals that the structure is ready for transport to the Golgi where mannose is removed yielding a carbohydrate chain containing five–nine mannose sugars. Further removal of mannose residues can lead to the core structure containing three mannose and two N-acetylglucosamine residues, which may then be elongated with a variety of different monosaccharides including galactose, N-acetylglucosamine (aka NAG or GlcNac), N-acetylgalactosamine, fucose, and sialic acid, many of which can also exist in sulfated form.

The enzymes involved in this essential process are evolutionarily conserved. However, the genes and their specific functions, have evolved uniquely for each selected organism. Therefore, each organism and each individual cell, depending on genetic background and influenced by nutritional and such things as disease status, will decorate secreted proteins in a unique manner.

The advent of biologic medicines (protein based therapeutics) presents the challenge of making sure that the primary protein sequence is specified but also that the manufacture of the protein – typically in a eukaryotic cell host capable of glycosylation – will take place with some degree of reproducibility. The large number of monoclonal antibody therapeutics absolutely require glycosylation for proper structural integrity but are generally made in rodent or other nonhuman cells. Thus, the term “biosimilar” rather than generic is the term being used to connote the variation which will necessarily result due to different manufacturing process even of the same genetic sequence.

 

Viral Glycoproteins

It should be obvious that the viral genome is not large enough to encompass the collection of enzymes required for glycosylation of any type and viral glycoproteins are formed by the host cell in which the virus is replicating. The study of the impact of glycan content and composition on viral infectivity and, more importantly, vaccine development is a subject which has been late to be addressed largely due to the technical difficulty and lack of methods for analyzing protein glycan composition. However, progress is being made. Raska et al. (J Biol Chem 2010 Jul 2; 285(27): 20860–20869. Glycosylation Patterns of HIV-1 gp120 Depend on the Type of Expressing Cells and Affect Antibody Recognition)  was able to perform such an analysis on the HIV-1 virus albeit almost 30 years after its emergence in human populations. The findings of this study may explain, in part, the difficulty in developing a vaccine against HIV.

 

SARS-CoV-2 spike protein (P0DTC2 uniprot.org) – as so popularly depicted – is a trimer poking out of the lipid coat that protects it’s genome. The spike protein, like gp120 in HIV, is the point of contact with the human cell ACE2 receptor it uses to gain entry. The spike protein contains two functional external subunits, designated S1 and S2. S1 separated by a furin cleavage site from S2, forms the apex of the trimeric spike structure, is responsible for attachment to the ACE2 receptor. S2 is responsible for fusion to the cell membrane. (PDB: 6VSB shows a 3D image of the protein structure, including glycan positions). There are 22 glycans per polypeptide or 66 per spike trimer protein (Watanabe et al. 2021 Site-specific glycan analysis of the SARS-CoV-2 spike. Science 17 Jul 2020:Vol. 369, Issue 6501, pp. 330-333 ).

Although shielding of receptor binding sites by glycans is a common feature of viral glycoproteins, Watanabe (ibid) note the low mutation rate of SARS-CoV-2 and that as yet, there have been no observed mutations to N-linked glycosylation sites.

The development of a vaccine or individual antibodies or antibody cocktails with neutralizing (viral entry blocking or virocidal activity) is also influenced by the presence or absence of glycans and how well they target the natural conformation of the spike protein. Papageorgiou et al. The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies. Cells 2020 Oct 22;9(11):2343. doi: 10.3390/cells9112343. SARS-CoV-2 Spike – Stanford Coronavirus Antiviral Research Database It should be noted that the mRNA vaccines (or other nucleic acid formats) may obviate these analysis because the immune response is to a spike protein made and glycosylated in the human host’s own body and therefore will be customized to each individual in some sense.

Glycans may themselves represent drug targets. Casolino et al. suggest an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition (Casolino et al. 2020. Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein ACS Cent Sci. 2020 Oct 28; 6(10): 1722–1734),

 

COVID19 Variants

SARS-CoV-2 lineage B.1.1.7 likely arose in the United Kingdom in September 2019 and is characterized by 17 mutations, including 8 in the spike protein (Rambaut et al., 2020). Other lineages, including B.1.351, initially detected in South Africa (Tegally et al., 2020), and most recently lineage P.1, first documented in the Amazonia region of Brazil (Faria et al., 2020), carry additional mutations. All three lineages are characterised by a N501Y (Asn to Tyr) mutation in the spike protein, while both B.1.351 and P.1 also carry the spike mutation E484K. In addition, both B.1.1.7 and B.1.351, but not P.1, have acquired short sequence deletions in the spike protein. N501Y is in the receptor-binding domain (RBD) but is not a glycosylation site.

Reference

See the CDC Emerging SARS-CoV-2 Variants | CDC

 

Read Full Post »


Need for Global Response to SARS-CoV-2 Viral Variants

Reporter: Aviva Lev-Ari, PhD, RN

NIH experts discuss SARS-CoV-2 viral variants

Editorial emphasizes need for global response.

 

The rise of several significant variants of SARS-CoV-2, the virus that causes COVID-19, has attracted the attention of health and science experts worldwide. In an editorial published today in JAMA: The Journal of the American Medical Association, experts from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, outline how these variants have arisen, concerns about whether vaccines currently authorized for use will continue to protect against new variants, and the need for a global approach to fighting SARS-CoV-2 as it spreads and acquires additional mutations.

The article was written by NIAID Director Anthony S. Fauci, M.D.; John R. Mascola, M.D., director of NIAID’s Vaccine Research Center (VRC); and Barney S. Graham, M.D., Ph.D., deputy director of NIAID’s VRC.

The authors note that the overlapping discovery of several SARS-CoV-2 variants has led to confusing terms used to name them. The appearance of SARS-CoV-2 variants is so recent that the World Health Organization and other groups are still developing appropriate nomenclature for the different variants.

Numerous SARS-CoV-2 variants have emerged over the last several months. The authors note that the variants known as B.1.1.7 (first identified in the United Kingdom) and B.1.351 (first identified in South Africa) concern scientists because of emerging data suggesting their increased transmissibility.

Variants can carry several different mutations, but changes in the spike protein of the virus, used to enter cells and infect them, are especially concerning. Changes to this protein may cause a vaccine to be less effective against a particular variant. The authors note that the B.1.351 variant may be partially or fully resistant to certain SARS-CoV-2 monoclonal antibodies currently authorized for use as therapeutics in the United States.

The recognition of all new variants, including a novel emergent strain (20C/S:452R) in California, requires systematic evaluation, according to the authors. The rise of these variants is a reminder that as long as SARS-CoV-2 continues to spread, it has the potential to evolve into new variants, the authors stress. Therefore, the fight against SARS-CoV-2 and COVID-19 will require robust surveillance, tracking, and vaccine deployment worldwide.

