This completes the account of immune defences. In summary, the T helper cells .. https://www.sciencedirect.com/topics/medicine-and-dentistry/t-helper-cell .. are the eyes and ears of the immune defences and their job is to recognize foreign intruders. Once they have done so they switch on a formidable piece of machinery. A hail of bullets and arrows is released (antibody) and front-line soldiers (phagocytes) and other specialist combat units (cytotoxic T cells) are mobilized and armed. The attack on the invader begins.
Summary 1 –
Setting up an immune response (see also Figure 11)
Microbe enters body and one of its antigens is
[ .. or read .. Trump enters the American body politic and one of his family is .. ]
engulfed by an APC (antigen-presenting cell)
and digested to a smaller molecule (peptide)
and displayed or ‘presented’ (with MHC class 2*) on the APC's surface.
Wandering T helper cell capable of recognizing this particular peptide/MHC class 2
"How Long Will a Vaccine Really Take? "THE TESTS - expert comments on different types of test for COVID-19 "‘We’re Flying Blind’: Why Testing for Coronavirus Antibodies Will Matter"" "
Posted February 20, 2020 by Ricki Lewis, PhD in Uncategorized
Vaccine developers look specifically to the molecular landscapes where viruses impinge upon our respiratory and immune system cells. Targeting COVID-19 is especially challenging, because efforts to develop a vaccine against its relative, the SARS coronavirus (SARS-CoV), elicit only partial responses. But those steps are now serving as jumping off points for pharma.
The relationship between viruses and humans can seem like a science fiction plot. The viruses that make us sick may be little more than snippets of genetic material borrowed, long ago, from human genomes. Packaged with their own proteins, viruses return to our bodies, taking over to make more of themselves.
A zoo of animal hosts
Coronaviruses present a “severe global health threat,” write researchers from Wuhan University and Sun Yat-sen University in the Journal of Medical Virology. The viruses aren’t new, nor do they infect only people. They cause:
* diarrhea in pigs, dogs, and cows
* fever and vasculitis in cats
* fever and anorexia in horses
* severe lung injury in mice
* lung disease and death from liver failure in whales
* respiratory tract infection in birds (bulbuls, sparrows, and chickens)
Bats’ immune response enables them to house coronaviruses without becoming sick, making them a dangerous reservoir of infection.
Some species spread coronaviruses without becoming sick, like the camels that carry MERS, and bats, which carry many viruses.
MERS-CoV (Middle Eastern Respiratory Syndrome .. https://www.cdc.gov/coronavirus/mers/index.html ) emerged in 2012 in the Arabian peninsula, and is rare but can be fatal. SARS and MERS show zoonotic (to other animals) as well as human-to-human transmission.
Two coronaviruses without a predilection for human bodies may also be important,epidemiologically speaking. HKU2, which killed 24,000 piglets in southern China from diarrhea in 2017, is the first “spillover .. https://wwwnc.cdc.gov/eid/article/23/9/17-0915_article ” from a bat coronavirus to livestock. And Beluga whale CoV/SW1 .. https://jvi.asm.org/content/82/10/5084 , although only distantly related to the human pathogens, could reveal how bat viruses get into sea creatures.
The coronaviruses are of four genera (equivalent to the “Homo” in “Homo sapiens”): alpha, beta, gamma, and delta. COVID-19, SARS, MERS, HCoV-OC43, and HKU1 are beta. Two other human coronaviruses, HCoV-229E and HCoV-NL63, are alpha.
Many viruses that plague humans have RNA as their genetic material. It’s copied into DNA in our cells.
Anatomy of COVID-19
A virus isn’t a cell, isn’t even considered alive. It’s a nucleic acid (DNA or RNA) wrapped in a coat of proteins, some attached to sugars (glycoproteins).
The “body” of COVID-19 is basically a genome enveloped in glycoproteins, with a smear of fat and bearing the crown of spikes that inspired the name “coronavirus.”
