We have the outline of the process units and target suppliers of different equipments. It is encouraging two protein subunits are commencing clinical trials. Each uses prior formulated adjunvates and antigens. We wish to base the adjuvant on a bespoke basis to address the uniqueness of the virus and suggestions are welcomed please. We have identified dispensing options. The ingredients and formulation detailing suggestions and advice on process options will help and be appreciated. Dr Chris Eaglen 00447711310442 and [email protected] Thank you and Best Wishes

With 16 years of attempts to address coronavirus variants and no agreement on platforms and very different approaches of types within each platform is the synthesis of vaccines most limited to chance than methodology. We were seeking a structured process working from all the partial and very, detailed understandings of the significant mechanisms. Analysis and descriptive detailing is enriched whilst synthesis and formulation needs advancing. Who are the leading synthesisers for Covid 19 vaccine and adjuvants please. We welcome proposals for a protein subunit with adjuvanted spike protein basis please.

SARS-CoV-2 Covid 19 Vaccine: As anyone produced a flowchart (flow sheet) for an adjunvated spike protein subunit vaccine which identifies the precursor and protein ingredients and incorporates the synthesis of the Coronavirus “Spike” S1 and S2 antigens in human (HEK-293) cells, so that the protein formation, glycosylation (for recognition by the immune antibodies) is as true to life as possible, or similar. We require the protein subunit vaccine to be relatively easy to make and to be suitable for vaccinating vulnerable people. We prefer using an inhaled powder please. Thank you Dr Chris Eaglen

Have you guys identified the e therapeutical compound yet

We are encouraged by the overview comparison of 3 approaches to the adjuvant in article: https://www.clinicaltrialsarena.com/comment/clover-biopharmaceuticals-covid-19-vaccine/ We need to await the stated Clinical trials for the determination about the effectiveness of the protection mentioned at the end of article: Extract:

Neutralising antibodies do not always correlate to protection, XXXX added, noting this disconnect is observed in rotavirus vaccines.

Although XXXXX S-Trimer vaccine has data showing it induced spike protein-specific antibodies the same as those in recovered Covid-19 patients, such a benchmark may be inappropriate, XXXX said. Antibodies induced by natural infection and vaccination are different, as the former is produced with moderation from the virus, XXXX added.

The composition of the compound has to be determined and is the purpose of this question.

This is the text of the article in the clinicaltrialsarena link and is that publisher's copyright. Comments with respect to the adjuvants will be appreciated.

Quoted article:

Clover Biopharmaceuticals’ Covid-19 protein subunit vaccine could potentially have the upper hand versus Novavax’s and IMV’s due to the former’s use of Dynavax Technologies’ FDA-approved adjuvant. However, it is premature to predict a clear frontrunner among the three vaccines due to information gaps such as how the spike protein antigen is constructed and reproduction platforms to be used for manufacturing.

On Monday (25 May), Novavax’s stock jumped as high as 17% during trading hours on announcing it had enrolled the first participants in its Phase I/II trial. IMV’s stock rose 20% on 21 May after announcing plans to enter clinical development. Dynavax was up 14% on 24 March upon its collaboration announcement with Clover Biopharmaceuticals.

Chengdu, China-based Clover Biopharmaceuticals initially called its S-Trimer vaccine a recombinant protein subunit vaccine but has since described it as “native-like,” or resembling the native SARS-CoV-2 spike protein. A synthetic spike protein antigen, such as in Novavax’s NVX‑CoV2373, would have a leg up compared to a native version, as the latter is at risk of reconfiguration once administered.

Clover’s vaccine may be at an additional disadvantage, as its spike protein antigen is produced via a mammalian cell-culture based expression system, which is a more expensive process. While Novavax hasn’t announced its production process, IMV’s vaccine DPX-Covid-19 only featuring viral peptides could benefit on this front.

Yet, IMV’s vaccine not featuring the entire spike protein drew the least expert enthusiasm. Peptides by themselves are not immunogenic, and DPX-Covid-19 does not have an adjuvant. Clover’s vaccine, though, is coupled with Dynavax’s toll-like receptor 9 (TLR9) agonist adjuvant, which is part of an approved vaccine.

The shape of the spike protein- prominent proteins found on the virus’ outer surface – in SARS-Cov-2 is essential to determining how to target the virus.