The authors also note the need for a pan-coronavirus vaccine. Once researchers know more about how the virus changes as it spreads, it may be possible to develop a vaccine that protects against most or all variants. While similar research programs are already in place for other diseases, such as influenza, the changing nature of SARS-CoV-2 indicates that they will be necessary for this virus.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-experts-discuss-sars-cov-2-viral-variants

 

Editorial
February 11, 2021

SARS-CoV-2 Viral Variants—Tackling a Moving Target

JAMAPublished online February 11, 2021. doi:10.1001/jama.2021.2088

In this issue of JAMA, Zhang and colleagues1 report the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in Southern California that accounted for 44% (37 of 85) of samples collected and studied in January 2021. The terminology of viral variation can be confusing because the media and even scientific communications often use the terms variantstrain, and lineage interchangeably. The terminology reflects the basic replication biology of RNA viruses that results in the introduction of mutations throughout the viral genome. When specific mutations, or sets of mutations, are selected through numerous rounds of viral replication, a new variant can emerge. If the sequence variation produces a virus with distinctly different phenotypic characteristics, the variant is co-termed a strain. When through genetic sequencing and phylogenetic analysis a new variant is detected as a distinct branch on a phylogenetic tree, a new lineage is born.

New variants become predominant through a process of evolutionary selection that is not well understood. Once identified, several questions arise regarding the potential clinical consequences of a new variant: Is it more readily transmitted; is it more virulent or pathogenic; and can it evade immunity induced by vaccination or prior infection? For these reasons, new viral variants are studied, leading to the terms variant under investigation or variant of concern.

To communicate effectively about new SARS-CoV-2 variants, a common nomenclature is needed, which like the virus, is evolving. Fortunately, the World Health Organization (WHO) is working on a systematic nomenclature that does not require a geographic reference, since viral variants can spread rapidly and globally. Currently, the terminology is overlapping, as reflected in the report by Zhang et al.1 This new variant (CAL.20C) is termed lineage 20C/S:452R in Nextstrain nomenclature,2 referring to the parent clade 20C and spike alteration 452R. Similarly, using a distinct PANGO nomenclature,3 this variant derives from lineage B (B.1.429 and B.1.427). While alterations in any viral genes can have implications for pathogenesis, those arising in the spike protein that mediates viral entry into host cells and is a key target of vaccines and monoclonal antibodies are of particular interest. The new variant, identified in California and termed 20C/S:452R, has 3 amino acid changes in the spike protein, represented using the single-letter amino acid nomenclature: S13I, W152C, and L452R. To interpret this new set of alterations, it is useful to review what is known about recent variants that have become predominant in other regions of the world.

During the early phase of the SARS-CoV-2 pandemic, there were only modest levels of genetic evolution; however, more recent information indicates that even a single amino acid substitution can have biological implications. Starting in April 2020, the original SARS-CoV-2 strain was replaced in many regions of the world by a variant called D614G, which was subsequently shown to increase the efficiency of viral replication in humans and was more transmissible in animal models.46 The D614G strain appears to position its receptor binding domain to interact more efficiently with the ACE2 receptor, and it is associated with higher nasopharyngeal viral RNA loads, which may explain its rise to dominance.

In October 2020, sequencing analysis in the UK detected an emerging variant, later termed B.1.1.7 or 20I/501Y.V1, which is now present and rapidly spreading in many countries.7 B.1.1.7 contains 8 mutations in the spike protein and maintains the D614G mutation. One of these, N501Y, appears to further increase the spike protein interaction with the ACE2 receptor. Epidemiological studies indicate that the B.1.1.7/20I/501Y.V1 strain is 30% to 80% more effectively transmitted and results in higher nasopharyngeal viral loads than the wild-type strain of SARS-CoV. Also of concern are retrospective observational studies suggesting an approximately 30% increased risk of death associated with this variant.8

Another notable variant, 20H/501Y.V2 or B.1.351, was first identified is South Africa, where it has rapidly become the predominant strain.9 Cases attributed to this strain have been detected in multiple countries outside of South Africa, including recent cases in the US. B.1.351 shares the D614G and N501Y mutations with B.1.1.1.7; thus, it is thought to also have a high potential for transmission. There are no data yet to suggest an increased risk of death due to this variant. Importantly, this constellation of mutations—9 total in the spike protein—add yet another dimension of concern. B.1.351 strains are less effectively neutralized by convalescent plasma from patients with coronavirus disease 2019 (COVID-19) and by sera from those vaccinated with several vaccines in development.1012 The decrement in neutralization can be more than 10-fold with convalescent plasma and averages 5- to 6-fold less with sera from vaccinated individuals. Fortunately, neutralization titers induced by vaccination are high, and even with a 6-fold decrease, serum can still effectively neutralize the virus.

Nonetheless, these data are concerning because they indicate that viral variation can result in antigenic changes that alter antibody-mediated immunity. This is highlighted by in vitro studies showing the B.1.351 strain to be partially or fully resistant to neutralization by certain monoclonal antibodies, including some authorized for therapeutic use in the US.12 The prevalent strains in the US appear to remain sensitive to therapeutic monoclonal antibodies; however, recent evolutionary history raises the concern that the virus could be only a few mutations away from more substantive resistance.

COVID-19 vaccine development has been an extraordinary success; however, it is unclear how effective these vaccines will be against the new variants. The interim data from 2 randomized placebo-controlled vaccine studies, the rAd26 from Janssen and a recombinant protein from Novavax, offer some insight. The Janssen study included sites in the US, Brazil, and South Africa with efficacy against COVID-19 at 72%, 66%, and 57%, respectively.13 Novavax reported efficacy from studies in the UK and South Africa with overall efficacy of 89% and 60%, respectively.14 Viral sequence data from infected patients showed that the B.1.351 strain was responsible for the majority of infections in South Africa. Lower vaccine efficacy in the South Africa cohort could be related to antigenic variation or to geographic or population differences. Despite the reduced efficacy, the rAd26 vaccine was 85% effective overall in preventing severe COVID-19, and protection was similar in all regions.

These data suggest that current vaccines could retain the ability to prevent hospitalizations and deaths, even in the face of decreased overall efficacy due to antigenic variation. It is unclear whether changes in vaccine composition will be needed to effectively control the COVID-19 pandemic; however, it is prudent to be prepared. Some companies have indicated plans to manufacture and test vaccines based on emerging variants, and such studies will provide important information on the potential to broaden the immune response.

