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Thriving Vaccines and Research: Weizmann Institute Coronavirus Research Development
Reporter:Amandeep Kaur, B.Sc., M.Sc.
In early February, Prof. Eran Segal updated in one of his tweets and mentioned that “We say with caution, the magic has started.”
The article reported that this statement by Prof. Segal was due to decreasing cases of COVID-19, severe infection cases and hospitalization of patients by rapid vaccination process throughout Israel. Prof. Segal emphasizes in another tweet to remain cautious over the country and informed that there is a long way to cover and searching for scientific solutions.
A daylong webinar entitled “COVID-19: The epidemic that rattles the world” was a great initiative by Weizmann Institute to share their scientific knowledge about the infection among the Israeli institutions and scientists. Prof. Gideon Schreiber and Dr. Ron Diskin organized the event with the support of the Weizmann Coronavirus Response Fund and Israel Society for Biochemistry and Molecular Biology. The speakers were invited from the Hebrew University of Jerusalem, Tel-Aviv University, the Israel Institute for Biological Research (IIBR), and Kaplan Medical Center who addressed the molecular structure and infection biology of the virus, treatments and medications for COVID-19, and the positive and negative effect of the pandemic.
The article reported that with the emergence of pandemic, the scientists at Weizmann started more than 60 projects to explore the virus from different range of perspectives. With the help of funds raised by communities worldwide for the Weizmann Coronavirus Response Fund supported scientists and investigators to elucidate the chemistry, physics and biology behind SARS-CoV-2 infection.
Prof. Avi Levy, the coordinator of the Weizmann Institute’s coronavirus research efforts, mentioned “The vaccines are here, and they will drastically reduce infection rates. But the coronavirus can mutate, and there are many similar infectious diseases out there to be dealt with. All of this research is critical to understanding all sorts of viruses and to preempting any future pandemics.”
The following are few important projects with recent updates reported in the article.
Mapping a hijacker’s methods
Dr. Noam Stern-Ginossar studied the virus invading strategies into the healthy cells and hijack the cell’s systems to divide and reproduce. The article reported that viruses take over the genetic translation system and mainly the ribosomes to produce viral proteins. Dr. Noam used a novel approach known as ‘ribosome profiling’ as her research objective and create a map to locate the translational events taking place inside the viral genome, which further maps the full repertoire of viral proteins produced inside the host.
She and her team members grouped together with the Weizmann’s de Botton Institute and researchers at IIBR for Protein Profiling and understanding the hijacking instructions of coronavirus and developing tools for treatment and therapies. Scientists generated a high-resolution map of the coding regions in the SARS-CoV-2 genome using ribosome-profiling techniques, which allowed researchers to quantify the expression of vital zones along the virus genome that regulates the translation of viral proteins. The study published in Nature in January, explains the hijacking process and reported that virus produces more instruction in the form of viral mRNA than the host and thus dominates the translation process of the host cell. Researchers also clarified that it is the misconception that virus forced the host cell to translate its viral mRNA more efficiently than the host’s own translation, rather high level of viral translation instructions causes hijacking. This study provides valuable insights for the development of effective vaccines and drugs against the COVID-19 infection.
Like chutzpah, some things don’t translate
Prof. Igor Ulitsky and his team worked on untranslated region of viral genome. The article reported that “Not all the parts of viral transcript is translated into protein- rather play some important role in protein production and infection which is unknown.” This region may affect the molecular environment of the translated zones. The Ulitsky group researched to characterize that how the genetic sequence of regions that do not translate into proteins directly or indirectly affect the stability and efficiency of the translating sequences.
Initially, scientists created the library of about 6,000 regions of untranslated sequences to further study their functions. In collaboration with Dr. Noam Stern-Ginossar’s lab, the researchers of Ulitsky’s team worked on Nsp1 protein and focused on the mechanism that how such regions affect the Nsp1 protein production which in turn enhances the virulence. The researchers generated a new alternative and more authentic protocol after solving some technical difficulties which included infecting cells with variants from initial library. Within few months, the researchers are expecting to obtain a more detailed map of how the stability of Nsp1 protein production is getting affected by specific sequences of the untranslated regions.
The landscape of elimination
The article reported that the body’s immune system consists of two main factors- HLA (Human Leukocyte antigen) molecules and T cells for identifying and fighting infections. HLA molecules are protein molecules present on the cell surface and bring fragments of peptide to the surface from inside the infected cell. These peptide fragments are recognized and destroyed by the T cells of the immune system. Samuels’ group tried to find out the answer to the question that how does the body’s surveillance system recognizes the appropriate peptide derived from virus and destroy it. They isolated and analyzed the ‘HLA peptidome’- the complete set of peptides bound to the HLA proteins from inside the SARS-CoV-2 infected cells.
After the analysis of infected cells, they found 26 class-I and 36 class-II HLA peptides, which are present in 99% of the population around the world. Two peptides from HLA class-I were commonly present on the cell surface and two other peptides were derived from coronavirus rare proteins- which mean that these specific coronavirus peptides were marked for easy detection. Among the identified peptides, two peptides were novel discoveries and seven others were shown to induce an immune response earlier. These results from the study will help to develop new vaccines against new coronavirus mutation variants.
