ARTICLE 1: COVAXIN, India's First COVID-19 Vaccine Candidate, Set For Phase I, II Human Trials

India, a leading manufacturer of generic medicines, is expected to play a key role in the race to develop a COVID-19 vaccine, with several institutes working in parallel

All IndiaReported by Parimal Kumar, Edited by Chandrashekar SrinivasanUpdated: June 29, 2020 11:11 pm IST

A potential COVID-19 vaccine, the first to be developed in India, has been given DCGI (Drug Controller General of India) approval for Phase I and II human clinical trials that are scheduled to start across the country in July.

Developed by Hyderabad-based Bharat Biotech, in association with ICMR (Indian Council for Medical Research), COVAXIN is an inactivated vaccine, created from a strain of the infectious SARS-CoV-2 virus, that has shown promise in preclinical studies, demonstrating extensive safety and effective immune responses.

Drug manufacturers around the world are racing to develop a vaccine against the novel coronavirus; a novel virus is one that has never previously been identified in humans, making the task of creating a vaccine that much harder.

India, a leading manufacturer of vaccines and generic medicines, is expected to play a key role in this race, with several institutes working on different drugs.

In May the government said as many as 30 groups were working on a vaccine. A top scientific advisor to the government said efforts that normally took 15 years and cost US$300 million were being condensed into a 12-month period.

Similar efforts are being mounted across the world, with a number of different drugs in different stages of trial. Last week the World Health Organisation (WHO) said AstraZeneca's vaccine was probably the leading candidate.

The British firm has already begun large-scale, mid-stage human trials of the drug developed by researchers at University of Oxford.

Other possible vaccines being tested include one by American firm Moderna, which is scheduled to go into Phase III clinical trials from mid-July.

China's military has been given permission to use a vaccine candidate developed in association with CanSino Biologics. According to Reuters the drug showed some promise in early clinical trials. The Ad5-nCoV is one of the eight vaccine candidates developed by Chinese firms to move into human trials.

Early last month US-based biopharmaceutical firm Gilead Sciences Inc. said a five-day course of its antiviral drug Remdesivir showed a modest benefit to patients with moderate COVID-19 symptoms.

The drug, which is administered intravenously, was the first to show improvement in condition of COVID-19 patients in formal clinical trials, according to news agency Reuters.

As pharma firms scramble to find that big breakthrough, which could mean millions in profits and millions of lives saved, experts have warned that early vaccines may come with limitations on what they can do.

The pandemic has already claimed over five lakh victims worldwide, including 16,475 in India. There are over 1.01 crore confirmed cases, including nearly 5.5 lakh in India - the fourth worst-affected country.

With input from Reuters

https://www.ndtv.com/india-news/coronavirus-vaccine-india-covaxin-india-s-first-covid-19-vaccine-candidate-set-for-phase-i-ii-human-trials-2254189

ARTICLE 2: SOME FACTS on RNA VACCINES: On the vaccine front, RNA vaccines are leading the way because they’re particularly suited to speedy development. And while no RNA vaccine has ever been licensed (WE SHOULD ASK - WHY??), the threat of a pandemic is a great incentive to accelerate their progress. In late February, biotech Moderna sent mRNA vaccines for Sars-CoV-2 to the US National Institutes of Health (NIH) for a first-in-man clinical trial.

RNA vaccines consist of messenger RNA strands. They are injected into the body, usually within lipid nanoparticles. These merge with cells. Once inside, the RNA sequence is translated by ribosomes to make a protein or parts of proteins. ‘Rather than generating proteins in a manufacturing plant and purifying them, you are getting the muscle to do the job and make the protein itself,’ says Robin Shattock, a virologist at Imperial College London, UK.

RNA can be synthesised in substantial quantities, outpacing vaccine production with live microbes or recombinant proteins. ‘For a traditional vaccine, you might want to grow a virus in cell culture and produce hundreds or thousands of litres,’ says Shattock. ‘RNA is simpler. You can produce it by a synthetic process, which is why it is particularly attractive for outbreak pathogens.’

https://www.chemistryworld.com/news/rna-vaccines-are-coronavirus-frontrunners/4011326.article

Immune response

Key to creating an effective vaccine is getting the immune system to recognise the virus as foreign. One way this happens is for dendritic immune cells to express antigenic proteins from the vaccine on their surfaces. With a protein-based vaccine, the cells absorb the protein and present it, but with RNA vaccines, the take up the mRNA, then make and present the encoded antigen protein. ‘Having protein made inside the cell seems to give better antigen presentation,’ says immunologist Drew Weissman from the University of Pennsylvania, US. This stimulates T cells and antibody-making B cells, as well as formation of long-lived memory cells

Antibodies are good at stopping viruses infecting cells, while certain T cells are especially effective at killing cells that are already infected. ‘If you want a really strong vaccine for a virus, you have to attract T cells,’ says Hoerr.