The recognition of a novel emergent variant, 20C/S:452R, in the most populous US state necessitates further investigation for implications of enhanced transmission. In particular, the L452R mutation in the spike protein could affect the binding of certain therapeutic monoclonal antibodies. The emergence of this and other new variants is likely to be a common occurrence until the spread of this virus is reduced. This emphasizes the importance of a global approach to surveillance, tracking, and vaccine deployment. The approach should be systematic and include in vitro assessment of sensitivity to neutralization by monoclonal antibodies and vaccinee sera, vaccine protection of animals against challenge with new strains, and field data defining viral sequences from breakthrough infections in vaccinees. The infrastructure and process used for tracking and updating influenza vaccines could be used to inform that process. Finally, SARS-CoV-2 will be with the global population for some time and has clearly shown its tendency toward rapid antigenic variation, providing a “wake-up call” that a sustained effort to develop a pan-SARS-CoV-2 vaccine is warranted.

SOURCE

https://jamanetwork.com/journals/jama/fullarticle/2776542

Other related articles published in this Open Access Online Scientific Journal include the following:

Rise of a trio of mutated viruses hints at an increase in transmissibility, speeding the virus’ leaps from one host to the next

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2021/02/01/rise-of-a-trio-of-mutated-viruses-hints-at-an-increase-in-transmissibility-speeding-the-virus-leaps-from-one-host-to-the-next/

 

Read Full Post »


Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines

Reporter: Aviva Lev-Ari, PhD, RN

 

The UK’s COVID-19 vaccine rollout commenced in December, and requires an individual to receive two doses of the same vaccine, either Pfizer/BioNTech’s BNT162b2 or AstraZeneca/Oxford’s ChAdOx1, with a maximum interval of 12 weeks between doses. As of February 3, 10 million first doses have been administered.

Com-COV has been classified as an “Urgent Public Health” study by the National Institutes for Health and Research (NIHR), and it’s hoped that the data produced may offer greater flexibility for vaccine delivery going forward.

“Given the inevitable challenges of immunizing large numbers of the population against COVID-19 and potential global supply constraints, there are definitely advantages to having data that could support a more flexible immunization program, if ever needed and approved by the medicines regulator,” Jonathan Van-Tam, deputy chief medical officer and senior responsible officer for the study, said in a press release.

The study will run for a 13-month period and will recruit over 800 patients across eight sites in the UK, including London – St George’s and UCL, Oxford, Southampton, Birmingham, Bristol, Nottingham and Liverpool.

Com-COV has eight different arms that will test eight different combinations of doses and dose intervals. This is tentative and subject to change should more COVID-19 vaccines be approved for use in the UK. The eight arms include the following dose combinations:

  • Pfizer/BioNTech and Pfizer/BioNTech – 28 days apart
  • Pfizer/BioNTech and Pfizer/BioNTech – 12 weeks apart – (control group)
  • Oxford/AstraZeneca and Oxford/AstraZeneca – 28 days apart
  • Oxford/AstraZeneca and Oxford/AstraZeneca – 12 weeks apart – (control group)
  • Oxford/AstraZeneca and Pfizer/BioNTech – 28 days apart
  • Oxford/AstraZeneca and Pfizer/BioNTech – 12 weeks apart
  • Pfizer/BioNTech and Oxford/AstraZeneca – 28 days apart
  • Pfizer/BioNTech and Oxford/AstraZeneca – 12 weeks apart

Aside from the logistical benefits of using alternative vaccines, there is scientific value to exploring how different vaccines and doses affect the human immune system.

Dr Peter English, consultant in communicable disease control, pointed out that the antigen used across the currently authorized COVID-19 vaccines is the same Spike protein. Therefore, the immune system can be expected to respond just as well if a different product is used for boosting. “It is also the case that many vaccines work better if a different vaccine is used for boosting – an approach described as heterologous boosting,” English said, referencing previously successful trials using Hepatitis B vaccines.

“It is also even possible that by combining vaccines, the immune response could be enhanced giving even higher antibody levels that last longer; unless this is evaluated in a clinical trial we just won’t know,” added Van-Tam.

If warranted by the study data, the Medicines and Healthcare products Regulatory Agency may consider reviewing and authorizing modifications to the UK’s vaccine regimen approach – but only time will tell.

“We need people from all backgrounds to take part in this trial, so that we can ensure we have vaccine options suitable for all. Signing up to volunteer for vaccine studies is quick and easy via the NHS Vaccine Research Registry,” Professor Andrew Ustianowski, national clinical lead for the NIHR COVID Vaccine Research Program, said

SOURCE

First-of-its-Kind Study Will Test Combination of Different COVID-19 Vaccines | Technology Networks

https://www.technologynetworks.com/biopharma/news/first-of-its-kind-study-will-test-combination-of-different-covid-19-vaccines-345245?utm_campaign=NEWSLETTER_TN_Biopharma

WATCH VIDEO

Different Types of COVID-19 Vaccines With Dr Seth Lederman Video | Technology Networks

https://www.technologynetworks.com/biopharma/videos/different-types-of-covid-19-vaccines-with-dr-seth-lederman-345207

Read Full Post »


Google Cloud launches Vaccine Management Tools using ML & AI for Vaccine Distribution Efforts

Reporter: Aviva Lev-Ari, PhD, RN

 

Google Cloud announced Monday new artificial intelligence and machine learning tools to help with vaccine rollout efforts from vaccine information and scheduling, to distribution and analytics, to forecasting and modeling COVID-19 cases.

https://www.fiercehealthcare.com/tech/google-cloud-rolls-out-tools-for-vaccine-logistics-as-tech-giants-jump-into-distribution?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiWldZMVlXVmlNelprWXpNMyIsInQiOiJEQ3BsYnRMQTBPQU1HNDBqVFVhQnpKV3BlRUdIbXRBMWgwWFFEYktjWnc3XC9xWm9tNUNJcnNNR3M5cjNuZEhoYlFRQzZFTXAxU1NFUnFQc2o4Q09HYjBFMFRhejBMaWhuN1FLalU1U2xQQWV3bm1iZEtJQkk1aWRGVkVSOFVcL2tIIn0%3D

Read Full Post »


Rise of a trio of mutated viruses hints at an increase in transmissibility, speeding the virus’ leaps from one host to the next

Reporter: Aviva Lev-Ari, PhD, RN

“We have uncontrolled viral spread in much of the world,” says Adam Lauring, an infectious disease physician and virologist at the University of Michigan. “So the virus has a lot of opportunity to evolve.”

“The variants may be more transmissible, but physics has not changed,” says Müge Çevik, an infectious disease physician at the University of St. Andrews in Scotland.

Many changes don’t affect the virus’ function, and some even harm SARS-CoV-2’s ability to multiply, but they keep happening. “Viruses mutate; that’s what they do,” says Akiko Iwasaki, an immunologist at Yale School of Medicine in Connecticut.

U.K., Brazil, and South Africa. In the United Kingdom, variant B.1.1.7 likely drove the region’s record-setting spike of COVID-19 cases in January. The variant is now circulating in more than 60 countries, including the United States—and projections suggest it will become the most common virus variety in the U.S. by mid-March.