Gearing up ‘chain terminators’ to battle the coronavirus
Prof. Rotem Sorek and his lab discovered a family of enzymes within bacteria that produce novel antiviral molecules. These small molecules manufactured by bacteria act as ‘chain terminators’ to fight against the virus invading the bacteria. The study published in Nature in January which reported that these molecules cause a chemical reaction that halts the virus’s replication ability. These new molecules are modified derivates of nucleotide which integrates at the molecular level in the virus and obstruct the works.
Prof. Sorek and his group hypothesize that these new particles could serve as a potential antiviral drug based on the mechanism of chain termination utilized in antiviral drugs used recently in the clinical treatments. Yeda Research and Development has certified these small novel molecules to a company for testing its antiviral mechanism against SARS-CoV-2 infection. Such novel discoveries provide evidences that bacterial immune system is a potential repository of many natural antiviral particles.
Resolving borderline diagnoses
Currently, Real-time Polymerase chain reaction (RT-PCR) is the only choice and extensively used for diagnosis of COVID-19 patients around the globe. Beside its benefits, there are problems associated with RT-PCR, false negative and false positive results and its limitation in detecting new mutations in the virus and emerging variants in the population worldwide. Prof. Eran Elinavs’ lab and Prof. Ido Amits’ lab are working collaboratively to develop a massively parallel, next-generation sequencing technique that tests more effectively and precisely as compared to RT-PCR. This technique can characterize the emerging mutations in SARS-CoV-2, co-occurring viral, bacterial and fungal infections and response patterns in human.
The scientists identified viral variants and distinctive host signatures that help to differentiate infected individuals from non-infected individuals and patients with mild symptoms and severe symptoms.
In Hadassah-Hebrew University Medical Center, Profs. Elinav and Amit are performing trails of the pipeline to test the accuracy in borderline cases, where RT-PCR shows ambiguous or incorrect results. For proper diagnosis and patient stratification, researchers calibrated their severity-prediction matrix. Collectively, scientists are putting efforts to develop a reliable system that resolves borderline cases of RT-PCR and identify new virus variants with known and new mutations, and uses data from human host to classify patients who are needed of close observation and extensive treatment from those who have mild complications and can be managed conservatively.
Moon shot consortium refining drug options
The ‘Moon shot’ consortium was launched almost a year ago with an initiative to develop a novel antiviral drug against SARS-CoV-2 and was led by Dr. Nir London of the Department of Chemical and Structural Biology at Weizmann, Prof. Frank von Delft of Oxford University and the UK’s Diamond Light Source synchroton facility.
To advance the series of novel molecules from conception to evidence of antiviral activity, the scientists have gathered support, guidance, expertise and resources from researchers around the world within a year. The article reported that researchers have built an alternative template for drug-discovery, full transparency process, which avoids the hindrance of intellectual property and red tape.
The new molecules discovered by scientists inhibit a protease, a SARS-CoV-2 protein playing important role in virus replication. The team collaborated with the Israel Institute of Biological Research and other several labs across the globe to demonstrate the efficacy of molecules not only in-vitro as well as in analysis against live virus.
Further research is performed including assaying of safety and efficacy of these potential drugs in living models. The first trial on mice has been started in March. Beside this, additional drugs are optimized and nominated for preclinical testing as candidate drug.
Scientists have recognized human genes that fight against the SARS-CoV-2 viral infection. The information about genes and their function can help to control infection and aids the understanding of crucial factors that causes severe infection. These novel genes are related to interferons, the frontline fighter in our body’s defense system and provide options for therapeutic strategies.
Sumit K. Chanda, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys reported in the article that they focused on better understanding of the cellular response and downstream mechanism in cells to SARS-CoV-2, including the factors which causes strong or weak response to viral infection. He is the lead author of the study and explained that in this study they have gained new insights into how the human cells are exploited by invading virus and are still working towards finding any weak point of virus to develop new antivirals against SARS-CoV-2.
With the surge of pandemic, researchers and scientists found that in severe cases of COVID-19, the response of interferons to SARS-CoV-2 viral infection is low. This information led Chanda and other collaborators to search for interferon-stimulated genes (ISGs), are genes in human which are triggered by interferons and play important role in confining COVID-19 infection by controlling their viral replication in host.
The investigators have developed laboratory experiments to identify ISGs based on the previous knowledge gathered by the outbreak of SARS-CoV-1 from 2002-2004 which was similar to COVID-19 pandemic caused by SARS-CoV-2 virus.
The article reports that Chanda mentioned “we found that 65 ISGs controlled SAR-CoV-2 infection, including some that inhibited the virus’ ability to enter cells, some that suppressed manufacture of the RNA that is the virus’s lifeblood, and a cluster of genes that inhibited assembly of the virus.” They also found an interesting fact about ISGs that some of these genes revealed control over unrelated viruses, such as HIV, West Nile and seasonal flu.
Laura Martin-Sancho, Ph.D., a senior postdoctoral associate in the Chanda lab and first author of the study reported in the article that they identified 8 different ISGs that blocked the replication of both SARS-CoV-1 and CoV-2 in the subcellular compartments responsible for packaging of proteins, which provide option to exploit these vulnerable sites to restrict infection. They are further investigating whether the genetic variability within the ISGs is associated with COVID-19 severity.
The next step for researchers will be investigating and observing the biology of variants of SARS-CoV-2 that are evolving and affecting vaccine efficacy. Martin-Sancho mentioned that their lab has already started gathering all the possible variants for further investigation.