It is a race, but a race against the virus rather than each other

Weissman is one of the pioneers of mRNA vaccines. Around 10 years ago, he and Katalin Karko developed the technology licensed by Moderna and BioNTech for mRNA vaccines. Karko is now at BioNTech, which focuses on cancer and rare diseases, but still works with Weissman on infectious diseases.

Weissman plans to start clinical trials for two mRNA vaccines against HIV, one against influenza and another against genital herpes. One of these is with BioNTech, the others are supported by the NIH. The flu vaccine is furthest advanced. The hope is that this will be universal flu vaccine, capable of protecting against the flu virus as it mutates over years, and will achieve at least 75% protection, as opposed to 30 to 40% with today’s vaccines.

At Imperial, Shattock eagerly downloaded the sequence of the coronavirus when it was released by Chinese scientists. He used it to sequence RNA for the spike glycoprotein. ‘We made a template for our RNA-based vaccine in two weeks,’ says Shattock. ‘The normal cycle for developing a vaccine is two years.’

He deployed a pseudovirus with an HIV backbone incorporating the spike protein to test whether his RNA sequences generated enough antibodies to block viral entry. He started in mice and expects results within weeks. ‘Our strategy is to encode all of the spike protein, but others are encoding parts of it,’ he explains. ‘Which strategy is best we will know over the next few weeks when people start to generate data from animal models.

Because most RNA vaccine development so far has been directed towards highly profitable personalised treatments for cancer and rare diseases, production is mostly geared towards small numbers of doses. ‘Economics pushed it in that direction,’ says Shattock. ‘There is no licensed RNA that is being manufactured in tens or hundreds of millions of doses. That infrastructure needs to be built.’ The Covid-19 outbreak could provide the stimulus to develop those facilities.

Shattock speculates that two or three RNA vaccines will ultimately be selected for larger trials against Sars-CoV-2. ‘It is a race, but a race against the virus rather than each other,’ he says. ‘Some people will be faster, but I don’t think there will be huge differences.’ There could be rare side effects, which early tests will not pick up, so redundancy is advantageous.

Depending on the societal impact of Covid-19, regulators may have to consider a fast-track process to get mRNA vaccines to people sooner. Otherwise, a vaccine may not be approved for two years, and mRNA vaccines could once again end up sidelined, waiting for the next big outbreak.

ARTICLE 3: A better spike

On 13 January, 3 days after Chinese researchers first made public the full RNA sequence of SARS-CoV-2, NIAID immunologist Barney Graham sent Moderna an optimized version of a gene that would become the backbone of its vaccine. Sixty-three days later, the first dose of the vaccine went into Haller and other volunteers participating in the small trial at the Kaiser Permanente Washington Health Research Institute. In 2016, Graham had made a Zika virus vaccine that went from lab bench to the first volunteer in what he then thought was a lightning-fast 190 days. “We beat that record by nearly 130 days,” he says.

The effort benefited from lessons Graham learned from his past vaccine efforts, including his work on respiratory syncytial virus (RSV). The search for an RSV vaccine has a checkered past: in 1966, a trial of a candidate vaccine was linked to the death of two children. Later studies identified the problem as vaccine-triggered antibodies that bound to the surface protein of the virus but did not neutralize its ability to infect cells. This antibody-viral complex, in turn, sometimes led to haywire immune responses.

Best shot

The World Health Organization has tallied dozens of vaccine candidates, based on a variety of technologies. Two have started human safety trials (*).

PlatformCandidatesProtein subunit18RNA8*DNA3Nonreplicating vector8*Replicating vector5Inactivated virus2Attenuated virus2Viruslike particle1

Studying the 3D structures of the RSV surface protein, Graham discovered that the dynamic molecule had different orientations before and after fusing with the cell. Only the pre-fusion state, it turned out, triggered high levels of neutralizing antibodies, so in 2013 he engineered a stable form of the molecule in that configuration. “It was so clear at that point that if you didn’t have structure, you didn’t really know what you were doing,” Graham says. An RSV vaccine that built on this concept has worked well in early trials.