The genome is a single strand of RNA that is termed “positive-sense.” That means that the infected cell treats the viral genome as if were it’s own messenger RNA (mRNA), translating it into proteins. A “negative-sense” RNA virus requires more manipulation; a host enzyme must make a positive-sense copy.
A coronavirus genome typically is 26,000-32,000 bases long. That’s hefty for a virus, but tiny compared to a human gene. Our BRCA1 gene, for example, is 125,951 bases long. Coronavirus RNAs are embellished with “caps” and “tails” like those of human mRNAs.
Once ensconced in a human cell, a half dozen or more viral mRNAs are peeled off. The first, representing about two-thirds of the viral genome, encodes 16 protein “tools” that viruses require to replicate. Making this toolkit is a little like downloading an installer for new software.
The tools (“non-structural proteins”) are enzymes needed to produce the other encoded proteins, and transcription factors to continually renew the RNA instructions.
The other third of the viral genome encodes four “structural” proteins that are the nuts and blots that build the virus:
* Spike .. https://www.pnas.org/content/106/14/5871 , or S protein, is made early in infection. One part of it, S1, grabs a receptor molecule sticking out of a host cell and another part fuses to the cell membrane. Three copies of the S protein form each spike.
* Membrane (M) glycoprotein lies beneath the spikes, where it shapes mature viral particles and binds the inner layers.
* Lipid (fat) is borrowed from host cell membranes during past infections.
* Envelope (E) glycoproteins control the assembly, release, and infectivity of mature viruses.
* Nucleocapsid (N) proteins knit a characteristic shell of identical subunits, like the panes of a greenhouse, that binds and packages the RNA genome. It also serves as a cloaking device, hiding viruses from our immune system’s interferons and RNA interference.
All coronaviruses share the “tools,” but differ in a few additional structural proteins tailored to the host species.
COVID-19’s Spikes Bind at ACE2 Receptors
Viruses have co-evolved with us, using proteins that jut from our cell surfaces. HIV and West Nile virus enter through CCR5 receptors, which dot white blood cells. Influenza viruses bind sialic acid residues. Coxsackievirus and adenovirus target part of an antibody. And herpes simplex uses 3 different doorways.
ACE2 raises blood pressure in us, but is a receptor for COVID-19.
To us, ACE2 is an enzyme that has an effect on blood pressure.
To COVID-19, ACE2 is a receptor, an entranceway, in the airways and alveoli (air sacs) as well as in blood vessel linings. ACE2 is also a receptor .. https://www.ncbi.nlm.nih.gov/pubmed/14647384 .. for SARS-CoV and NL63-CoV. (MERS-CoV uses a different receptor.)
The key to developing vaccines and treatments is the three-dimensional shapes of the parts of the virus that contact our cells.
SARS and NL63-CoV bind to a helical part of ACE2 that snakes up from cell membranes, forming distinctive tunnels and bridges that comprise a “hot spot” for viruses. The attraction of a virus to a cell receptor hot spot is a little like a tired commuter emerging from a subway station and seeing a Starbucks sign, moving towards the coffee shop as if dragged by a tractor beam. The viral hot spot that beckons both SARS and COVID-19 is a shared drug and vaccine target – and so all the work on developing a SARS vaccine is now in the spotlight.
Researchers knew from SARS that the S1 parts of the viral spikes hug the ACE2 receptor at a region of five amino acids (protein building blocks). Even though four of the amino acids differ in COVID-19, they are similar in size and charge to their counterparts in SARS.
If S1 attaches SARS to the ACE2 receptor like a boat docking, would COVID-9 tie up at exactly the same points?
Teaming a traditional crystal structure approach with computational methods, Pei Hao, of the Chinese Academy of Sciences and colleagues modeled the interface, showing that COVID-19 indeed binds ACE2 just like SARS does, with slightly less force. In a Letter to the Editor of Science China Life Sciences .. http://engine.scichina.com/publisher/scp/journal/SCLS/doi/10.1007/s11427-020-1637-5?slug=fulltext , they conclude that the new virus “poses a significant public health risk for human transmission via the S-protein-ACE2 binding pathway.”