“It’s vitally important that we don’t take our foot off the pedal of basic research efforts now that vaccines are helping control the pandemic,” reported in the article by Chanda.
“We’ve come so far so fast because of investment in fundamental research at Sanford Burnham Prebys and elsewhere, and our continued efforts will be especially important when, not if, another viral outbreak occurs,” concluded Chanda.
Why wait for more info? A new case of cerebral sinus venus thrombosis was reported in a 25 year old man who became critically ill from a cerebral hemorrhage. And for women age 20-50, CSVT occurred in 1 in 13,000, or 4-15X higher than background.
UPDATED on 4/14/2021
How UK doctor linked rare blood-clotting to AstraZeneca Covid jab
We have put together the following mechanism for thrombosis including central vein sinus thrombosis as a complication of both J&J and the AstraZeneca vaccines. This unifying mechanism explains the predilection of cerebral veins and higher risk in younger women. Please share your thoughts on the proposed mechanism.
We have submitted the attached manuscript to SSRN. Sharing this promptly considering the public health significance.
Thanks
Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.
Best regards,
Ajay
Ajay Gupta, M.B.,B.S., M.D.
Clinical Professor,
Division of Nephrology, Hypertension and Kidney Transplantation
University of California Irvine
President & CSO, KARE Biosciences (www.karebio.com)
Title: SARS-CoV-2 vaccination induced thrombosis: Is chemoprophylaxis with antiplatelet agents warranted?
Guest Authors:
Kate Chander Chiang1
Ajay Gupta, MBBS, MD1,2
Affiliations
(1) KARE Biosciences, Orange, CA 92869
(2) Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868
*Corresponding author:
Ajay Gupta, MBBS, MD
Clinical Professor of Medicine,
Division of Nephrology, Hypertension and Kidney Transplantation
University of California Irvine (UCI) School of Medicine,
Orange, CA 92868
Tel: +1 (562) 412-6259
E-mail: ajayg1@hs.uci.edu
Word Count
Abstract: 359
Main Body: 1,648
Funding: No funding was required.
Conflict of Interest: AG and KCC have filed a patent for use of Ramatroban as an anti-thrombotic and immune modulator in SARS-CoV-2 infection. The patents have been licensed to KARE Biosciences. KCC is an employee of KARE Biosciences.
Author Contributions: AG and KCC conceptualized, created the framework, wrote and reviewed the manuscript.
The COVID-19 vaccines, Vaxzevria® (AstraZeneca) and the Janssen vaccine (Johnson & Johnson) are highly effective but associated with rare thrombotic complications. These vaccines are comprised of recombinant, replication incompetent, chimpanzee adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses, which protect against COVID-19. The immune responses are highly effective in preventing symptomatic disease in adults irrespective of age, gender or ethnicity. However, both vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). Megakaryocytes also express CAR, leading us to postulate adenovirus vector uptake and expression of spike glycoprotein by megakaryocytes. Spike glycoprotein induces expression of cyclooxygenase -2 (COX-2), leading to generation of thromboxane A2 (TxA2). TxA2 promotes megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to CVST. The mechanisms proposed are consistent with the following clinical observations. First, a massive increase in TxA2 generation promotes platelet activation and thromboinflammation in COVID-19 patients. Second, TxA2 generation and platelet activation is increased in healthy women compared to men, and in younger mice compared to older mice; and, younger age and female gender appear to be associated with increased risk of thromboembolism as a complication of adenoviral vector based COVID-19 vaccine. The roll out of both AstraZeneca and Janssen vaccines has been halted for adults under 30-60 years of age in many countries. We propose that antiplatelet agents targeting TxA2 receptor signaling should be considered for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to adults under 30-60 years of age. In many Asian and African countries, only adenovirus-based COVID-19 vaccines are available at present. A short course of an antiplatelet agent such as aspirin could allow millions to avail of the benefits of the AstraZeneca and Janssen COVID-19 vaccines which could be otherwise either denied to them or put them at undue risk of thromboembolic complications.
COVID-19 disease is caused by a novel positive-strand RNA coronavirus (SARS-CoV-2), which belongs to the Coronaviridae family, along with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) coronaviruses.1 The genome of these viruses encodes several non-structural and structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.2 The majority of the vaccines for COVID-19 that employ administration of viral antigens or viral gene sequences aim to induce neutralizing antibodies against the viral spike protein (S), preventing uptake through the ACE2 receptor, and thereby blocking infection.3
The Janssen COVID-19 vaccine (Johnson & Johnson) is comprised of a recombinant, replication- incompetent Ad26 vector, encoding a stabilized variant of the SARS-CoV-2 Spike (S) protein. The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria®) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, encoding the S protein.4 In US Phase III trials, Vaxzevria has been demonstrated to have 79% efficacy at preventing symptomatic COVID-19, and 100% efficacy against severe or critical disease and hospitalization, with comparable efficacy across ethnicity, gender and age.5 However, Vaxzevria has been associated with thrombotic and embolic events including disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), occurring within 14 days after vaccination, mostly in people under 55 years of age, the majority of whom have been women.6 Data from Europe suggests that the event rate for thromboembolic events may be about 10 per million vaccinated. Antibodies to platelet factor 4/heparin complexes have been recently reported in a few patients.7 However, the significance of this finding remains to be established. As of April 12, 2021, about 6.8 million doses of the Janssen vaccine have been administered in the U.S.8 CDC and FDA are reviewing data involving six reported U.S. cases of CVST in combination with thrombocytopenia.8 All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination.8
SARS-CoV-2 is known to cause thromboinflammation leading to thrombotic microangiopathy, pulmonary thrombosis, pedal acro-ischemia (“COVID-toes”), arterial clots, strokes, cardiomyopathy, coronary and systemic vasculitis, deep venous thrombosis, pulmonary embolism, and microvascular thrombosis in renal, cardiac and brain vasculature.9-14 Cerebral venous sinus thrombosis (CVST) has also been reported in COVID-19 patients.15 Amongst 34,331 hospitalized COVID-19 patients, CVST was diagnosed in 28.16 In a multicenter, multinational, cross sectional, retrospective study of 8 patients diagnosed with CVST and COVID-19, seven were women.17 In another series of 41 patients with COVID-19 and CVST, the average age was about 50 years (SD, 16.5 years).17 The pathobiology of thrombotic events associated with the AstraZeneca vaccine should be viewed in the context of mechanisms underlying thromboinflammation that complicates SARS-CoV-2 infection and COVID-19 disease.