An independently arising lineage called P.1 might also be driving a wave of cases in Manaus, Brazil, where it accounted for nearly half of new COVID-19 infections in December. On January 26, Minnesotan officials reported the first U.S. case of P.1 in a resident who previously traveled to Brazil. And a third lineage raising alarms, known as B.1.351, was first spotted amid a December wave of infections in South Africa. On January 28, the first known U.S. cases of the variant were reported in South Carolina.

One specific mutation, known as N501Y, popped up independently in all three variants, suggesting it could provide an advantage to the virus. “That’s a sign that there is natural selection going on,” Lauring says. The N501Y mutation affects the virus’ spike protein, which is the key it uses to unlock entry into its host’s cells.

Another possibility is that new variants cause people who are infected to harbor more copies of the virus. This results in greater viral “shedding” in airborne droplets spewed when people talk, sing, cough, and breath.

mutations in 501Y.V2 could diminish the effectiveness of antibodies in the blood of people previously infected with the virus. But understanding whether that could lead to more re-infections, or if it could affect vaccine efficacy.

Dramatically scale up production of high-filtration masks for the general public.

Based on:

Why some coronavirus variants are more contagious‹and how we can stop them

https://www.nationalgeographic.com/science/2021/01/why-some-coronavirus-variants-are-more-contagious/?cmpid=org=ngp::mc=crm-email::src=ngp::cmp=editorial::add=SpecialEdition_20210129

Read Full Post »


A Platform called VirtualFlow: Discovery of Pan-coronavirus Drugs help prepare the US for the Next Coronavirus Pandemic

Reporter: Aviva Lev-Ari, PhD, RN

 

ARTICLE|ONLINE NOW, 102021

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening

Open AccessPublished:January 04, 2021DOI:https://doi.org/10.1016/j.isci.2020.102021

 

The work was made possible in large part by about $1 million in cloud computing hours awarded by Google through a COVID-19 research grant program.

The work reported, below was sponsored by

  • a Google Cloud COVID-19 research grant. Funding was also provided by the
  • Fondation Aclon,
  • National Institutes of Health (GM136859),
  • Claudia Adams Barr Program for Innovative Basic Cancer Research,
  • Math+ Berlin Mathematics Research Center,
  • Templeton Religion Trust (TRT 0159),
  • U.S. Army Research Office (W911NF1910302), and
  • Chleck Family Foundation

 

Harvard University, AbbVie form research alliance to address emergent viral diseases

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Harvard University and AbbVie today announced a $30 million collaborative research alliance, launching a multi-pronged effort at Harvard Medical School to study and develop therapies against emergent viral infections, with a focus on those caused by coronaviruses and by viruses that lead to hemorrhagic fever.

The collaboration aims to rapidly integrate fundamental biology into the preclinical and clinical development of new therapies for viral diseases that address a variety of therapeutic modalities. HMS has led several large-scale, coordinated research efforts launched at the beginning of the COVID-19 pandemic.

“A key element of having a strong R&D organization is collaboration with top academic institutions, like Harvard Medical School, to develop therapies for patients who need them most,” said Michael Severino, vice chairman and president of AbbVie. “There is much to learn about viral diseases and the best way to treat them. By harnessing the power of collaboration, we can develop new therapeutics sooner to ensure the world is better prepared for future potential outbreaks.”

“The cataclysmic nature of the COVID-19 pandemic reminds us how vital it is to be prepared for the next public health crisis and how critical collaboration is on every level—across disciplines, across institutions and across national boundaries,” said George Q. Daley, dean of Harvard Medical School. “Harvard Medical School, as the nucleus of an ecosystem of fundamental discovery and therapeutic translation, is uniquely positioned to propel this transformative research alongside allies like AbbVie.”

AbbVie will provide $30 million over three years and additional in-kind support leveraging AbbVie’s scientists, expertise and facilities to advance collaborative research and early-stage development efforts across five program areas that address a variety of therapeutic modalities:

  • Immunity and immunopathology—Study of the fundamental processes that impact the body’s critical immune responses to viruses and identification of opportunities for therapeutic intervention.

Led by Ulirich Von Andrian, the Edward Mallinckrodt Jr. Professor of Immunopathology in the Blavatnik Institute at HMS and program leader of basic immunology at the Ragon Institute of MGH, MIT and Harvard, and Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Host targeting for antiviral therapies—Development of approaches that modulate host proteins in an effort to disrupt the life cycle of emergent viral pathogens.

Led by Pamela Silver, the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Antibody therapeutics—Rapid development of therapeutic antibodies or biologics against emergent pathogens, including SARS-CoV-2, to a preclinical or early clinical stage.

Led by Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at HMS, and by Jochen Salfeld, vice president of immunology and virology discovery at AbbVie.

  • Small molecules—Discovery and early-stage development of small-molecule drugs that would act to prevent replication of known coronaviruses and emergent pathogens.

Led by Mark Namchuk, executive director of therapeutics translation at HMS and senior lecturer on biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS, and Steve Elmore, vice president of drug discovery science and technology at AbbVie.

  • Translational development—Preclinical validation, pharmacological testing, and optimization of leading approaches, in collaboration with Harvard-affiliated hospitals, with program leads to be determined.

SOURCE

https://hms.harvard.edu/news/joining-forces

 

 

A Screen Door Opens

Virtual screen finds compounds that could combat SARS-CoV-2

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

Less than a year ago, Harvard Medical School researchers and international colleagues unveiled a platform called VirtualFlow that could swiftly sift through more than 1 billion chemical compounds and identify those with the greatest promise to become disease-specific treatments, providing researchers with invaluable guidance before they embark on expensive and time-consuming lab experiments and clinical trials.

Propelled by the urgent needs of the pandemic, the team has now pushed VirtualFlow even further, conducting 45 screens of more than 1 billion compounds each and ranking the compounds with the greatest potential for fighting COVID-19—including some that are already approved by the FDA for other diseases.

“This was the largest virtual screening effort ever done,” said VirtualFlow co-developer Christoph Gorgulla, research fellow in biological chemistry and molecular pharmacology in the labs of Haribabu Arthanari and Gerhard Wagner in the Blavatnik Institute at HMS.

The results were published in January in the open-access journal iScience.

The team searched for compounds that bind to any of 15 proteins on SARS-CoV-2 or two human proteins, ACE2 and TMPRSS2, known to interact with the virus and enable infection.

Researchers can now explore on an interactive website the 1,000 most promising compounds from each screen and start testing in the lab any ones they choose.

The urgency of the pandemic and the sheer number of candidate compounds inspired the team to release the early results to the scientific community.

“No one group can validate all the compounds as quickly as the pandemic demands,” said Gorgulla, who is also an associate of the Department of Physics at Harvard University. “We hope that our colleagues can collectively use our results to identify potent inhibitors of SARS-CoV-2.