Even more recently, researchers from the University of Texas at Austin and the National Institute of Allergy and Infectious Disease used electron microscopy to zero in on a “pre-fusion” spike protein triplet nearing the receptor. They imaged one of the three spikies rotating upward to latch onto the receptor, revealing precisely where a vaccine must fit. The work is published in Science .. https://science.sciencemag.org/content/early/2020/02/18/science.abb2507 .
A Fish, A Bat, and A Human Walk Into a Seafood Market …
Comparing genome sequences is a classic way to sort out evolutionary relationships, and the comings and goings of viruses are evolution in action. Evolutionary trees, whether going back millions of years to dinosaurs or just years to viruses, depict descent from shared ancestors. The meme of chimps leading directly to humans is and has always been incorrect.
The pinecone soldierfish Myripristis murdjan may pass COVID-19 from bats to us.
COVID-19 and the SARS-CoV have a common ancestor .. https://www.biorxiv.org/content/10.1101/2020.01.29.925867v1.full.pdf , a bat coronavirus. But COVID-19 is actually closer to the bat virus, sharing 96% of its genome sequence, compared to about 86% with SARS-CoV. And muddying the waters further, COVID-19’s spike gene shares a 39-base insertion with a type of soldierfish that swims in the South China Sea.
Somehow, the virus that evolved into COVID-19 may have started in a bat in 2013 and gotten into fish that ended up in the Wuhan Huanan Seafood Wholesale Market at the epicenter of the pandemic.
- [ INSERT: Well well. That COULD let the pangolin off the hook. Scientists are still searching for the source of COVID-19: why it matters [...] For example, in the 2002/2003 SARS-CoV outbreak civets were identified as the intermediate host. In the most recent outbreak pangolins have been implicated. But there are huge gaps in this theory given that the coronavirus identified in pangolins .. https://www.biorxiv.org/content/10.1101/2020.02.17.951335v1 .. has only a 90% similarity with the human viruses. https://investorshub.advfn.com/boards/read_msg.aspx?message_id=154335396 ] -
The confusion arises from the promiscuity of RNA viruses. Over the ages, they swap genetic material, mutate, and lose and gain pieces of themselves. The result is a constant spawning of patchwork genomes that under some circumstances harm the host species. And our bodies help it all along, sneezing, oozing, bleeding, or crapping out zillions of viruses before either expiring or recovering.
Did COVID-19 Come From Us?
How does a virus find itself at a door to a host cell? The “escaped gene” hypothesis leads the classic list of three explanations .. https://www.pnas.org/content/114/12/E2401 .. for a virus, such COVID-19’s, emergence:
* Viruses were ancient intermediates between collections of self-replicating chemicals and the first cells. (The virus-first or primordial viral world hypothesis).
* Viruses were once cells invaded by parasites that robbed them of the ability to manufacture their own proteins. As viruses, they infect cells to make the proteins they need to reproduce. (The cellular regression hypothesis)
* Viruses evolved, many times in many organisms, as mobile genetic elements – aka “jumping genes” – that produced protein coverings and took bits of fatty membrane from cells. (The escaped gene hypothesis).
All three may have happened.
So what’s COVID-19’s story? Is a hint in what normally binds the receptor?
Perhaps sometime in the past, a virus formed, or came to include, human DNA or RNA instructions for making an integrin .. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034747 , which is a protein that binds to ACE2. Integrins glue our cells to surrounding connective tissue. The viral spike masquerades as the integrin, grabbing our cells.
In other words, a viral epidemic may arise as an accident, of sorts, of biochemistry and evolution.
Vaccine!