The experience came in handy in 2015, when a member of Graham’s lab made a pilgrimage to Mecca, Saudi Arabia, and came back ill. Worried that it might be MERS, which is endemic in Saudi Arabian camels and repeatedly jumps into humans there, Graham’s team checked for the virus and instead pulled out a common cold coronavirus. It was relatively easy to determine the structure of its spike, which then allowed the team to make stable forms of the spikes for the SARS and MERS viruses, and, in January, for SARS-CoV-2’s. That’s the basis of the Moderna COVID-19 vaccine, which contains mRNA that directs a person’s cells to produce this optimized spike protein.

Still a new strategy, no mRNA vaccine has yet reached a phase III clinical trial, let alone been approved for use. But producing huge numbers of vaccine doses may be easier for mRNA vaccines than for traditional ones, says Mariola Fotin-Mleczek of the German company CureVac, which is also working on mRNA vaccine for the new coronavirus. CureVac’s experimental rabies vaccine showed a strong immune response with a single microgram of mRNA. That means 1 gram could be used to vaccinate 1 million people. “Ideally, what you have to do is produce maybe hundreds of grams. And that would be enough,” Fotin-Mleczek says.

Many companies are relying on time-tested techniques. Sinovac Biotech is making a SARS-CoV-2 vaccine by chemically inactivating whole virus particles and adding an immune booster called alum. Sinovac used the same strategy for a SARS vaccine it developed and tested in a phase I clinical trial 16 years ago, says Meng Weining, a vice president at Sinovac. “We immediately just restarted the approach we already know.” The company’s SARS vaccine worked in monkeys and although there were concerns that an inactivated coronavirus vaccine might trigger the sort of antibody enhancement disease that occurred with the RSV vaccine, Meng stresses that no such problems surfaced in their animal studies.

Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai, says inactivated virus vaccines have the advantage of being a tried-and-true technology that can be scaled up in many countries. “Those manufacturing plants are out there, and they can be used,” says Krammer, who co-authored a status report about COVID-19 vaccines that appears online in Immunity.

CanSino is now testing another approach. Its vaccine uses a nonreplicating version of adenovirus-5 (Ad5), which also causes the common cold, as a “vector” to carry in the gene for the coronavirus spike protein. Other vaccine researchers worry that because many people have immunity to Ad5, they could mount an immune response against the vector, preventing it from delivering the spike protein gene into human cells—or it might even cause harm, as seemed to happen in a trial of an Ad5-based HIV vaccine made by Merck that was stopped early in 2007. But the same Chinese collaboration produced an Ebola vaccine, which Chinese regulators approved in 2017, and a company press release claimed its new candidate generated “strong immune responses in animal models” and has “a good safety profile.” “I think pre-existing Ad5 immunity and HIV vaccine risk are not a problem,” Hou Lihua, a scientist working on the project at the Institute of Biotechnology, wrote in an email to Science, noting that the Ebola vaccine trial results adds to their confidence that these will not be issues.

Disregard that [a vaccine is] going to take at least 18 months, but it’s just one bright light in some really devastating news across the world. Jennifer Haller, who received the first dose of an experimental COVID-19 vaccine

Other COVID-19 vaccine platforms include a laboratory-weakened version of SARS-CoV-2, a replicating but harmless measles vaccine virus that serves as the vector for the spike gene, genetically engineered protein subunits of the virus, a loop of DNA known as a plasmid that carries a gene from the virus, and SARS-CoV-2 proteins that self-assemble into “viruslike particles.” J&J is using another adenovirus, Ad26, which does not commonly infect humans, as its vector. These different approaches can stimulate different arms of the immune system, and researchers are already “challenging” vaccinated animals with SARS-CoV-2 to see which responses best correlate with protection.

Many researchers assume protection will largely come from neutralizing antibodies, which primarily prevent viruses from entering cells. Yet Joseph Kim, CEO of Inovio Pharmaceuticals, which is making a DNA COVID-19 vaccine, says a response by T cells—which clear infected cells—proved a better correlate of immunity in monkey studies of the company’s MERS vaccine, which is now in phase II trials. “I think having a balance of antibody and T cell responses probably is the best approach.”