A. Role of COX-2 and thromboxane A2 in thromboinflammation complicating adenovirus based COVID-19 vaccine encoding the Spike protein of SARS-CoV-2
Thromboinflammation in COVID-19 seems to be primarily caused by endothelial, platelet and neutrophil activation, platelet-neutrophil aggregates and release of neutrophil extracellular traps (NETs).13,18 Platelet activation in COVID-19 is fueled by a lipid storm characterized by massive increases in thromboxane A2 (TxA2) levels in the blood and bronchoalveolar lavage fluid.19,20 Cyclooxygenase (COX) enzymes catalyze the first step in the biosynthesis of TxA2 from arachidonic acid, and COX-2 expression is induced by the spike (S) protein of coronaviruses.21 We postulate that an aberrant increase in TxA2 generation induced by the spike protein expression from the AstraZeneca vaccine leads to thromboinflammation, thromboembolism and CVST. 4
The support for the above proposed mechanism comes from the following observations. First, when mice of different age groups were infected with SARS-CoV virus, the generation of TxA2 was markedly increased in younger mice compared to middle aged mice.22 Furthermore, in children with asymptomatic or mildly symptomatic SARS-CoV-2 infection, microvascular thrombosis and thrombotic microangiopathy occur early in infection.20 These observations are consistent with the higher risk for thrombosis in adults under 60 years of age, compared with the older age group.6,7 Second, platelets from female mice are much more reactive than from male mice.23 Furthermore, TxA2 generation, TxA2-platelet interaction and activation is increased in women compared to men.24,25 These observations are consistent with disproportionately increased risk of thrombosis in women following AstraZeneca and Janssen COVID-19 vaccines.
The adenoviral vector ChAdOx1, containing nCoV-19 spike protein gene, infects host cells through the coxsackievirus and adenovirus receptor (CAR).26 CAR-dependent cell entry of the viral vector allows insertion of the SARS-CoV-2 spike protein gene and expression of Spike protein by host cells (Figure 1). CAR is primarily expressed on epithelial tight junctions.27 CAR expression has also been reported in platelets,28 and since platelets are anucleate cells CAR expression by megakaryocytes can be inferred. Therefore, AstraZeneca and Janssen vaccines would be expected to induce expression of Spike protein in megakaryocytes and platelets (Figure 1).
Spike protein of coronaviruses in known to induce COX-2 gene expression.21,29 COX-2 expression is induced during normal human megakaryopoiesis and characterizes newly formed platelets.30 While in healthy controls <10% of circulating platelets express COX-2, in patients with high platelet generation, up to 60% of platelets express COX-2.30 Generation of TxA2 by platelets is markedly suppressed by COX-2 inhibition in patients with increased megakaryopoiesis versus healthy subjects.30 Therefore, we postulate that expression of Spike protein induces COX-2 expression and generation of thromboxane A2 by megakaryocytes. TxA2 promotes biogenesis of activated platelets expressing COX-2. Platelet TxA2 generation leads to platelet activation and aggregation, and thereby thromboinflammation (Figure 1).