SARS coronaviruses (yellow)
Spike protein took center stage as a vaccine candidate early in the SARS outbreak, because it elicits an antibody response in mice .. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058772/ . Various vaccine strategies – live weakened SARS, hitching spike genes to existing vaccines, circles of DNA housing spike genes and triplets of spike proteins in nanoparticles .. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058772/ – haven’t worked well enough. But genomic technology has exploded since SARS, leading to insights with astonishing rapidity.
In an exhaustive study preprinted in bioRxiv .. https://www.biorxiv.org/content/10.1101/2020.01.29.925867v1.full.pdf , Arunachalam Ramaiah of the University of California, Irvine and Vaithilingaraja Arumugaswami of UCLA catalogued where key parts of the four structural proteins of COVID-19 bind to the proteins that mark immune system cell surfaces. The work implicated the spike protein, but from the perspective of the immune response rather than the receptor.
Now pharma and biotech companies are charging ahead to create vaccines, partnering with BARDA .. https://www.phe.gov/about/barda/Pages/default.aspx , the Biomedical Advanced Research and Development Authority. Under Health and Human Services, BARDA was established in 2011 “to aid in securing our nation from chemical, biological, radiological, and nuclear threats, as well as from pandemic influenza and emerging infectious diseases,” by speeding the trajectory of diagnostic, vaccine, and treatment development.
----- OK, we can thank Obama for BARDA. Tick. How about Trump i wondered, and sure enough
US vaccine expert says he was removed from job for opposing unvetted Donald Trump-backed drug
United States President Donald Trump Source: AAP
A doctor who led a US agency helping to develop a coronavirus vaccine says he was removed from the job for questioning chloroquine, a drug endorsed Donald Trump that has not undergone thorough vetting.
Updated Updated 23/04/2020
The head of the US agency in charge of developing a vaccine against coronavirus said Wednesday that he was removed from his job for opposing the chloroquine treatment promoted by President Donald Trump.
Seriously. How would YOU feel if you were a scientist working in the Trump administration.
For fear of the capon it would take real integrity to speak out in honor of your expertise. -----
But vaccine and drug development .. https://www.biopharmadive.com/news/regeneron-hhs-coronavirus-antibody-development/571651/ .. take time. Until then, treatment remains supportive. Meanwhile, epidemiologists are filling in the denominators of the case:fatality stats to determine exactly how deadly the infection is, and assess if asymptomatic individuals are unwittingly spreading it.
I’ll end with a sobering thought from a pathogen’s point of view. Even if we vanquish COVID-19, a continuing if not escalating perfect storm of events foreshadows other viral epidemics: climate change, human travel, and our encroachment into the turfs of other animals.
Coronavirus updates LIVE: Novavax human trials begin in Melbourne as global COVID-19 cases surpass 5.4 million. Australian death toll stands at 102
"How Long Will a Vaccine Really Take?"
If you suspect you or a family member has coronavirus you should call (not visit) your GP or ring the national Coronavirus Health Information Hotline on 1800 020 080.
[...]
By Mary Ward and Megan Levy Updated May 26, 2020 — 9.28amfirst published at 3.55am
[...]
Human trials have begun for a COVID-19 vaccine at the Alfred Hospital in Melbourne, it has been announced this morning.
The trials, the first in the southern hemisphere, will test a vaccine developed by US biotech company Novavax.
“Administering our vaccine in the first participants of this clinical trial is a significant achievement, bringing us one step closer toward addressing the fundamental need for a vaccine in the fight against the global Covid-19 pandemic,” Stanley C. Erck, Novavax CEO and president said in a statement to Forbes.
Roughly 131 people aged 18 to 59 will take part in the trial.
Results are expected in July 2020.
The vaccine is one of over 100 vaccines currently being developed across the world.
LONGTERM - Why a vaccine may not be enough to end the pandemic
"How Long Will a Vaccine Really Take? "THE TESTS - expert comments on different types of test for COVID-19 "‘We’re Flying Blind’: Why Testing for Coronavirus Antibodies Will Matter"" "
We need to plan for many different Covid-19 vaccine scenarios. These four factors will influence the outcome.