Kim and others applaud the variety of strategies. “At this early stage, I think it makes sense to try anything plausible,” he says. As Stéphane Bancel, CEO of Moderna, says, “Nobody knows which vaccines are going to work.”

https://www.sciencemag.org/news/2020/03/record-setting-speed-vaccine-makers-take-their-first-shots-new-coronavirus

ARTICLE 4: Immunity and a Mutating Virus: Challenges along the Path for COVID-19

If long-term immunity is not achievable, SARS-CoV-2 could become one of the viruses that affect the population year after year.

Nancy R. Gough, PhDFollow May 16 · 5 min read

SARS-CoV-2 is an RNA virus of the coronavirus family. Of the 36 RNA virus families that cause human diseases, we only have vaccines for 10. In some cases, this is because the viruses in the family do not cause severe disease. So, there is no reason to pursue development of a vaccine. In others, it is because effective, safe vaccines have been difficult to create. Some vaccines, like the polio vaccines, provide durable immunity; others, like influenza vaccines, must be updated to provide immunity to new strains of the virus. It seems possible that there will not be a safe, effective vaccine against SARS-CoV-2 in the near future.

Immunity to a Mutating Virus

Genetic replication is an error-prone process that results in mutations. How quickly a virus mutates depends on how it replicates and whether it has an ability to repair errors that are introduced. RNA viruses mutant faster than DNA viruses. Coronaviruses tend to mutate more slowly than other RNA viruses because their enzymes involved in replicating their genetic material has some ability to “proofread.”

If the virus does not mutate into a less virulent (disease-causing) form, then eventually most people would get exposed to the virus. Just like now during the pandemic, some would get very sick, some would die, and some would have mild illness. Even Dr. Michael Ryan of the World Health Organization (WHO) is beginning to think that this SARS-CoV-2 may become an endemic virus, like some influenza viruses. This means that the virus will circulate among the global population, causing some rate of annual infection. Or as Dr. Ryan said in a press briefing on 13 May 2020, “This virus may never go away.”

If the immune response to the virus produces an effective adaptive response and the virus does not mutate to evade this response, some people will naturally develop some amount of immunity to SARS-CoV-2 after exposure to the virus. Thus, those who recover from COVID-19 would likely have some level of immunity to the virus that will either prevent them from getting COVID-19 again or prevent them from getting serious symptoms of the disease at least for a period of time.

We do not know if people will develop immunity, how many people will develop immunity, or how long that immunity will last. We do know that SARS-CoV-2 is mutating, as all viruses do. Many of the changes in the RNA of the virus do not change the proteins in the virus. Some do change the proteins but have no effect on the function of the protein or the ability of the immune system to recognize the viral proteins. Some change the function of the protein or the ability of the immune system to recognize the protein.

It seems likely that, even if some develop immunity, some will lose their immunity over time as the virus changes and mutations let the virus escape immune recognition. Mutation of the viral proteins needed for a virus-neutralizing immune response is one reason that developing a vaccine is challenging.

Tracking the amino acid mutations in SARS-CoV-2. The x axis is number of mutations. The colors represent countries with the patient with the virus. Each circle represents the sequence of the virus from a specific patient. At the time of this analysis, 2 of the viruses had more than 20 mutations compared to the first one sequenced. [Fromhttps://nextstrain.org/ncov/global?branchLabel=aa&m=div&p=full&r=division].

In addition to influencing immunity, mutations could changes properties of the virus related to virulence, which is the ability to spread and cause disease. The virus could become more virulent or less. Indeed, a preprint in medRxiv reported differences in virulence using a test that involved infecting cultured cells with virus isolated from patients with viruses with different mutations. Some of the mutated viruses were less virulent, some were more virulent, and some had an intermediate virulence.

A Slow Path to Natural Immunity

To achieve any immunity in the absence of a vaccine, people need to become infected with SARS-CoV-2. By limiting the spread of the pandemic, the world has reduced deaths due to COVID-19 and given the healthcare systems time to increase capacity for patients. However, limiting the spread also reduced the how fast the population will naturally develop immunity to the virus, if this is possible.