In most cases, it will take years to find out whether a compound is safe and effective in humans. For some of the compounds, however, researchers have a head start.

Hundreds of the most promising compounds that VirtualFlow flagged are already FDA approved or being studied in clinical or preclinical trials for other diseases. If researchers find that one of those compounds proves effective against SARS-CoV-2 in lab experiments, the data their colleagues have already collected could save time establishing safety in humans.

Other compounds among VirtualFlow’s top hits are currently being assessed in clinical trials for COVID-19, including several drugs in the steroid family. In those cases, researchers could build on the software findings to investigate how those drug candidates work at the molecular level—something that’s not always clear even when a drug works well.

It shows what we’re capable of computationally during a pandemic.

Hari Arthanari

SOURCE

https://hms.harvard.edu/news/screen-door-opens?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_1&utm_content=HMNews02012021

Read Full Post »


Inflammation and potential links with the microbiome: Mechanisms of infection by SARS-CoV-2

Reporter: Aviva Lev-Ari, PhD, RN

Mechanisms of infection by SARS-CoV-2, inflammation and potential links with the microbiome

Published Online:https://doi.org/10.2217/fvl-2020-0310

Human coronaviruses (HCoVs) were first isolated from patients with the common cold in the 1960s [1–3]. Seven HCoVs known to cause disease in humans have since been identified: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, the SARS coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus and the novel SARS-CoV-2 [4]. The latter was identified after a spike in cases of pneumonia of unknown etiology in Wuhan, Hubei Province, China during December 2019 and was initially named novel coronavirus (2019-nCoV) [5,6]. The virus was renamed SARS-CoV-2 according to the International Committee on Taxonomy of Viruses classification criteria due to its genomic closeness to SARS-CoV; the disease caused by this virus was named coronavirus disease (COVID-19) according to the WHO criteria for naming emerging diseases [7]. SARS-CoV-2 belongs to the genera Betacoronavirus and shares a different degree of genomic similarity with the other two epidemic coronaviruses: SARS-CoV (∼79%) and Middle East respiratory syndrome coronavirus (∼50%) [8].

COVID-19 has caused considerable morbidity and mortality worldwide and has become the central phenomenon that is shaping our current societies. Human-to-human transmission is the main route of spread of the virus, mainly through direct contact, respiratory droplets and aerosols [9–12]. Management of COVID-19 has been extremely challenging due to its high infectivity, lack of effective therapeutics and potentially small groups of individuals (i.e., asymptomatic or mild disease) rapidly spreading the disease [13–17]. Although research describing COVID-19 and the mechanisms of infection by SARS-CoV-2 and its pathogenesis has expanded rapidly, there is still much to be learnt. Important gaps in knowledge which remain to be elucidated are the dynamic and complex interactions between the virus and the host’s immune system, as well as the potential interspecies communications occurring between ecological niches encompassing distinct microorganisms in both healthy individuals and persons living with chronic diseases, and how these interactions could determine or modulate disease progression and outcomes.

In this review, we describe recent insights into these topics, as well as remaining questions whose answers will allow us to understand how interactions between the virus, the immune system and microbial components could possibly be related to disease states in patients with COVID-19, as well as existing studies of the microbiome in patients with COVID-19.

SOURCE

Read Full Post »


Early Details of Brain Damage in COVID-19 Patients

Reporter: Irina Robu, PhD

 

COVID-19 has currently claimed more American lives than World War I, Vietnam War and the Korean war combined. And while it is mainly a respiratory disease, COVID-19 infection affects other organs, including the brain. Researchers at Harvard-affiliated Massachusetts General Hospital found that COVID patients with neurological symptoms show more than some metabolic disturbances in the brain as patients who have suffered oxygen deprivation.

During the course of the pandemic, thousand patients with COVID-19 have been seen at MGH and the severity of the neurological symptoms varies from temporary loss of smell to more severe symptoms such as dizziness, confusion, seizures, and stroke. According to the principal investigator of the study, Eva Maria Ratai, Department of Radiology used 3 Tesla Magnetic Resonance Spectroscopy (MRS) to identify neurochemical abnormalities even the structural imagining findings are normal. COVID-19 patients’ brains showed N-acetyl-aspartate (NAA) reduction, choline elevation, and myo-inositol elevation, comparable to what is seen with these metabolites in other patients with leukoencephalopathy after hypoxia without COVID.

Their research indicated that one of patients with COVID-19 indicate the most severe white matter damage, whereas another had COVID-19 associated necrotizing leukoencephalopathy at the time of imaging. And the patient that experience cardiac arrest showed subtle white matter changes on structural MR. The control cases included one patient with damage due to hypoxia from other causes: one with sepsis-related white matter damage, and a normal, age-matched, healthy volunteer.

The main question still remains whether the decrease in the oxygen of the brain is causing the white matter to change or whether the virus itself is attacking white matter. The conclusion is that MRS can be used as a disease and therapy monitoring tool.

SOURCE

Small study reveals details of brain damage in COVID-19 patients

Read Full Post »


Mechanistic link between SARS-CoV-2 infection and increased risk of stroke using 3D printed models and human endothelial cells

Reporter: Adina Hazan, PhD

 

Kaneko, et al.  from UCLA aimed to explore why SARS-CoV-2 infection is associated with an increased rate of cerebrovascular events, including

  • ischemic stroke and
  • intracerebral hemorrhage

While some suggested mechanisms include an overall systemic inflammatory response including increasing circulating cytokines and leading to a prothrombotic state, this may be only a partial answer. A SARS-CoV-2 specific mechanism could be likely, considering that both angiotensin-converting enzyme-2 (ACE2), the receptor necessary for SARS-CoV-2 to gain entry into the cell, and SARS-CoV-2 RNA have been reportedly detected in the human brain postmortem.

One of the difficulties in studying vasculature mechanisms is that the inherent 3D shape and blood flow subject this tissue to different stressors, such as flow, that could be critically relevant during inflammation. To accurately study the effect of SARS-CoV-2 on the vasculature of the brain, the team generated 3D models of the human middle cerebral artery during intracranial artery stenosis using data from CT (computed tomography) angiography. This data was then exported with important factors included such as

  • shear stress during perfusion,
  • streamlines, and
  • flow velocity to be used to fabricate 3D models.

These tubes were then coated with endothelial cells isolated and sorted from normal human brain tissue resected during surgery. In doing so, this model could closely mimic the cellular response of the vasculature of the human brain.

Surprisingly, without this 3D tube, human derived brain endothelial cells displayed very little expression of ACE2 or, TMPRSS2 (transmembrane protease 2), a necessary cofactor for SARS-COV-2 viral entry.

Interestingly,

  • horizontal shear stress increased the expression of ACE2 and
  • increased the binding of spike protein to ACE2, especially within the stenotic portion of the 3D model.