Novavax’s Australia-based Phase I (NCT04368988) will recruit about 130 patients, and preliminary immunogenicity and safety data are expected in July. Clover’s Phase I will also be based in Australia but has not yet been scheduled, while IMV’s Phase I is slated to start in the summer.

Novavax, which has a $2.64bn market cap, has so far received $388m from the international foundation Coalition for Epidemic Preparedness Innovations, with Clover Biopharmaceuticals receiving $39.6m. IMV, which has a CAD 265.4m market cap, has submitted several grant applications in Canada, said a spokesperson.

Protein subunit vaccines are one of several vaccine types under investigation for Covid-19, with at least 60 assets from discovery to Phase I stage listed on the GlobalData database. While Moderna’s mRNA vaccine mRNA-1273 is the perceived frontrunner in the Covid-19 vaccine race, with positive interim Phase I data released on 18 May, this news service reported 16 April that Moderna has many long-term success obstacles ahead. Future Phase II immunogenicity data may not forecast Phase III protection results, and as reported on 14 May a registrational field trial expected to start in the summer is likely to require around 25,000 volunteers. A challenge trial could be considered for quick protection data, but such a trial design also has its own operational and ethical conundrums.

Clover Biopharmaceuticals adjuvant choice key for efficacy edge

Novavax is utilising its matrix-M saponin-based adjuvant with NVX‑CoV2373. However, a general issue with a saponin-based adjuvant is that it needs to be combined with another adjuvant, said David Dowling, PhD, principal investigator, Adjuvant Discovery and Development Laboratory, Harvard Institutes of Medicine, Boston. While a saponin-based adjuvant can enhance immune response, the second adjuvant is needed to polarise the immune system to prevent side effects such as antibody-dependent enhancement (ADE), he explained. ADE is a particular concern in Covid-19, as it was previously observed with SARS and MERS, he noted.

Clover’s S-Trimer vaccine has the advantage of being combined with an adjuvant, and in particular with Dynavax’s TLR9 agonist adjuvant CpG1018, as CpG1018 is part of an already approved vaccine, Dowling noted. Adjuvants face rigorous testing, which means a significant investment from companies, and thus they are not normally licensed out, added Gordon Dougan, PhD, professor, Department of Medicine, Cambridge University, UK.

Adjuvants from a branded product would have stronger safety data, which is critical as autoimmunity issues is a recurring concern with adjuvants, noted Dougan. Dynavax’s Heplisav-B has the same adjuvant as Clover’s S-Trimer and was approved in November 2017 for hepatitis B virus in adults. Novavax’s adjuvant is not part of an approved product, but the company announced positive topline results from its Phase III seasonal influenza trial (NCT04120194) of NanoFlu, which uses the same matrix-M adjuvant as NVX‑CoV2373. Phase III showed noninferior data versus Sanofi Pasteur’s (EPA:SAN) Fluzone in those 65 years and over. If an adjuvant is shown to work in older adults, who have weaker immune systems, it is also likely to work in younger adults, Dowling noted. Novavax’s Phase I NVX‑CoV2373 trial is recruiting participants aged 18 to 59 years.

That said, Dowling noted, it is hard to know if the adjuvant is mechanistically important to any vaccine, and so specific Covid-19 data are important. Before Clover Biopharmaceuticals announced its collaboration with Dynavax, it publicised it was working with GlaxoSmithKline for the latter’s adjuvant. GSK’s vaccine data shows this adjuvant is better suited in younger adults than older people, Dowling said. GSK advised the same to the project.

IMV, on the other hand, announced animal model data showing that DPX-Covid-19’s peptide epitopes generated an antibody response after two doses without requiring an adjuvant. However, peptide vaccines are definitely likely to need an adjuvant, said Don Diamond, PhD, professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, California. It is unlikely that several peptides would be effective in activating the immune system, particularly in older adults, Dowling explained. Peptides are so small that the immune system may not recognise them, and they are not immunogenic by themselves, Dougan added.

Novavax’s Phase I trial is investigating adjuvanted and unadjuvanted versions of NVX‑CoV2373. Another adjuvant advantage is that the antigen amount needed for each vaccine would reduce. This means decreased manufacturing costs, with more total doses for the same number of antigens produced, Dowling explained.

An adjuvant would also reduce the ADE risk, as it directs the immune system to the right kind of response, Dowling noted. The IMV spokesperson said all of IMV’s assets are formulated on its DPX platform, which has had positive safety data so far. Most adverse events were Grade 1–2 and localised at the injection site, he added. IMV’s most advanced therapeutic vaccine is in Phase II and the most advanced prophylactic vaccine is in Phase I.