Extravascular spaces of the lungs comprise populations of mature and immature megakaryocytes that originate from the bone marrow, such that lungs are a major site of platelet biogenesis, accounting for approximately 50% of total platelet production or about 10 million platelets per hour.31 More than 1 million extravascular megakaryocytes have been observed in each lung of transplant mice.31 Following intramuscular injection of the AstraZeneca and Janssen vaccines, the adenovirus vector will traverse the veins and lymphatics to be delivered to the pulmonary circulation thereby exposing lung megakaryocytes in the first pass. Interestingly, under thrombocytopenic conditions, haematopoietic progenitors migrate out of the lung to repopulate the bone marrow and completely reconstitute blood platelet counts.31
B. Predilection of cerebral venous sinuses for thrombosis following vaccination
Recent studies have demonstrated that arterial, venous and sinusoidal endothelial cells in the brain uniquely express markers of the lymphatic endothelium including podoplanin.32 Podoplanin serves as a ligand for CLEC2 receptors on platelets.33 Thromboxane A2 dependent CLEC2 signaling leads to platelet activation (Figure 1), while a TxA2 receptor antagonist nearly abolish CLEC2 signaling and platelet activation.33 TxA2 dependent CLEC2 signaling promotes release of exosomes and microvesicles from platelets, leading to activation of CLEC5A and TLR2 receptors respectively on neutrophils, neutrophil activation and release of neutrophil extracellular traps (NETs) (Figure 1).34 Neutrophil activation, more than platelet activation, is associated with thrombotic complications in COVID-19.13,18,35 As proposed above, the expression of podoplanin, a unique molecular signature of cerebral endothelial cells, may be responsible for the predilection of brain vascular bed to thromboinflammation and CVST as a complication of COVID-19 vaccines. 5
C. Chemoprophylaxis with antiplatelet agents
In animal models of endotoxin mediated endothelial injury and thromboinflammation, antagonism of TxA2 signaling prevents ARDS, reduces myocardial damage and increases survival.36-38
Considering the key role played by platelets in thromboinflammation, we propose consideration of antiplatelet agents, either aspirin or TxA2 receptor antagonists, as chemoprophylactic agents when the AstraZeneca vaccine is administered to adults between 18 and 60 years of age.39 High bleeding risk because of another medical condition or medication would be contraindications to use of antiplatelet agents.39 Medical conditions that increase bleeding risk include previous gastrointestinal bleeding, peptic ulcer disease, blood clotting problems, and kidney disease.39 Medications that increase bleeding risk include nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants or anti-platelet agents.39 Aspirin appears to be safe in COVID-19. In a retrospective observational study in hospitalized patients with COVID-19, low-dose aspirin was found to be effective in reducing morbidity and mortality; and was not associated with any safety issues including major bleeding.40 Therefore, aspirin is likely to be safe as an adjunct to COVID-19 vaccines even in the event of a subsequent infection with SARS-CoV-2 virus.
Can aspirin influence the host immune response to the COVID-19 vaccines? This issue merits further investigation. When healthy adults > 65 years of age were given influenza vaccine and randomized to receive 300 mg aspirin or placebo on days 1, 2, 3, 5 and 7, the aspirin group showed 4-fold or greater rise in influenza specific antibodies.41 The risk-benefit analysis, based on above information, suggests that a one to three week course of low-dose aspirin merits consideration in order to prevent the thromboembolic events associated with the AstraZeneca vaccine.
SUMMARY
Thromboembolic disease including disseminated intravascular coagulation and cerebral venous sinus thrombosis have been reported in association with AstraZeneca and Janssen COVID-19 vaccines. Many countries have halted use of these vaccines either entirely or for adults under 30 to 60 years of age. European and North American countries generally have access to mRNA vaccines. However, in Asian and African countries the choices are limited to adenovirus based COVID-19 vaccines. The governments in such countries are forging ahead with vaccinating all adults, including those under 60 years of age, with Vaxzevria, Covishield (the version of Vaxzevria manufactured by the Serum Institute of India) or the Janssen vaccines. This has led to grave concern and anxiety amongst the citizens and medical professionals. Considering the profound global public health implications of limiting the use of these vaccines, it is critical to understand the pathobiology of vaccination induced thrombotic events in order to guide strategies aimed at prevention. In this regard, studies are urgently needed to examine lipid mediators and thromboxane A2 – platelet axis following vaccination with these vaccines, compared with mRNA vaccines. The risk-benefit analysis based on information presented here suggests that chemoprophylaxis using a short course of low-dose aspirin in adults under 60 years of age may be justified in conjunction with adenovirus based COVID-19 vaccines in order to prevent thromboembolic events and enhance safety. 6
Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.
REFERENCES
1. Ortiz-Prado E, Simbaña-Rivera K, Gómez-Barreno L, et al. Clinical, molecular, and epidemiological characterization of the SARS-CoV-2 virus and the Coronavirus Disease 2019 (COVID-19), a comprehensive literature review. Diagn Microbiol Infect Dis. 2020;98(1):115094.
2. Du L, He Y, Zhou Y, Liu S, Zheng B-J, Jiang S. The spike protein of SARS-CoV — a target for vaccine and therapeutic development. Nature Reviews Microbiology. 2009;7(3):226-236. 7
3. Kyriakidis NC, López-Cortés A, González EV, Grimaldos AB, Prado EO. SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates. npj Vaccines. 2021;6(1).
4. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. 2021;397(10269):99-111.
7. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. New England Journal of Medicine. 2021.
9. Ackermann M, Verleden SE, Kuehnel M, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. New England Journal of Medicine. 2020.
10. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York City. N Engl J Med. 2020;382(24):2372-2374.
11. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine. 2020;382(18):1708-1720.
12. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, et al. Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients. Blood. 2020.
13. Nicolai L, Leunig A, Brambs S, et al. Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated with Respiratory Failure and Coagulopathy. Circulation. 2020.
14. Song W-C, Fitzgerald GA. COVID-19, microangiopathy, hemostatic activation, and complement. Journal of Clinical Investigation. 2020.
15. Mowla A, Shakibajahromi B, Shahjouei S, et al. Cerebral venous sinus thrombosis associated with SARS-CoV-2; a multinational case series. J Neurol Sci. 2020;419:117183.
16. Baldini T, Asioli GM, Romoli M, et al. Cerebral venous thrombosis and severe acute respiratory syndrome coronavirus-2 infection: A systematic review and meta-analysis. Eur J Neurol. 2021.