By exposing the endothelial cells to liposomes expressing the SARS-CoV-2 spike protein, they also were able to explore key upregulated genes in the exposed cells, in which they found that

  • “binding of SARS-CoV-2 S protein triggered 83 unique genes in human brain endothelial cells”.

This included many inflammatory signals, some of which have been previously described as associated with SARS-COV-2, and others whose effects are unknown. This may provide an important foundation for exploring potential therapeutic targets in patients susceptible to cerebrovascular events.

Overall, this study shows important links between the

  • mechanisms of SARS-CoV-2 and the
  • increase in ischemic events in these patients. It also has important implications for
  • treatment for SARS-CoV-2, as high blood pressure and atherosclerosis may be increasing ACE2 expression in patients, providing the entry port for viral particles into brain endothelia.

SOURCE:

https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032764

Other related articles published in this Open Access Online Scientific Journal include the following:

The Impact of COVID-19 on the Human Heart

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/09/29/the-impact-of-covid-19-on-the-human-heart/

 

SAR-Cov-2 is probably a vasculotropic RNA virus affecting the blood vessels: Endothelial cell infection and endotheliitis in COVID-19

Reporter: Aviva Lev-Ari, PhD, RN – Bold face and colors are my addition

https://pharmaceuticalintelligence.com/2020/06/01/sar-cov-2-is-probably-a-vasculotropic-rna-virus-affecting-the-blood-vessels-endothelial-cell-infection-and-endotheliitis-in-covid-19/

 

Diagnosis of Coronavirus Infection by Medical Imaging and Cardiovascular Impacts of Viral Infection, Aviva Lev-Ari, PhD, RN  Lead Curator – e–mail: avivalev-ari@alum.berkeley.edu

Read Full Post »


Allocation and Prioritization of Vaccine Dose Administration Schedules: Cover more people or Adhere to Immunization Protocol

Curators:

This curation has four parts:

Part 1:

Waiting on the Covid booster would allow more people to be vaccinated sooner.

  • By Michael Segal, MD, PhD

Part 2:

Expert Opinion by Clinical Authority in Practice of Cardiac Imaging:

  • The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

Part 3:

Expert Opinion by Scientific Authority in Population Biology

  • The Voice of Prof. Marcus W. Feldman, PhD

Part 4:

Summary

  • The Voices of Prof. Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

Introduction

Aviva Lev-Ari
@AVIVA1950

We agree the protocol should not be changed

Quote Tweet

Pearl Freier
@PearlF
FDA’s Peter Marks explained why the 2 dose regimen for Pfizer/BioNtech vaccine shouldn’t be changed to 1 dose in attempt to reach more patients while there’s limited supply. Aside from 95% effectiveness w/ 2 dose regimen based on clinical data, he said no one knows how long 1/n

Pearl Freier
@PearlF

Replying to

1 dose would be effective for & no one knows if only given 1 dose if patient would get an immune response that “would just dwindle” “And we know that can happen because we know already that people who get very mild covid-19 tend to lose their immune responses pretty quickly.” 2/n

Pearl Freier
@PearlF

We need to make sure that those who get the vaccine regimen are people who know they’ve gotten that protection [95% effective]. Because that’s something we know, whereas the other [1 dose] is conjecture. And I would hate for people to change their behavior on the basis of 3/n

Pearl Freier
@PearlF

one dose of vaccine where we don’t know what’s really happening.” Peter Marks/FDA said (6 min mark) youtube.com/watch?v=uePet5 (
Research!America Alliance Member Meeting with Dr. Peter Marks
With several COVID-19 vaccine candidates under FDA review, Dr. Peter Marks, Director of FDA’s Center for Biologics Evaluation and Research (CBER), joined us …
youtube.com

 (she/her/hers)

@lisabari

Replying to

It will be really interesting to learn more about the immune response from J&J’s one dose regimen.

Pearl Freier
@PearlF

I think they’re expecting data from J&J in January

Part 1:

Waiting on the Covid booster would allow more people to be vaccinated sooner.

By Michael Segal, MD, PhD

https://www.wsj.com/articles/a-shot-instead-of-two-at-saving-lives-11607643152

A Shot (Instead of Two) at Saving Lives

Waiting on the Covid booster would allow more people to be vaccinated sooner.

By Michael Segal

Dec. 10, 2020 6:32 pm ET

Recent days brought good news and bad news about coronavirus vaccines. The developments could add up to months of delay in getting most Americans inoculated. But there’s a way to make use of the good news to speed up herd immunity.

The bad news is that in July the U.S. passed up an opportunity to secure by June 2021 more than 100 million doses of the Pfizer vaccine, now expected to receive emergency-use authorization in the next few days. Instead, officials followed a balanced-portfolio strategy that reserved as many as 300 million doses of the AstraZeneca vaccine, whose prospects are unclear.

The good news is that the Pfizer and Moderna vaccines performed at the upper end of expectations, with 95% efficacy after two doses. And intriguingly, Pfizer’s submission to the Food and Drug Administration shows that the efficacy of the vaccine in preventing disease had largely kicked in by two weeks after the first dose, and there was no dramatic increase in efficacy after the booster was given three weeks later.

The protocol in Pfizer’s clinical trial was to give all participants two doses. The FDA is likely to approve this protocol, and standard procedure is to prescribe a drug according to protocol. But we are in a pandemic and supplies of vaccine are inadequate. There’s an alternative: vaccinating as many people as possible with a first dose and waiting on the booster until supplies are plentiful.

The Pfizer study wasn’t designed to put a number on first-dose efficacy, but the data in Pfizer’s “cumulative incidence curves” suggest at least 75% efficacy for two weeks after one dose. The question is whether to use the 100 million doses on 50 million people, of whom two doses would protect roughly 47.5 million, or to give one dose each to 100 million people and protect at least 75 million.

States have the authority to allocate vaccines as they choose, but they’re unlikely to deviate from the study protocol unless a federal authority—whether the Centers for Disease Control and Prevention or a coronavirus “czar”—suggests this as an option.

Even under such an approach, some essential personnel—such as doctors and nurses who work directly with coronavirus patients and health aides who work in multiple nursing homes—should get two doses as soon as possible, given their high-risk role in the pandemic response.

The U.S. will have more than these 100 million doses of the Pfizer vaccine. Some will come from Moderna, and the federal government could use the Defense Production Act to snatch some Pfizer doses that the company contracted to sell to other countries. Even so, supply will be constrained at first, and officials need to think clearly and flexibly about how to allocate the limited doses that will be available soon.

Harvard epidemiologist Michael Mina expressed his disappointment with society’s decision making during the pandemic: “I’m just astounded by the dysfunction, the willingness to just stay the course as hundreds of thousands of people die, and the unwillingness to innovate in literally any way.” Here’s a simple innovation that could save many lives.

Dr. Segal is a neurologist and neuroscientist.