Protein/peptide construction, manufacturing critical for differentiation

Another avenue of differentiation between protein subunit vaccines could come down to the spike protein antigen. Novavax’s NVX‑CoV2373 features a recombinant version of SARS-CoV-2’s spike protein, whereas Clover’s S-Trimer vaccine has a native-like spike protein.

While only Novavax has noted that its vaccine has the prefusion configuration of the spike protein, this is likely to also be the case with Clover’s, as a postfusion configuration has its receptor-binding domains (RBDs) hidden, and RBD is the critical target in generating neutralising antibodies, said Andrew Ward, PhD, professor, Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, California. A prefusion configuration is also representative of an infectious virus, he added.

A native spike protein antigen, however, is at risk of converting from a prefusion to a postfusion configuration once administered, thus hiding the RBD, Ward noted. Nevertheless, there is still the possibility that enough RBD remains exposed even in the postfusion configuration, he added. Different RBDs can trigger different types or levels of neutralising antibodies, Dougan explained.

Another potential concern with a native spike protein antigen is that during the purification step to extract the spike protein, inserted sugars or lipids could lead to unwanted protein variations, noted Ciro Leonardo Pierri, PhD, spike protein researcher, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Italy. However, this could be irrelevant as long as the vaccine can still trigger neutralising antibodies, he added.

In contrast to Novavax’s and Clover’s vaccines, IMV’s DPX-Covid-19 only has 23 SARS-CoV-2 peptide epitopes as opposed to the entire spike protein. A potential advantage of this approach is that the vaccine could induce a more specific immune response, Pierri and Ward said. Considering how large the spike protein is, other types of antibodies could be generated, Pierri explained.

The RBD is only one-tenth of the entire spike protein, Ward added. The IMV spokesperson said the selected peptides have demonstrated in preclinical studies the ability to elicit a target-specific, robust and sustained immune response. Still, featuring the entire spike protein helps stimulate the immune system overall, and a domino effect would then lead the immune system to find the RBD, Ward said.

How the spike protein is replicated for manufacturing is one more point of distinction between the three companies’ strategies, Dougan said. As per the 16 April article, mRNA vaccines such as Moderna’s may have manufacturing edge over vaccines that carry viral proteins, as the latter approach has additional steps that include cell line and purification procedures. A company that uses a yeast platform may have the scale-up advantage, as it is cheaper versus mammalian cells, Dougan added. Clover Biopharmaceuticals, which did not respond to a request for comment, is producing its vaccine via a mammalian cell expression system.

When asked about its manufacturing approach, a Novavax spokesperson forwarded the media release from yesterday (27 May) stating it had acquired Praha Vaccines in a transaction worth $167m, which covers biologics manufacturing facilities and other assets in the Czech Republic. This facility would provide an annual capacity of over one billion doses of antigen in 2021 for NVX‑CoV2373. For IMV, the antigen peptides in DPX-Covid-19’s are synthetic and do not require biologic manufacturing, the company spokesperson said. Perhaps IMV’s approach is more scalable as it only features peptides, Ward added.

Nevertheless, none of these three protein subunit vaccines has human immunogenicity results yet. While Novavax’s NVX‑CoV2373 has preclinical data from microneutralising assays showing that the vaccine was able to induce neutralising antibodies, this is only the first milestone of many in indicating a vaccine can offer protection, said Diamond, who has a research focus on cancer and viral vaccines. Neutralising antibodies do not always correlate to protection, Dougan added, noting this disconnect is observed in rotavirus vaccines.

Although Clover’s S-Trimer vaccine has data showing it induced spike protein-specific antibodies the same as those in recovered Covid-19 patients, such a benchmark may be inappropriate, Dougan said. Antibodies induced by natural infection and vaccination are different, as the former is produced with moderation from the virus, he added.

We are interested in the impact of the following three recent findings on the earlier assumptions about Covid 19 SAR 2 COV and what changes are required to the vaccines being designed and formulated please:

Extracts of the three issues are quoted. Please refer to full articles. Thank you.