17. Abdalkader M, Shaikh SP, Siegler JE, et al. Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature. J Stroke Cerebrovasc Dis. 2021;30(6):105733.
18. Petito E, Falcinelli E, Paliani U, et al. Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019. The Journal of Infectious Diseases. 2020. 8
19. Archambault A-S, Zaid Y, Rakotoarivelo V, et al. Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites. medRxiv. 2020:2020.2012.2004.20242115.
20. Diorio C, McNerney KO, Lambert M, et al. Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Advances. 2020;4(23):6051-6063.
21. Liu M, Gu C, Wu J, Zhu Y. Amino acids 1 to 422 of the spike protein of SARS associated coronavirus are required for induction of cyclooxygenase-2. Virus Genes. 2006;33(3):309-317.
22. Vijay R, Hua X, Meyerholz DK, et al. Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection. J Exp Med. 2015;212(11):1851-1868.
23. Leng X-H, Hong SY, Larrucea S, et al. Platelets of Female Mice Are Intrinsically More Sensitive to Agonists Than Are Platelets of Males. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(2):376-381.
24. Kim BS, Auerbach DA, Sadhra H, et al. A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction. In: Cold Spring Harbor Laboratory; 2019.
25. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105(14):1650-1655.
26. Cohen CJ, Xiang ZQ, Gao G-P, Ertl HCJ, Wilson JM, Bergelson JM. Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor. Journal of General Virology. 2002;83(1):151-155.
27. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci U S A. 2001;98(26):15191-15196.
28. Assinger A. Platelets and infection – an emerging role of platelets in viral infection. Front Immunol. 2014;5:649.
29. Yan X, Hao Q, Mu Y, et al. Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein. Int J Biochem Cell Biol. 2006;38(8):1417-1428.
30. Rocca B, Secchiero P, Ciabattoni G, et al. Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A. 2002;99(11):7634-7639.
31. Lefrançais E, Ortiz-Muñoz G, Caudrillier A, et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544(7648):105-109.
32. Mezey É, Szalayova I, Hogden CT, et al. An immunohistochemical study of lymphatic elements in the human brain. Proceedings of the National Academy of Sciences. 2021;118(3):e2002574118.
35. Ng H, Havervall S, Rosell A, et al. Circulating Markers of Neutrophil Extracellular Traps Are of Prognostic Value in Patients With COVID-19. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41(2):988-994.
36. Carey MA, Bradbury JA, Seubert JM, Langenbach R, Zeldin DC, Germolec DR. Contrasting Effects of Cyclooxygenase-1 (COX-1) and COX-2 Deficiency on the Host Response to Influenza A Viral Infection. The Journal of Immunology. 2005;175(10):6878-6884.
37. Kuhl PG, Bolds JM, Loyd JE, Snapper JR, FitzGerald GA. Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia. Am J Physiol. 1988;254(2 Pt 2):R310-319.
38. Altavilla D, Canale P, Squadrito F, et al. Protective effects of BAY U 3405, a thromboxane A2 receptor antagonist, in endotoxin shock. Pharmacol Res. 1994;30(2):137-151.
39. Peters AT, Mutharasan RK. Aspirin for Prevention of Cardiovascular Disease. JAMA. 2020;323(7):676.
40. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin Use Is Associated With Decreased Mechanical Ventilation, Intensive Care Unit Admission, and In-Hospital Mortality in Hospitalized Patients With Coronavirus Disease 2019. Anesthesia & Analgesia. 2021;132(4).
41. Saleh E, Moody MA, Walter EB. Effect of antipyretic analgesics on immune responses to vaccination. Human Vaccines & Immunotherapeutics. 2016;12(9):2391-2402.
Subject: APRIL 13. 2021 – J&J Statement – Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine. ->> Are there relations between these FINDINGS?
Johnson & Johnson Statement on COVID-19 Vaccine
NEW BRUNSWICK, N.J., April 13, 2021– The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.
In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.
We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.
The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.
For more information on the Janssen COVID-19 vaccine, click here.
Please All send me your Expert Opinion on the relations between these FINDINGS?
Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca | Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.
Reporter: Dr. Premalata Pati, Ph.D., Postdoc
SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.
It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?
Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.
This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.
Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.
(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.
The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.
Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.
Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection
Forthcoming directions by Bing Chen and Team
The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:
Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants
Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.
In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.
Main Source:
Abstract
Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.
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
Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.
Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in more than 113 million persons infected and 2.5 million deaths (1). However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection. Although a standardized case definition does not yet exist for these manifestations, in the broadest sense they represent a failure to return to a baseline state of health after acute SARS-CoV-2 infection. The various terms used to describe this condition have included postacute (or late) sequelae of COVID-19, post-COVID condition or syndrome, long COVID, and long-haul COVID. In this article, we use the general umbrella term of “postacute COVID-19” to refer to multiple disease processes that may have varying degrees of overlap (including but not limited to sequelae of critical illness and hospitalization in persons with COVID-19) and the entity of long COVID, which refers to prolonged health abnormalities in persons previously infected with SARS-CoV-2 who may or may not have required hospitalization. Of note, there is not yet a consensus on terminology, which will likely evolve with a better understanding of this condition.