Copyright ©2020 Dow Jones & Company, Inc. All Rights Reserved. 87990cbe856818d5eddac44c7b1cdeb8

Appeared in the December 11, 2020, print edition.

Part 2:

Expert Opinion by Clinical Authority in Practice of Cardiac Imaging:

The Voice of Dr. Justin D. Pearlman, MD, PhD, FACC

From: Justin MDMEPhD <jdpmdphd@gmail.com>

Date: Saturday, December 12, 2020 at 10:40 PM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Re: I NEED YOUR EXPERT OPINION on Mickey Segal’s WSJ op-ed on vaccine dose allocation

Michael Segal proposes off-label use of the Pfizer 2-injection Covid-19 vaccine, based on data that suggested “75% protection at 2 weeks.” There was no controlled study reported of any sustained benefit from the single injection beyond 2 weeks, because those who received a first injection of vaccine received the designed booster at 2 weeks. Dr. Segal suggests it would be irresponsible to use the medication in the manner designed and tested. Instead, he could have proposed a study to determine the duration and degree of benefit from a single dose injection. However, one might argue that could delay the release of an effective regimen for the possibility that his proposed 1 dose regimen might be adequate for some, and possibly for more than the two weeks observed. Even if his guess is correct on both counts, both in his guess that the partial benefit at two weeks might be adequate and that it might last longer than the observed two weeks, it could still be deemed irresponsible to impose his guess for obvious reasons. His guess might be wrong, and could deprive many of the regimen that was validated as effective. Diverting an effective validated regimen to a guess could put many in harms way who would have been protected by the designed 2 dose regimen. He admits to low confidence in his recommendation when he proposes that essential workers should get the validated 2-dose regimen. Why does his recommendation stop there – why not propose a quarter dose to 4 times as many, or 1/8 dose to 8 times as many? Why apply the argument just to the two-dose regimen? He could also guess that a half dose of the single injection successful vaccines might be adequate. The motivation to second guess supply choices and doses is understandable, but it is not sound, as it is just a guess, not a validated regimen.

In addition, he also argues for 20-20 hindsight in the government distributing funds to mulitiple vaccines, instead of disproportionate purchase from Pfizer. Trials are limited in size, and further data will be collected on those vaccinated. Balanced investment may save more lives, not fewer, depending on those outcomes.

On Sat, Dec 12, 2020, 8:20 PM Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu> wrote:

Dear Dr. Pearlman,

Please send me 1/2 –1 page as a Critic of 

  • Mickey Segal’s WSJ op-ed on vaccine dose allocation, below

Part 3:

Expert Opinion by Scientific Authority in Population Biology

The Voice of Prof. Marcus W. Feldman, PhD

From: Marcus W Feldman <mfeldman@stanford.edu>

Date: Sunday, December 13, 2020 at 6:52 PM

To: “Aviva Lev-Ari, PhD, RN” <AvivaLev-Ari@alum.berkeley.edu>

Subject: Re: Mickey Segal’s WSJ op-ed on vaccine dose allocation

RE Segal’s note:

We need more details on the longer term efficacy of the one-dose regimen. Once we have such data, the question of whether 100 million one-dose treatments will be more protective of the population than 50 million two-dose treatments can be addressed. The question of how many hospitalizations and/or deaths would be avoided by going straight to the one-dose regimen can’t be answered. Both approaches leave unanswered whether the transmission of the virus from a vaccinated person is reduced. I would estimate that we need 300 million 2-dose treatments to vaccinate all under 16 year olds.

On Dec 13, 2020, at 1:56 PM, Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu> wrote:

Dear Prof. Feldman,

Please send me 1/2 –1 page as a Critic of 

  • Mickey Segal’s WSJ op-ed on vaccine dose allocation, below

Part 4:

Summary

The Voices of Prof. Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

The Voice of Prof. Stephen J. Williams, PhD

In light of just approved Moderna vaccine, AstraZenaca & JNJ forthcoming vaccine and the approved Pfizer BioNTech coverage should be over 200 million in US, making rationing of second booster shot unnecessary.  However, there is still a concern among the developing and underdeveloped nations that access to these vaccines will be restricted.

The following curation are articles related to this matter from the AAAS and CDC.

CDC advisory panel takes first shot at prioritizing who gets the first shots of COVID-19 vaccines
By Jon CohenDec. 1, 2020 , 8:25 PM
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Health care workers and elderly people living in long-term care facilities should receive top priority for COVID-19 vaccines in the United States if, as expected, one or more becomes available next month in limited supply. That’s what a group that advises the U.S. Centers for Disease Control and Prevention (CDC) on such fraught issues decided today in a near-unanimous vote.

After hearing detailed presentations from CDC scientists who explained the rationale for this specific prioritization scheme, the Advisory Committee on Immunization Practices (ACIP) voted 13 to one to support their proposal. Under the scheme, the first phase of vaccination, known as 1a, would begin with about 21 million health care workers and about 3 million adults who live in long-term care facilities. As spelled out in the 4-hour-long virtual meeting, these groups are at highest risk of becoming seriously ill or dying from COVID-19, and protecting them first, in turn, reduces the burden on society.

“I agree strongly with the decision of the committee,” says Stanley Perlman, a veteran coronavirus researcher and clinician at the University of Iowa who advised ACIP but is not part of it. “The discussions were incredibly thoughtful with everyone recognizing that we needed to make difficult choices. Of course, these allocation issues will become irrelevant once there are enough doses of useful vaccines.”

‘Just beautiful’: Another COVID-19 vaccine, from newcomer Moderna, succeeds in large-scale trial
By Jon CohenNov. 16, 2020 , 7:00 AM
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

SIGN UP FOR OUR DAILY NEWSLETTER
Get more great content like this delivered right to you!

Now, there are two. Another COVID-19 vaccine using the same previously unproven technology as the vaccine from Pfizer and BioNTech, the U.S. and German companies that reported success on 9 November, appears to work remarkably well. And this time, the maker, U.S. biotech Moderna, is releasing a bit more data to back its claim than the other two companies.

An independent board monitoring Moderna’s 30,000-person vaccine trial met on Sunday and reported to the company and U.S. government health officials that only five people in the vaccinated group developed confirmed cases of COVID-19, whereas 90 people who received placebo shots became ill with the disease. That’s an efficacy of 94.5%, the company reported in a press release this morning. Although the clinical trial measurement may not translate into an equally high level of real-world protection, the success indicates the vaccine is Iikely more than effective enough to stop the pandemic if it can be widely distributed.

“That efficacy is just beautiful, and there’s no question about the veracity of it either,” says Lawrence Corey, a virologist at the Fred Hutchinson Cancer Research Center who co-led the clinical trials network that is testing the vaccine.