Population immunity is sometimes referred to as “herd immunity.” Herd immunity refers to the percentage of the population that must become immune to a pathogen so that the pathogen does not cause epidemic spread of infection. This percentage varies based on the average number of people a single infected individual infects. The reasons that the road maps to the new normal involve a vaccine is that vaccination is a way to medically induce herd immunity. For SARS-CoV-2, scientists predict that herd immunity will require ~50–70% of the population to have immunity.

Studies of the antibody and T cell responses to SARS-CoV-2 will help determine if herd immunity is possible. Such information will also inform vaccine development.

https://medium.com/@ngough_bioserendipity/immunity-and-a-mutating-virus-challenges-along-the-path-for-covid-19-c946e8fe7af7

ARTICLE 5: Many People Lack Protective Antibodies After COVID-19 Infection

F. Perry Wilson, MD, MSCE DISCLOSURES June 24, 2020

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr. F. Perry Wilson.

In what seems like 10 years ago but was actually just 6 weeks ago, on this very website, I said this: "This is the COVID that allows us to open up more quickly, assuming that antibodies are protective, which — let's be honest — if they aren't, we're sort of screwed no matter what."

Cut to a couple of days ago, when I came across this article in Nature — the first deep dive attempting to answer the question of just how protective those coronavirus antibodies are.

And, at first blush at least, the news isn't great.

Researchers recruited patients who had recovered from COVID-19 from the Rockefeller University Hospital in New York. The 111 individuals enrolled had to have been asymptomatic for at least 14 days. They also recruited 46 asymptomatic household contacts and some controls who had never had COVID-19.

Now, a brief refresher on antibodies. There are several different types, but we broadly think about immunoglobulin M as the acute antibody, generated in the throes of the illness, and immunoglobulin G as the long-term antibody. But here's the thing: The mere presence of antibodies does not mean that those antibodies are protective. The researchers tease this apart for us.

Source: Wikimedia Commons

They zeroed in on two types of anti-coronavirus antibodies: a group that binds to the spike protein (that's the crown part of the corona), and more specifically, antibodies that bind to the receptor binding domain of the spike protein. This is the key, if you will, that opens the door of your cells (a receptor called ACE2) to infection. It's a good bet that if there is an antibody that will shut down the virus, it's one that will block the receptor binding domain.

Should we start with the good news?

Source: Robbiani DF, et al. Nature. Epub 18 June 2020.

Compared with controls, IgG and IgM levels were higher among those who had recovered from COVID-19. As expected in this convalescent group, a bigger difference was seen in IgG compared with IgM. You can see in this graph that IgM levels seem to go down a bit over time.

And, I'll note, about 20%-30% of people didn't have antibody titers significantly above controls. But broadly, okay — the majority of people made antibodies.

But that's not the key thing here. Were these neutralizing antibodies? Do they stop viral replication?

To figure this out, the researchers genetically engineered a SARS-CoV-2 pseudovirus which expressed the spike protein and let it run amok infecting ACE2-expressing cells in culture.

Source: Robbiani DF, et al. Nature. Epub 18 June 2020.

They then added varying dilutions of patient plasma to the petri dishes to determine how much plasma you would need to shut the virus down by 50%, the so-called "neutralizing titer" 50 (NT50).

The results here were not so encouraging.

Thirty-three percent of the individuals tested had an NT50 of less than 50, which implies essentially no immunity to repeat infection; 79% had an NT50 less than 1000 — they may have partial immunity. Only two people tested had an NT50 greater than 5000.

Higher overall antibody titers were associated with neutralizing ability, as might be expected.

Source: Robbiani DF, et al. Nature. Epub 18 June 2020.

Individuals who had been hospitalized for COVID-19 were more likely to have neutralizing antibodies than those who hadn't been hospitalized, suggesting that those with more severe illness are more likely to be immune in the future.

Overall, this is fairly concerning. Without neutralizing antibodies, an end to coronavirus transmission seems unlikely. But let's also remember the empiric data: We don't yet have any significant numbers of individuals who have been documented to have cleared COVID-19 and then become reinfected. And even without high levels of neutralizing antibodies, a second infection is likely not to be as bad as the first.

There's another nugget of hope in this study. The researchers didn't stop by simply measuring how many people had neutralizing antibodies. They actually sequenced 89 different anti-COVID antibodies to determine which specific antibodies were highly neutralizing. They identified 52 that had neutralizing ability and several that had potent neutralizing ability, targeted to specific amino acids on the receptor binding domain.