Coronavirus May Be a Blood Vessel Disease, Which Explains Everything

Many of the infection’s bizarre symptoms have one thing in common

Dana G Smith

May 29 ·

In April, blood clots emerged as one of the many mysterious symptoms attributed to Covid-19, a disease that had initially been thought to largely affect the lungs in the form of pneumonia. Quickly after came reports of young people dying due to coronavirus-related strokes. Next it was Covid toes — painful red or purple digits.

What do all of these symptoms have in common? An impairment in blood circulation. Add in the fact that 40% of deaths from Covid-19 are related to cardiovascular complications, and the disease starts to look like a vascular infection instead of a purely respiratory one.

Months into the pandemic, there is now a growing body of evidence to support the theory that the novel coronavirus can infect blood vessels, which could explain not only the high prevalence of blood clots, strokes, and heart attacks, but also provide an answer for the diverse set of head-to-toe symptoms that have emerged.

“All these Covid-associated complications were a mystery. We see blood clotting, we see kidney damage, we see inflammation of the heart, we see stroke, we see encephalitis [swelling of the brain],” says William Li, MD, president of the Angiogenesis Foundation. “A whole myriad of seemingly unconnected phenomena that you do not normally see with SARS or H1N1 or, frankly, most infectious diseases.”

“If you start to put all of the data together that’s emerging, it turns out that this virus is probably a vasculotropic virus, meaning that it affects the [blood vessels],” says Mandeep Mehra, MD, medical director of the Brigham and Women’s Hospital Heart and Vascular Center.

In a paper published in April in the scientific journal The Lancet, Mehra and a team of scientists discovered that the SARS-CoV-2 virus can infect the endothelial cells that line the inside of blood vessels. Endothelial cells protect the cardiovascular system, and they release proteins that influence everything from blood clotting to the immune response. In the paper, the scientists showed damage to endothelial cells in the lungs, heart, kidneys, liver, and intestines in people with Covid-19.

“The concept that’s emerging is that this is not a respiratory illness alone, this is a respiratory illness to start with, but it is actually a vascular illness that kills people through its involvement of the vasculature,” says Mehra.

A respiratory virus infecting blood cells and circulating through the body is virtually unheard of.

Also:

New Research Points to Treatment for COVID-19 Cytokine Storms, Solution to Global Pandemic

TOPICS:Cincinnati Children's Hospital Medical CenterCOVID-19GeneticsImmunologyPediatricsPopularPublic Health

By CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER MAY 31, 2020

This is a microscopic photo of a blood smear from a transgenic mouse that mimics the human immune disorder, secondary HLH (hemophagocytic lymphohistiocytosis). The image shows macrophage immune cells (indicated by arrow) flooding healthy tissue cells during a cytokine storm caused by HLH in a very similar fashion t what occurs in patients with severe COVID-19 disease. Researchers reporting in the Journal of Allergy and Clinical Immunology say the HLH data were a factor in a decision to test the anti-inflammatory drug ruxolitinib (used to treat secondary HLH) in patients with COVID-19 in China. Credit: Cincinnati Children’s

How mice that model immune disease’s cytokine storms may point to solution for global pandemic.

A transgenic mouse developed at Cincinnati Children’s to model the deadly childhood immune disease HLH (hemophagocytic lymphohistiocytosis) may play a key role in saving lives during the COVID-19 virus pandemic.

One of the genetically engineered mouse strain’s inventors–Cincinnati Children’s cancer pathologist Gang Huang, PhD– is co-investigator on a small clinical trial that successfully tested a drug used to treat to HLH (ruxolitinib) to dramatically reverse respiratory and multi-system inflammation in severely ill COVID-19 patients. Data from the Phase II clinical study is published in the Journal of Allergy and Clinical Immunology.

The study involved 43 hospitalized patients diagnosed with severe COVID-19 between February 9 and February 28 in Wuhan, China, believed to be ground zero for the pandemic. The multi-center study was led by Jianfeng Zhou, MD, PhD, Department of Hematology at Tongji Hospital, Tongji Medical College and Huazhong University of Science in Wuhan.

Zhou is a longtime collaborator of Huang and colleagues at the Cincinnati Children’s HLH Center of Excellence, part of the Cancer and Blood Diseases Institute.

Ruxolitinib Shows Signs of Benefit

Patients taking ruxolitinib were randomly selected to receive two daily 5mg oral doses of the anti-inflammatory drug, plus the standard of care treatment for COVID-19. A randomly selected control group of 21 patients received a placebo along with the standard of care treatment.