Moderna’s COVID-19 vaccine ready to ship pending FDA approval -U.S. health chief

Source: https://www.reuters.com/article/health-coronavirus-usa-azar-idUSKBN28R265?taid=5fdc062c54859c0001437b9b&utm_campaign=trueanthem&utm_medium=trueanthem&utm_source=twitter

WASHINGTON (Reuters) – U.S. Health and Human Services Secretary Alex Azar on Thursday said nearly 6 million doses of Moderna Inc’s experimental COVID-19 vaccine were poised to ship nationwide as soon as it secures Food and Drug Administration approval. Azar, in an interview on CNBC, said federal health officials had allotted 5.9 million doses to send to the nation’s governors, who are managing each state’s distribution. “We’re ready to start shipping this weekend to them for rollout Monday, Tuesday, Wednesday of next week. We’re ready to go,” he said. An FDA panel of outside advisers is weighing the safety and effectiveness of Moderna’s vaccine candidate at a meeting on Thursday. The agency will weigh the committee’s conclusions in making its approval decision.

The strategy seems to have been produce multiple vaccines from multiple sources which reduce the strain on manufacturing of required doses.
However, many underdeveloped nations as well as developing nations are worried about the nationalism of access to these vaccines.  Please read below:

Abstract

The 2030 Agenda for Sustainable Development (AfSD) has the vision to leave no one behind, particularly low-income countries. Yet COVID-19 seems to have brought up new rules and approaches. Through document and critical discourse analysis, it emerges that there has been a surge in COVID-19 vaccines and treatments nationalism. Global solidarity is threatened, with the USA, United Kingdom, European Union and Japan having secured 1.3 billion doses of potential vaccines as of August 2020. Vaccines ran out even before their approval with three candidates from Pfizer-BioNTech, Moderna and AstraZeneca having shown good Phase III results in November 2020. Rich countries have gone years ahead in advance vaccines and treatments purchases. This is a testimony that the 2030 AfSD, especially SDG 3 focusing on health will be difficult to achieve. Low-income countries are left gasping for survival as the COVID-19 pandemic relegates them further into extreme poverty and deeper inequality. The paper recommends the continued mobilisation by the World Health Organisation and other key stakeholders in supporting the GAVI vaccine alliance and the Coalition for Epidemic Preparedness Innovations (COVAX) global vaccines initiative that seeks to make two billion vaccine doses available to 92 low and middle-income countries by December 2021.

Others have voiced their concerns on this matter:

 

Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis

From: Anthony D So 1 2Joshua Woo 2 BMJ2020 Dec 15;371:m4750. doi: 10.1136/bmj.m4750.

Abstract

Objective: To analyze the premarket purchase commitments for coronavirus disease 2019 (covid-19) vaccines from leading manufacturers to recipient countries.

Design: Cross sectional analysis.

Data sources: World Health Organization’s draft landscape of covid-19 candidate vaccines, along with company disclosures to the US Securities and Exchange Commission, company and foundation press releases, government press releases, and media reports.

Eligibility criteria and data analysis: Premarket purchase commitments for covid-19 vaccines, publicly announced by 15 November 2020.

Main outcome measures: Premarket purchase commitments for covid-19 vaccine candidates and price per course, vaccine platform, and stage of research and development, as well as procurement agent and recipient country.

Results: As of 15 November 2020, several countries have made premarket purchase commitments totaling 7.48 billion doses, or 3.76 billion courses, of covid-19 vaccines from 13 vaccine manufacturers. Just over half (51%) of these doses will go to high income countries, which represent 14% of the world’s population. The US has reserved 800 million doses but accounts for a fifth of all covid-19 cases globally (11.02 million cases), whereas Japan, Australia, and Canada have collectively reserved more than one billion doses but do not account for even 1% of current global covid-19 cases globally (0.45 million cases). If these vaccine candidates were all successfully scaled, the total projected manufacturing capacity would be 5.96 billion courses by the end of 2021. Up to 40% (or 2.34 billion) of vaccine courses from these manufacturers might potentially remain for low and middle income countries-less if high income countries exercise scale-up options and more if high income countries share what they have procured. Prices for these vaccines vary by more than 10-fold, from $6.00 (£4.50; €4.90) per course to as high as $74 per course. With broad country participation apart from the US and Russia, the COVAX Facility-the vaccines pillar of the World Health Organization’s Access to COVID-19 Tools (ACT) Accelerator-has secured at least 500 million doses, or 250 million courses, and financing for half of the targeted two billion doses by the end of 2021 in efforts to support globally coordinated access to covid-19 vaccines.

Conclusions: This study provides an overview of how high income countries have secured future supplies of covid-19 vaccines but that access for the rest of the world is uncertain. Governments and manufacturers might provide much needed assurances for equitable allocation of covid-19 vaccines through greater transparency and accountability over these arrangements.

The Voice of Adina Hazan, PhD

I have a few issues with the proposal and the asserted outcomes:

The author suggests that back in July 2020 “the U.S. passed up an opportunity to secure by June 2021 more than 100 million doses of the Pfizer vaccine…[by] follow[ing] a balanced-portfolio strategy”. By stating that the U.S. “passed up an opportunity” at that time when all available evidence could not indicate which vaccine would prove successful is taking a “hindsight is 2020” approach. Instead, an all-or-nothing portfolio in July 2020 for one vaccine over another would have been at best unwise and at worst could have passed up the “right” vaccine.

In addition, the author’s core suggestion is that every person in America and the world needs the vaccine at the same time, aka as soon as possible. Considering the incredibly striated outcomes of patients that contract COVID-19, this is not the case. We know that males up until 85 years old with have a much worse prognosis than women, for example1. In addition, all data suggests that the lowest risk group is children, with a death rate in the U.S. of 0.1%1. Trying to vaccinate all children with a vaccine whose long-term effects are, at this time, unknown, for a disease with such a low death rate is not urgent and may warrant waiting for more evidence. Instead of trying to inoculate everyone as fast as possible, the two-dose approach that is currently implemented ensures that those most at risk receive the maximum protection, instead of leaving them at higher risks even after vaccination. In this way, the vaccine will do what it was originally intended to do: protect the most vulnerable immediately, and in turn begin to alleviate the strain on the overall population as a result of this disease.

  1. S. CDC website (Deaths by Age Group, 12/18/2020)

The Voice of Aviva Lev-Ari, PhD, RN

  • I recommand to adhere to administration protocol.
  • I agree with Dr. Joel Jertock:

It is very clear that the current COVID vaccination protocols call for two shots, three weeks apart, for maximum protection.

Limiting personnel to a single shot, “to spread the available vaccines further” just means wasting those doses.  It is similar to taking an antibiotic for only 5 days instead of the recommended 10 days, “to make the pills last longer.”

References on Vaccine Development 

Development of Medical Counter-measures for 2019-nCoV, CoVid19, Coronavirus

Read Full Post »

« Newer Posts - Older Posts »