By Umair Irfan Jun 3, 2020, 8:20am EDT
There are dozens of Covid-19 coronavirus vaccines being tested right now, but no guarantee any of them will succeed. Mladen Antonov/AFP via Getty Images
Without a vaccine or treatment, the world has been forced to adopt severe tactics to slow the spread of Covid-19 .. https://www.vox.com/coronavirus-covid19 : social distancing, shutdowns, closures, and cancellations. As states in the US begin to reopen, it’s clear there is still much hardship to come — for those laid off, for businesses forced to implement costly new health measures, for those still at risk of infection.
“This is an extraordinary time we’re living in right now,” said Anna Durbin, a vaccine researcher and a professor of international health at the Johns Hopkins School of Public Health. “The pandemic is motivating a lot of [vaccine] efforts around the world.”
Yet as tempting as it is to predict how the vaccine will fit into the great epic of Covid-19, it’s impossible to know exactly how it will play out.
The kinds of vaccines we get and how well they’re distributed could determine whether this virus will fade away or will linger forever. And many of the decisions that could affect those outcomes are being made now.
There are four key elements that will determine how a vaccine will play out — how effective it will be, when it will be ready, how much of it would be available, and what the world does in the meantime to limit Covid-19. Here are some of the possibilities, and how they could change the course of the pandemic.
Efficacy: Will the vaccine grant lifelong immunity, or will immunity weaken in a few years?
A vaccine is a drug that primes the immune system to fight off an infection from a specific pathogen, protecting the recipient from a future infection.
Given the number of trials underway, some researchers are optimistic that not just one, but multiple Covid-19 vaccines will likely come to fruition. But the amount of protection they provide could vary. On the high end of possibilities, the vaccine could provide what’s called “sterilizing immunity .. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011745/ ,” meaning the recipient would be safe from infection potentially forever. This would be along the long lines of the smallpox vaccine.
Then there are lesser degrees of protection that could allow the virus could take root but the vaccine would coach the host’s immune system to fight it off before it can do too much damage. The inoculated could experience mild symptoms and transmit the disease, but the vaccine would prevent the more dangerous outcomes. This is how some influenza vaccines work.
One variable shaping efficacy is how quickly the virus mutates. A faster rate of mutation would increase the likelihood that the vaccine would not generate an effective immune response to the virus. SARS-CoV-2, the virus behind Covid-19, is a single-stranded RNA virus. Such viruses are notorious for high mutation rates .. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000003 , but those mutations don’t necessarily occur in a way that would weaken protection from a vaccine.
“Measles is also a single-stranded RNA virus. It mutates a little but it doesn’t mutate away from the vaccine,” said Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia. “I think that you’re not going to need to do what you do with influenza where you have to get a yearly vaccine. Influenza is a moving target. That’s not going to be this virus.”
“On the other hand, the vaccines will likely induce immunity that is short-lived and incomplete,” Offit said.
That is, the vaccine will likely offer protection that lasts a few years rather than decades or the near-lifetime immunity granted by some vaccines for other viruses.
And by “incomplete,” Offit explained that the vaccine would likely prevent the most severe manifestations of Covid-19, but it would likely do little to stop asymptomatic infections or milder forms of the illness.
This theory is based on what scientists have learned from how people have responded to other coronaviruses and how long people have retained immunity after an infection or a vaccination. For instance, people can get reinfected by the coronaviruses that cause the common cold within a couple of years of their first infection.
It may be the case that one type of Covid-19 vaccine is recommended for some age groups or people with preexisting conditions, while another type of vaccine is deployed to the general public. If immunity fades over time, people will need periodic boosters or revaccinations. And some people’s immune systems may not respond to the vaccine at all. “There may be people out there who are fundamentally unvaccinatable,” said Benjamin Neuman, a virologist at Texas A&M University Texarkana.
Timing: How soon until scientists find a vaccine that works?