“Ruxolitinib recipients had a numerically faster clinical improvement,” study authors write in their report. “Significant chest CT improvement, a faster recovery from lymphopenia and favorable side-effect profile in ruxolitinib group were encouraging and informative to future trials to test efficacy of ruxolitinib in a larger population.”

And also:

SARS-CoV-2 Spike Protein Shares Sequence with a Human Protein

Eight amino acids are identical to part of the human epithelial sodium channel, leading researchers to suspect the virus might interfere with the channel’s function.

Abby Olena

Jun 1, 2020

Scientists determined earlier this year that there is a cleavage site in the SARS-CoV-2 spike protein for furin, a human protease, and that the spike protein is split into two subunits at that spot. This cleavage has been implicated in helping break the virus open so it can enter human cells.

In a paper published May 26 in eLife, researchers found that the spike protein’s furin cleavage site is identical to a sequence in the human epithelial sodium channel, which likewise must be cut by furin in order to be activated. The authors propose that the virus may be competing with the sodium channel for furin, and possibly disrupting its function, but that remains to be demonstrated.

“The paper’s really nice because it gets at this common view that many viruses co-opt parts of human cells to help them survive,” says David Perlin, who studies infectious diseases and is the chief scientific officer at Hackensack Meridian Health’s Center for Discovery and Innovation in New Jersey. He was not involved in the study.

This discovery came about when researchers at nference, an artificial intelligence company, started looking to see whether are there any sequences of amino acids in SARS-CoV-2 proteins that seemed surprising or unusual. One that stuck out, says Venky Soundararajan, nference’s chief scientific officer, was a stretch of four amino acids present in the spike protein of 10,956 of 10,967 SARS-CoV-2 isolates from around the world, but not in the protein’s sequence in related coronaviruses, such as SARS-CoV or varieties that infect bats or pangolins. Other groups had reported in February and April that this insertion forms a cleavage site for the human protease furin, which is thought to sever the two subunits of the spike protein to facilitate entry into human cells.

Soundararajan and colleagues strengthened this idea when they determined that the furin cleavage site is identical to a proven furin cleavage sequence in the alpha subunit of the human epithelial sodium channel, which plays a role in managing the balance of salt and fluid in many of the body’s cells. This site is essential in the process of assembling the channel’s subunits into a functional whole capable of regulating sodium levels in a cell.

Next, the researchers turned to a platform they developed, which uses a database of single-cell RNA expression data from 65 previously published human and mouse studies, to look into gene expression of the sodium channel and other human genes known to be involved in SARS-CoV-2 infections. They found that expression of the epithelial sodium channel’s gene overlaps with that of the gene for furin and for the primary SARS-CoV-2 receptor, ACE2, in the cell types most affected by the virus.

The coupling of ACE2, the epithelial sodium channel, and furin in the epithelial cells of the nasal cavity, the respiratory tract, and the gut supports the idea that those regions are the initial hubs of infection in the human body, Soundararajan says. Perlin warns against making assumptions about ACE2 abundance based on transcript levels. “We have to always be a little careful going from gene expression to what’s assembled on the membrane,” he says.

Based on this RNA co-expression, the authors hypothesize that during a SARS-CoV-2 infection, the viral spike protein might compete with the human sodium channel for furin cleavage. If this competition disrupts the activation of the sodium channel, it could become dysregulated, which could interfere with its role in regulating fluid balance. This could explain why COVID-19 patients sometimes end up with large amounts of fluid in the lungs.

The study “is all computationally based with no wet experiments. Hence we have zero information on what the authors are suggesting is at all correct,” cautions Vincent Racaniello, a virologist at Columbia University who was not involved in the work, in an email to The Scientist. He also questioned the idea that the cleavage of the SARS-CoV-2 spike protein by human furin could usurp cleavage of the epithelial sodium channel.

It’s also not clear that this sodium channel is downregulated during viral infection. But if furin has a higher affinity for the virus and there is a high viral load in the same region where this sodium channel is expressed, “there is potential there that you’d have less processing of that alpha subunit of the sodium channel and this potentially could also [affect] sodium channel function locally,” says Perlin. “Is that what’s happening? I’m not sure, but it’s an interesting hypothesis.”

“Most computational analysis requires some experimental validation,” says Dario Ghersi, a computational biologist at the University of Nebraska Omaha who did not participate in the study. That this recognition site is present in the majority of SARS-CoV-2 isolates implies that it is important to the virus, meaning the sequence could be of interest for vaccine and therapeutic development. “What they found seems pretty solid to me,” he adds.