And here's the thing: Most of the people in the study had those highly neutralizing antibodies; they just weren't the main antibodies they were producing. Why is this good news? Because it suggests a pathway for a successful vaccine. We can make these potent neutralizing antibodies; it's just that many of us don't. But a vaccine designed to promote that particular antibody response could be highly successful.

All in all, this was a study that suggested that the tunnel we are in now may be a bit longer than we had hoped, but it also shows a light at the end.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Program of Applied Translational Research. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @methodsmanmd and hosts a repository of his communication work at www.methodsman.com.

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Article 6: Clinical trial of COVID-19 vaccine (India)

The ICMR has selected 12 institutes, including one from Odisha, for clinical trial of the country's first indigenous COVID-19 vaccine, an official said on Thursday.

Bhubaneswar, Jul 2 () TheICMRhas selected 12 institutes, including one from Odisha, forclinical trialof the country's first indigenous COVID-19 vaccine, an official said on Thursday. Bhubaneswar-based Institute of Medical Sciences and SUM Hospital under the SOA Deemed to be University, has been chosen by the Indian Council for Medical Research (ICMR) for undertaking human clinical trials of India's firstcoronavirusvaccine, an official of the institute said.

ICMR has developed the indigenous COVID-19 vaccine (BBV152 COVID vaccine) partnered withBharat Biotech International Limited(BBIL).

The 12 institutes have been asked by the ICMR to fast track clinical trials of the vaccine as it is being considered as one of the top priority projects which are being monitored at the topmost level of the government.

"The vaccine is derived from a strain of SARS-CoV-2 isolated by ICMR-National Institute of Virology, Pune. ICMR and BBIL are jointly working for the pre-clinical as well as clinical development of this vaccine," an official said.

In a letter to the selected institute where the clinical trial is to be done, the ICMR also informed that it is envisaged to launch the vaccine for public health use latest by August 15, 2020 after completion of all clinical trials.

BBIL is working expeditiously to meet the target, however, the final outcome will depend on the cooperation of all clinical trial sites involved in this project, the ICMR told the selected institutes.

In view of the public health emergency due to COVID-19 pandemic and urgency to launch the vaccine, the selected institutes are strictly advised to fast track all approvals related to the initiation of the clinical trial and ensure that the subject enrolment is initiated during the first week of July.

Apart from IMS and SUM Hospital here, the other institutes selected for the clinical trial are located in Visakhapatnam, Rohtak, New Delhi, Patna, Belgaum (Karnataka), Nagpur, Gorakhpur, Kattankulathur (Tamil Nadu), Hyderabad, Arya Nagar, Kanpur (Uttar Pradesh) and Goa.

AAM RG SRY

https://health.economictimes.indiatimes.com/news/pharma/icmr-selects-12-institutes-for-clinical-trial-of-covid-19-vaccine/76760506

ARTICLE 7: Antibody Dependent Enhancement by Dr. Doug

https://www.homeopathy2health.com/forum/covid-medical-for-laymen/is-a-coronavirus-vaccine-a-ticking-time-bomb

... a coronavirus vaccine is a highly dangerous undertaking due to a peculiar trojan horse mechanism known as Antibody Dependent Enhancement (ADE).

.....

This inherent unpredictability problem is highlighted in the following scenario: A coronavirus vaccine may not be dangerous initially. If the initial testing looks positive, mass vaccination efforts would presumably be administered to a large portion of the population. In the first year or two, it may appear that there is no real safety issue, and over time, a greater percentage of the world population will be vaccinated due to this perceived “safety”. During this interim period, the virus is busy mutating.

Eventually, the antibodies that vaccinated individuals have floating around in their bloodstream are now rendered non-neutralizing because they fail to bind to the virus with the same affinity due to the structural change resulting from the mutation. Declining concentrations of the antibody over time would also contribute to this shift towards non-neutralization. When these previously vaccinate people are infected with this different strain of SARS-CoV-2, they could experience a much more severe reaction to the virus.

.......

The ADE response is actually much more complicated than the picture I outlined above. There are other competing and non-competing factors in our immune system that contribute to the ADE response, many of which are not fully understood. Part of that equation is a variety of different types of T-cells that modulate this response, and these T-Cells respond to other portions (epitopes) of the virus. In a vaccine, our body is normally presented with a small part of the virus (like the Spike protein), or a modified (attenuated or dead) virus which is more benign.