A lot can change between now and whenever a vaccine for Covid-19 will become available. It may be months, it may be years — it’s not clear how long it will take, and that has huge implications for public health decisions we make in the meantime.
There is a global effort underway to speed up vaccine development. Governments are making efforts to fast-track funding and regulatory approvals, like combining phases of clinical trials. Companies are also putting their own researchers on the task. Nonprofit groups and philanthropists are also chipping in. That’s why some researchers are optimistic that a Covid-19 vaccine could arrive in record time. “This is as accelerated as it gets,” Offit said.
But the history of vaccine development shows that it can be a long, frustrating process. For instance, the mumps vaccine holds the record for fastest development time, which was four years. Most vaccines have taken much longer, often more than a decade.
Vaccine trials often begin with testing in animals like monkeys before testing in humans. This macaque is part of a Covid-19 vaccine trial in Thailand. Mladen Antonov/AFP via Getty Images
The timing of when a vaccine comes out is critical because it determines the landscape where a vaccine would be released. Within the next two years, odds are Covid-19 will have spread, but the vast majority of the world’s population would still be unexposed and vulnerable to infection.
As time goes on and the virus spreads, more people in a population will have been exposed to the virus, so fewer doses of the vaccine would be needed. The massive trade-off is that allowing the virus to spread further would come with more deaths and strain on the health care system.
A longer wait for a vaccine could mean increasing fatigue from pandemic control measures. Lockdowns and stay-at-home orders have already proven to be immensely costly and controversial. But a sudden relaxation of these measures without a vaccine or viable treatment for Covid-19 would allow the pandemic to continue spreading.
At the same time, the unprecedented resources flowing toward a vaccine doesn’t mean it will arrive any sooner. Even in the best of times, developing a vaccine is an enormous technical challenge that pushes the frontiers of science, demands the focus of swarms of researchers, and requires grueling trial and error. Despite the dozens of candidates under review, there is no guarantee any of them will pan out.
And those candidates that do show promise then need to undergo extensive testing for safety. A Covid-19 vaccine would have to be administered to millions, if not billions, of people. That means the rate of complications from the drug has to be so low that giving it to so many people is still a net positive.
For instance, one concern with vaccines is the risk of a problem known as vaccine enhancement or immune enhancement .. https://www.pnas.org/content/117/15/8218 . That’s where the recipient’s immune system overreacts to the vaccine and may worsen the disease. It’s rare, but the likelihood of it has to be reduced as much as possible and balanced against the efficacy of a vaccine.
Still, a vaccine that offers imperfect protection could still be distributed; a vaccine that hasn’t met minimum safety thresholds could not.
In contrast, a treatment is only administered to people who are already ill, or as a preventive measure to people who face a high likelihood of getting infected. The risks and side effects for a treatment are more tolerable because they are weighed relative to the damage from the virus.
Reaching the point where a vaccine is ready to deploy requires extensive, slow, tedious, and expensive testing in humans. Until a vaccine reaches the necessary safety benchmarks, its use will be delayed. That’s a big reason pharmaceutical companies have been reluctant to invest in vaccine development on their own. But this testing is also why vaccines are some of the safest medical tools ever developed.
Some vaccines could be used before testing is completed under compassionate use guidelines, or for people in high-risk roles. A research team at Oxford University’s Jenner Institute .. https://www.nytimes.com/2020/04/27/world/europe/coronavirus-vaccine-update-oxford.html .. said they may have a vaccine ready for emergency use as soon as September. However, a widespread rollout will take much longer.
Distribution: Will countries compete or collaborate on a global vaccination campaign?
The next obstacle to ending the Covid-19 pandemic with a vaccine is getting to enough people inoculated to achieve herd immunity .. https://www.jhsph.edu/covid-19/articles/achieving-herd-immunity-with-covid19.html . That’s where enough members of a population are immune to the virus, making it so that the virus can’t spread easily. The herd immunity threshold in a population can range from 60 percent to more than 90 percent, depending on how readily the pathogen can spread. At those levels, even people who aren’t immune receive protection since the virus is less likely to jump from person to person.