A useful article to the use of analytical approach with reference to some issues and output aspects is:

COVID-19 coronavirus vaccine design using reverse ... - bioRxiv

www.biorxiv.org › content

23 Mar 2020 - The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, ...by E Ong - ‎2020 - ‎Cited by 5

Two very good articles on the current adjuvant options. Progress is emerging and the efforts to shape the protein subunit vaccine candidates in the WHO list will help all as currently there is no significant collaboration across the many candidates leading to less than optimal outcomes for the costs and dispersed efforts. The pandemic is advancing with winter ahead and more international cooperation is required to produce the vaccines to help the billions of people.

Potential adjuvants for the development of a SARS-CoV-2 ...

www.ncbi.nlm.nih.gov › pmc › articles › PMC7301105

5 days ago - Keywords: COVID-19, SARS, SARS-CoV-2, Adjuvant, Vaccine, Coronavirus, MERS ... Further, the addition of alum to the vaccine formula significantly augmented ... Subunit vaccines based on S1 protein and RBD epitopes of MERS-CoV when ...

Highly pathogenic coronaviruses: thrusting vaccine ...

www.ncbi.nlm.nih.gov › pmc › articles › PMC7260574

30 May 2020 - In this review, we will briefly describe coronavirus vaccine design targets, ... and focus on how to improve the efficacy of vaccines through adjuvant formulations. ... Viral vector vaccines encoding full-length S protein or S1 subunits have been ...by C He

We have a proposal for the vaccine proteins derived from a genome assessment and consideration of the roles of each of 8 proteins. The four are: S1 + S2 + 30CL PRO + NS8 (NSP8). The central region of the S spike is not included currently.

The adjuvant for the inhaled application has been identified as an existing composition. Vaccine experimental technicians and their vaccine/virus laboratory are required to undertake the tests of the complex to determine the relative composition of the protein ingredients with and without the adjuvant. For researchers and vaccine developers we are interested in the in-vitro work for this protein sub unit vaccine. Please contact Chris Eaglen at [email protected]. Thank you.

WHO Draft Landscape of Covid-19 SARS-COV-2 candidates issued July 2nd on web. There are 4 Protein Subunit candidates in the 18 candidates in clinical trials. There are 129 additional candidates of which 48 are Protein Subunit candidates. Hopefully preliminary results will emerge in the next 3 months from the 18 candidates.

We need to team with an experimental laboratory or institute or pharma/vaccine organisation to determine the validity of the S1+S2+30CL PRO+NS8 protein combination and determine the blending ratio and confirm the adjuvant. Please contact [email protected] if you can assist. Thank you.

The work of the scientists in the USA to create their version is accessible through: You can download their white paper from the MIT review.

Some scientists are taking a DIY coronavirus vaccine, and nobody knows if it’s legal or if it works – MIT Technology Review We all can learn new approaches.

https://www.technologyreview.com/2020/07/29/1005720/george-church-diy-coronavirus-vaccine/

Preston Estep was alone in a borrowed laboratory, somewhere in Boston. No big company, no board meetings, no billion-dollar payout from Operation Warp Speed, the US government’s covid-19 vaccine funding program. No animal data. No ethics approval.

What he did have: ingredients for a vaccine. And one willing volunteer.

Estep swirled together the mixture and spritzed it up his nose.

Nearly 200 covid-19 vaccines are in development and some three dozen are at various stages of human testing. But in what appears to be the first “citizen science” vaccine initiative, Estep and at least 20 other researchers, technologists, or science enthusiasts, many connected to Harvard University and MIT, have volunteered as lab rats for a do-it-yourself inoculation against the coronavirus. They say it’s their only chance to become immune without waiting a year or more for a vaccine to be formally approved.

Among those who’ve taken the DIY vaccine is George Church, the celebrity geneticist at Harvard University, who took two doses a week apart earlier this month. The doses were dropped in his mailbox and he mixed the ingredients himself.

Church believes the vaccine designed by Estep, his former graduate student at Harvard and one of his proteges, is extremely safe. “I think we are at much bigger risk from covid considering how many ways you can get it, and how highly variable the consequences are,” says Church, who says he has not stepped outside of his house in five months. The US Centers for Disease Control recently reported that as many as one-third of patients who test positive for covid-19 but are never hospitalized battle symptoms for weeks or even months after contracting the virus. “I think that people are highly underestimating this disease,” Church says.