A vaccine does not expose the entirety of our immune system to the actual virus. These types of vaccines will only elicit antibodies that recognize the portion of the virus which is present in the vaccine. The other portions of the virus are not represented in the antibody pool. In this scenario, it is much more likely that the vaccine-induced antibodies can be rendered as non-neutralizing antibodies, because the entire virus is not coated in antibodies, only the portion that was used to develop the vaccine. In a real infection, our immune system is exposed to every nook and cranny of the entire virus, and as such, our immune system develops a panacea of antibodies that recognize different portions of the virus and, therefore, coat more of the virus and neutralize it. In addition, our immune system develops T-Cell responses to hundreds of different peptide epitopes across the virus; whereas in the vaccine the plethora of these T-Cell responses are absent.

Researchers are already aware that the T-Cell response plays a cooperative role in either the development of, or absence of, the ADE response. Based on these differences and the skewed immunological response which is inherent with vaccines, I believe that the risk of ADE is an order of magnitude greater in a vaccine-primed immune system rather than a virus-primed immune system. This will certainly become more apparent as COVID-19 progresses over the years, but the burden of proof rests on the shoulders of the vaccine industry to demonstrate that ADE will not rear its ugly head in the near term or the far term. Once a vaccine is administered and people develop antibodies to some misrepresentation of the virus, it cannot be reversed. Again, this is a problem that could manifest itself at a later date.

Merck takes distance; you don't want to embark on a possible genocide. Ken Frazier, CEO of the world's leading vaccine producer, the pharmaceutical company Merck & Co., in an interview with Professor Tsedal Neeley, from Harvard Business School, recalled that the fastest vaccine ever brought to market was medicine. from Merck against mumps, it took about four years! - Merck's vaccine for Ebola took five and a half years and was only approved in Europe this month. - The tuberculosis vaccine took 13 years! Rotavirus 15 years! and chickenpox 28 years !. - Frazier explained that the vaccine development process takes a long time because it requires rigorous scientific evaluation. In the case of Covid, "we don't even understand the virus itself or how the virus affects the immune system ..." - "No one knows for sure if any of these vaccine programs will produce a vaccine like this or not. What worries me most is that the public is so eager, so desperate to get back to normal, that they are pushing us [into the industry pharmaceutical] to move things faster and faster ”, he warned. - "There are many examples of vaccines in the past that stimulated the immune system but did not provide protection. And, unfortunately, there are some cases where they not only did not provide protection, but helped the virus to invade the cell because the vaccine was incomplete ... ". Regarding its immunogenic properties, we have to be very careful, "said Frazier. - Ultimately, "if a vaccine is to be used in billions of people, it is better to know what that vaccine does ...". - "When people tell the public that there will be a vaccine by the end of 2020, for example, I think they do the public a disservice. We don't want to rush the vaccine before we have rigorous science. - We have seen in the past, for example, with swine flu, that this vaccine has done more harm than good. We don't have a great history of introducing vaccines quickly in the midst of a pandemic. We have to take that into account ... ", reflected the CEO. - In the last quarter of the last century, only 7 new vaccines were developed, 4 of them by Merck, against pathogens for which there were previously in the vaccine. - For Frazier, the announcement of the arrival of a vaccine leads politicians and the population to reduce their attention with the virus. - "There are seven thousand five hundred million people on the planet now. And we have never had a vaccine that has been used in a population of this size ...", said the executive. - Frasier explained that it will be necessary to solve not only the problem of manufacturing on a scale that meets this number of people, but also to find ways to distribute the drug, particularly in areas of the world where people cannot afford the vaccine and also where the challenge of reaching those in need is greater. - "We need politicians who have the will and integrity to tell people the truth ...", said the CEO of Merck. - "And when you think about sending the children back to school, we will have to find a way to do it safely because the parents are arrested if the children are at home." - "We must find a way to open schools, not to mention the fact that remote learning does not work for all children ...", said Frasier. ° Source: https://hbswk.hbs.edu/item/merck-ceo-ken-frazier-speaks-about-a-covid-cure-racism-and-why-leaders-need-to-walk-the-talk ° I share an opinion on the prospect of a vaccine that guarantees protection against Covid. ° Note: HIV is another example: 40 years and no vaccine.