Reported symptoms are wide-ranging and may involve nearly all organ systems, with fatigue, dyspnea, cognitive dysfunction, anxiety, and depression often described (2–5). Although abnormalities in imaging studies and functional testing have been reported, the long-term clinical significance of some of these findings is not yet clear (3, 6, 7). Postacute manifestations of COVID-19 have been seen in persons of all demographic groups and include reports of multisystem inflammatory syndrome in children (8, 9). Although the epidemiology of the diverse manifestations of postacute COVID-19 is not yet known, the expansive global burden of SARS-CoV-2 infection suggests that the potential public health effects of postacute COVID-19 are significant if even a small proportion of persons with SARS-CoV-2 infection have prolonged recovery or do not return to their baseline health.
On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop (available via videocast at https://videocast.nih.gov/watch=38878 and https://videocast.nih.gov/watch=38879) to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps. The speakers and participants included epidemiologists, clinicians, clinical and basic scientists, and members of the affected community. The videocast was open to the general public and had more than 1200 registered participants.
COVID-19 survivors face a sharply elevated risk of developing psychiatric or neurologic disorders in the six months after they contract the virus — a danger that mounts with symptom severity, new research shows.
In what is purported to be the largest study of its kind to-date, results showed that among 236,379 COVID-19 patients, one third were diagnosed with at least one of 14 psychiatric or neurologic disorders within a 6-month span.
The rate of illnesses, which ranged from depression to stroke, rose sharply among those with COVID-19 symptoms acute enough to require hospitalization.
“If we look at patients who were hospitalized, that rate increased to 39%, and then increased to about just under 1 in 2 patients who needed ICU admission at the time of the COVID-19 diagnosis,” Maxime Taquet, PhD, University of Oxford Department of Psychiatry, Oxford, United Kingdom, told a media briefing.
Incidence jumps to almost two thirds in patients with encephalopathy at the time of COVID-19 diagnosis, he added.
The study, which examined the brain health of 236,379 survivors of COVID-19 via a US database of 81 million electronic health records, was published online April 6 in The Lancet Psychiatry.
High Rate of Neurologic, Psychiatric Disorders
The research team looked at the first-time diagnosis or recurrence of 14 neurologic and psychiatric outcomes in patients with confirmed SARS-CoV-2 infections. They also compared the brain health of this cohort with a control group of those with influenza or with non-COVID respiratory infections over the same period.
The Effects of Loneliness and Our Brain function:poorer physical and mental health
One review of the science of loneliness found that people with stronger social relationships have a 50 per cent increased likelihood of survival over a set period of time compared with those with weaker social connections. Other studies have linked loneliness to cardiovascular disease, inflammation, and depression.
For loneliness researchers the pandemic has provided an unprecedented natural experiment in the impact that social isolation might have on our brains. As millions of people across the world emerge from months of reduced social contact, a new neuroscience of loneliness is starting to figure out why social relationships are so crucial to our health.
Neural basis of Emotion
Desire for Social Interaction
Are there neurological differences between people who experience short-term isolation and those who have been isolated for long stretches of time? What kinds of social interactions satisfy our social cravings? Is a video call enough to quell our need for social contact, or do some people require an in-person connection to really feel satiated?
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Julianne Holt-Lunstad, a psychology professor at Brigham Young University in the US and the author of two major studies on social isolation and health. “We have a lot of data that very robustly shows that both isolation and loneliness put us at increased risk for premature mortality—and conversely, that being socially connected is protective and reduces our risk,” she says.
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“Trying to investigate isolation or loneliness is not as straightforward in humans. In humans, being lonely is not necessarily correlated with how many people are around you,” says Tomova. She is particularly interested in the impact that the pandemic might have had on young people whose cognitive and social skills are still developing. “I think we will see potentially some differences in how their social behavior developed or things like that,” she says. But as is always the case in the uncertain world of loneliness research, the opposite could be true. “It could also be that most people are fine, because maybe social media does fulfill our social needs really well.”
The Weird Science of Loneliness and Our Brains – Social isolation as been linked to poorer physical and mental health, but scientists are finally starting to understand its neurological impact
FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus – J&J single vaccine – Authorized on 2/28/2021
Reporter: Aviva Lev-Ari, PhD, RN
J&J’s Covid-19 vaccine gets vote of confidence from FDA advisory panel
The committee voted 22-0 on the question of whether the benefits of Johnson & Johnson’s Covid-19 vaccine outweigh its risks. FDA emergency use authorization would bring the public a third vaccine for the novel coronavirus.
The U.S. is one step closer to making available another Covid-19 vaccine after a panel of experts voted unanimously Friday to recommend emergency use authorization for a shot developed by Johnson & Johnson.
The independent panel, comprised of mostly physicians, voted 22-0 to support the vaccine with no one abstaining. These votes aren’t binding on the FDA, but the agency often follows the recommendations of its panels. A decision could come as early as this weekend. The two Covid vaccines currently cleared for emergency use received their authorizations the day after their respective advisory panel meetings.
The Johnson & Johnson vaccine would offer an alternative to the ones currently available from the Pfizer and BioNtech alliance, and Moderna. Those messenger RNA vaccines must be distributed and stored at ultra-cold temperatures, then thawed before use. Those shots are given as two doses, weeks apart. The J&J vaccine can be kept at refrigerator temperatures. Another key difference is that the J&J jab requires a single shot. Together, those features will make the J&J vaccine easier to distribute to more people in more places through distribution channels that are already in place.