Harmless as the experimental vaccine may be, though, whether it will protect anyone who takes it is another question. And the independent researchers who are making and sharing it might be stepping onto thin legal ice, if they aren’t there already.

A simple formula

The group, calling itself the Rapid Deployment Vaccine Collaborative, or Radvac, formed in March. That’s when Estep sent an email to a circle of acquaintances, noting that US government experts were predicting a vaccine in 12 to 18 months and wondering if a do-it-yourself project could move faster. He believed there was “already sufficient information” published about the virus to guide an independent project.

Estep says he quickly gathered volunteers, many of whom had worked previously with the Personal Genome Project (PGP), an open-science initiative founded in 2005 at Church’s lab to sequence people’s DNA and post the results online. “We established a core group, most of them [from] my go-to posse for citizen science, though we have never done anything quite like this,” says Estep, also a cofounder of Veritas Genetics, a DNA sequencing company.

To come up with a vaccine design, the group dug through reports of vaccines against SARS and MERS, two other diseases caused by coronaviruses. Because the group was working in borrowed labs with mail-order ingredients, they wouldn’t make anything too complicated. The goal, says Estep, was to find “a simple formula that you could make with readily available materials. That narrowed things down to a small number of possibilities.” He says the only equipment he needed was a pipette (a tool to move small amounts of liquid) and a magnetic stirring device.

In early July, Radvac posted a white paper detailing its vaccine for anyone to copy. There are four authors named on the document, as well as a dozen initials of participants who remain anonymous, some in order to avoid media attention and others because they are foreigners in the US on visas.

The Radvac vaccine is what’s called a “subunit” vaccine because it consists of fragments of the pathogen—in this case peptides, which are essentially short bits of protein that match part of the coronavirus but can’t cause disease on their own. Subunit vaccines already exist for other diseases such as hepatitis B and human papillomavirus, and some companies are also developing subunits for covid-19, including Novavax, a biotechnology company which this month secured a $1.6 billion contract from Operation Warp Speed.

To administer its vaccine, the Radvac group settled on mixing the peptides with chitosan, a substance from shrimp shells, which coats the peptides in a nanoparticle able to pass the mucous membrane. Alex Hoekstra, a data analyst with training in molecular biology who previously volunteered on the PGP staff, and who also squirted the vaccine up his nose, describes the sensation as, “like getting saline up your nose. It’s not the world’s most comfortable feeling.” Extracted from MIT review. Copyright is MIT's.

The findings from Covid 19 and Sars 2 COV observations and inputs to date mapped into programme and project considerations to help recognise the vast extent of issues where silo approach has been limited but was essential at the outset.

Dr Chris Eaglen MSc Project Management London UK [email protected] undertaking value for money, contract and commercial reviews and getting back on track reviews 00447711310442

Aspects of programme and project team human behaviours to be addressed to improve delivery

A. SILO versus INTEGRATED and COMPLETE GROUPING APPROACHES

A challenge is overcoming the silo approach which missed out integration grouping impacts on resources, costs and time required for development and delivery impacts

Breakdown silos is a start but was done without considering what was needed for interfacing/integration into working functional outcomes

Determine how to link and integrate components to function is required for the project’s success

Learn from other areas where the depth of integration is very complex and addressed: Overground Railways and Underground Railways, Space, and Large Scale Physics, Nuclear, Oil and Gas, Petrochemical and New Towns/Cities and Pandemic (COVID 19, SARS 2 COV) programme and projects. Need to address complicated project requirements and improve characterisation

Areas written into outline but not understood in detail and not labelled as key issues to address as early as possible

Lack of depth of knowledge scoping

B. WHAT RESULTS FROM THE BASIC PACKAGE AND BUY APPROACH

Inherit Biases and the Not discovered or declared areas and not budgeted and scheduled areas

Dark Data is hidden or is/are unknows and the inadequately unknown elements are not addressed

What is not fully understood, articulated or not in the budget at launch and not declared openly impact later to delay completion and commissioning and results in opening delays

Does not address areas where there is/are lessons yet to be learnt by Boards. Executives and project areas: Procurement, Planning, Scheduling, Finance

The mixing of buy, build, develop and first-off elements, sections, packages is an issue where demolish, design, build, adapt and deliver are not fully determined when the launch phase is underway.