Panel members expressed support for the J&J vaccine, saying that the safety and efficacy data supported its authorization. But panelists also cautioned the public against picking vaccine favorites.
“It’s important that people do not think one vaccine is better than another,” said Cody Meissner, an infectious disease expert and professor of pediatrics at the Tufts University School of Medicine. “There is no preference for one vaccine over another and all vaccines work with what appears to be equal safety and equal efficacy as of this time.”
FDA plays a critical role in protecting the United States (U.S.) from threats such as emerging infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic.
FDA is issuing this guidance to provide sponsors of requests for Emergency Use Authorization (EUA) for COVID-19 vaccines with recommendations regarding the data and information needed to support the issuance of an EUA under section 564 of the FD&C Act (21 U.S.C. 360bbb-3) for an investigational vaccine to prevent COVID-19 for the duration of the COVID-19 public health emergency.
FDA Statement on Vaccines and Related Biological Products Advisory Committee Meeting
The following is attributed to Acting Commissioner Janet Woodcock, M.D. and Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research
SILVER SPRING, Md., Feb. 26, 2021 /PRNewswire/ — Following today’s positive advisory committee meeting outcome regarding the Janssen Biotech Inc. COVID-19 Vaccine, the U.S. Food and Drug Administration has informed the sponsor that it will rapidly work toward finalization and issuance of an emergency use authorization. The agency has also notified our federal partners involved in vaccine allocation and distribution so they can execute their plans for timely vaccine distribution.
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
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.
Google Cloud is the latest company to put its tech muscle behind efforts to vaccinate millions of Americans against the COVID-19 virus.
The company launched artificial intelligence and machine learning tools Monday to help organizations forecast and model COVID-19 cases to better inform vaccine allocation. The cloud-based tools also are designed to assist with vaccine distribution, appointment scheduling, eligibility screening and communications.
The technology, called the Intelligent Vaccine Impact solution, also analyzes consumer sentimentaround the COVID-19 vaccine. Understanding how local communities feel about the risks and benefits of the vaccine is critical to being able to increase confidence in vaccination, Google Cloud executives said. The sentiment analysis tool, which was developed in partnership with behavioral intelligence data company Syntasa, will help public health agencies develop a more tailored and informed vaccination campaign.
“We’ve created a set of core technologies to help regional and local governments deliver successful COVID-19 public health strategies, ranging from vaccine information and scheduling, to distribution and analytics, to forecasting and modeling COVID-19 cases,” said Mike Daniels, vice president of the global public sector at Google Cloud, in a blog post.
The new solution helps increase vaccine availability and equitable access to those who need it and assists governments in building awareness, confidence and acceptance of vaccines, Daniels wrote.
“We designed our solution to easily integrate with existing technologies, knowing that governments will administer their vaccine distributions in unique ways,” he said.
As the COVID-19 vaccine distribution effort in the U.S. gets off to a bumpy start, tech giants are seizing the business opportunity and throwing their considerable resources into the effort to overcome logistical hurdles. Microsoft is partnering with a number of organizations on vaccine management efforts for both government and healthcare customers. The tech giant worked with business partners including Accenture, Avanade, EY and Mazik Global to deploy vaccine management solutions that enable registration capabilities for patients and providers, phased scheduling for vaccinations, streamlined reporting and management dash-boarding with analytics and forecasting.
IBM launched supply chain management software and a blockchain-based approach to verify and track vaccines, certify that patients have had the vaccine and keep track of which patients received which vaccine.
Salesforce rolled out a cloud-based vaccine management solution that’s being used by government agencies and healthcare organizations including Northwell Health, Illinois’ Lake County, University of Massachusetts Amherst and Gavi, the Vaccine Alliance. And Oracle set up an electronic health record database and public health applications to track vaccinations and side effects.
As part of its efforts, Google Cloud researchers developed a machine learning approach that combines AI with a foundation of epidemiology to help with COVID-19 forecasting, Daniels said in the blog post. Researchers also developed an AI-driven “what-if” model to be used for COVID-19 response and other infectious disease policy intervention decision-making.
Government leaders can use data to see how forecasts change in response to policy changes, such as mask mandates, modified reopening plans or vaccination programs.
Google Cloud’s solution also includes a vaccine information portal to help overwhelmed local governments address questions and concerns from the public, Daniels said.
“Working in partnership with SpringML, MTX, Deloitte and other partners, Google Cloud has built several vaccine information portals that help people learn about vaccine availability, determine if they qualify, sign up for vaccination, and submit their information so that when they are eligible they can be vaccinated as quickly as possible,” he said in the blog post.
The solution also offers consumers online registration and prescreening, location searches and appointment setting as well as automated reminders. The solution relies on Google Cloud Healthcare API to transmit data using common formats such as HL7 or FHIR—which interoperate with existing healthcare and immunization systems, the tech giant said.
Several states including North Carolina and New York have already deployed Google Cloud’s vaccine management solution.
“Our newest effort is to develop a process and technology to streamline accessing information for North Carolinians,” said Sam Gibbs, deputy secretary for technology and operations for the state of North Carolina, in a statement. “This technology will provide a central location for residents to find information such as when it is their turn to get their vaccine or guidance to easily locate a vaccination location.”
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.
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.
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
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
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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
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 …
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.
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.
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.
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.
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.”
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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.
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:
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.
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.
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.”
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