Lack of advancement in detail

Not addressing faults/gaps and revelation of the unknown unknowns or the put to one side issues

Determine what is accessible and what is not readily accomplished and why

C. CATCH UP AND CONSEQUENTIAL BOTTLENECK DELAY REDUCTION

Iterate the quarterly reviews to obtain earliest confirmation that omissions and future bottlenecks are raised and defined as key issue to the Board and Executive and establish the technical/delivery groups to better define the surfacing aspects, with technical, costing and scheduling reports

What elements have insufficient technical inputs and/or definition or inadequate technical expertise due to new type of project for the management

Determine what is for the discovery phase and what is not fully determined and a key trackable issue

Change resourcing to address Blizzard of challenges especially for later Board and delivery teams

Identify arms-length understandings and weak existing leadership and management and technical people without the experience of previous exact project

Seeking out inconsistencies in understanding and actionable issues

Provide decision support

Fault detection

Domain knowledge

When a fault will be recognised in long period projects and in complex evolving phased projects

Depth of misunderstanding

Removal of the unknown and undeclared issues

What is going wrong

Launch interventions

Phased approval

Stabilise quarterly the project by addressing findings and actioning the findings

More urgent

D. HUMAN BEHAVIOUR IMPACTS

Project formers and launchers may and prefer to dominate the process and may not want to expose their dependencies on the knowledge of others or to be identified with previous omissions or oversights

Lack of group experience and aversion to form new groups where additional people with specific backgrounds are required

Human effort is required to understand the context as much as possible

People may not have sufficient hands on experience to address complexities

Address Inflated expectations

Address Scepticism realistically

Addressing Boundary commentators and providing explanations

Addressing Hard ball tactics objectively

Personal interventions encouraged to address issues

Make use of learning and owning up

Not all deliberate faults

Progressive opportunities

Decision support for people not wanting to accept they were not aware

Where participants can achieve or will agree to compliance for outcomes

E. TECHNICAL ISSUES

Does the project know the approach to a stage can be built/constructed or can be assembled or is achievable to function or do we not know if it is or not or we do not want to reveal the uncertainty. This is part of the reason for Delay due to gaps in a Project/Programme can arise due to the inability of the Design and/or Delivery Team or its contractors/suppliers being able to cope with the Project/Programme tasks which resulted in some having to support from aspects of the delivery and not being able to meet their originally designated work in time.

Need to later add scopes and functions and to react to earlier mistakes or oversights

Inadequate planning based on full technical and delivery details

Uncertainty

Find Better methods

Determine what the project Doesn’t know

Directly inferring properly

What methods to use for complete understanding

Isolating undesirable consequences

Detecting causality

Diagnosis of faults and missing areas of work

Research

Maintenance issues

Reliability

Knowledge and consequence depths

A lot of detailed thinking

Liabilities

F. USER GROUPS

Incorporating user group representatives who attend Board and Executive meetings and obtain access to papers and reports but have some independence from the line managements.

Address Pain points

Ask how are you covering that matter

What else is needed

G. ADDRESSING THE SHORTAGES OF ENGINEERS AND PROGRAMMERS FOR CODING IT AND Instrument/Control SYSTEMS

There is the need to address the transfer of legacy computing and control and instrumentation and communications systems to current equipment, platforms and functional units. Coding specialists in legacy computer languages and in programming obsolete equipment are required, These works are better undertaken early in projects and may require separately funded contracts to enable the full extent of the work to be determined. Engineers having to address legacy issues and to transfer operations to different equipment and languages than those in the legacy systems may require additional time and assistance to understand the details of the legacy systems and code functions.

H. ADDRESSING LEGACY OBSOLESCENCE AND END OF LIFE EQUIPMENT, COMPONENTS AND ASSEMBLIES AND UNIQUE COMBINATIONS OF EQUIPMENT

Where legacy equipment from the 50s to the 90s are functional units and components that have to be incorporated into a project using new versions of functional units and materials there is the additional requirement to create the new versions, or source reengineered units. Similarly where unique combinations of equipment are required it is possible that prototyping the configuration is required to remove the risks that the combination does not function as required. These obsolescent and end of life unit replacement works are better undertaken early in a project. They may be separately funded contracts to provide the time to enable the full extent of the issues arising to be assessed and to remove the risk of delays from replacement developments.