Depending on the prevalence of the virus at the time, that could mean vaccinating the majority of people on Earth. It’s not clear that the world will muster the resources, knowledge, and political will to do this.
“People don’t realize the full extent, that we as a country, we as a global community, have never vaccinated adult populations in the numbers that we need” to end the Covid-19 pandemic, said Saad Omer, a vaccine researcher and director of the Yale Institute for Global Health. “The numbers you would need for normalization — numbers you would need for NFL games to resume with crowds, the numbers you would need for a sense of normalcy, where grandma-can-attend-your-wedding kind of normalcy — would require vaccine-level herd immunity, and that would mean pretty high numbers.”
Billions of doses will be needed, which demands a robust supply chain and manufacturing capacity. Very little of this infrastructure exists now, and building it up would require extensive government and private sector investment.
A related issue is that different types of vaccines — mRNA, viral fragments, inactivated viruses — require entirely different manufacturing techniques, so one assembly line can’t be easily repurposed for another. Each approach requires its own infrastructure.
An employee of the Russian biotech firm BIOCAD, which is developing a Covid-19 vaccine, works on a vaccine production line. Manufacturing a coronavirus vaccine will be its own tedious, expensive process. Olga Maltseva/AFP via Getty Images
Vaccinating everyone would also demand legions of workers trained to administer it all over the world. It’s a process that will take years of sustained effort, and planning needs to begin right away. “Just the logistics for it are pretty substantial,” Omer said. “My concern is that we’re not preparing for it now.”
And at the outset, there won’t be enough vaccines for everyone, which means making difficult decisions about whom to prioritize for immunization.
Whether there will be enough vaccines to go around will depend on decisions and investments being made now. Philanthropists like Bill Gates .. https://www.vox.com/future-perfect/2020/4/14/21215592/bill-gates-coronavirus-vaccines-treatments-billionaires , economists, and some nonprofits are calling to start building vaccine factories for different candidates immediately, even before testing is complete, with the expectation that many of these vaccine candidates will not be selected.
The extent of global collaboration can therefore shape how quickly the pandemic phases out. If only a handful of countries have a Covid-19 vaccine and aren’t willing to help distribute it, the virus can continue to spread in other areas of the world. And until there’s herd immunity, the virus could be reimported into countries, even with a vaccine.
Public health responses: Can we keep up pandemic control measures until, and after, a vaccine arrives?
Since a Covid-19 vaccination campaign will likely take a long time, many of the current tactics to slow the pandemic will still be needed to an extent after a vaccine is available.
And limiting the spread of the virus can boost the effectiveness of a vaccine across a population, even if the vaccine itself doesn’t grant robust, long-term immunity to an individual. For instance, a vaccine that protects older people, coupled with social distancing and mask-wearing, would do more to slow the pandemic than any of these methods on their own. So a vaccine is ultimately one tacticin a suite of methods to control Covid-19.
Some businesses like this fish and chip shop in the United Kingdom have limited their offerings and imposed distance requirements to help limit the spread of the coronavirus. Huw Fairclough/Getty Images
“If the [moderately efficacious] vaccine is used outside of these comprehensive public health responses — contact tracing, social distancing — it would only protect the individual person for one to two years,” said Neuman.
Another element that could influence a Covid-19 vaccination campaign is the availability and effectiveness of treatments for the virus. Right now, there is no specific treatment recommended for general use — some experimental drugs like remdesivir .. https://www.vox.com/2020/5/1/21243012/remdesivir-coronavirus-covid-19-fda-drug-gilead .. have been allowed for emergency and compassionate use. However, if a widely available medicine were developed, it would relieve some of the urgency for developing a vaccine.
Treatments could also help optimize the distribution of vaccines. If a treatment is more effective in some groups but not others, say, the elderly, the more vulnerable group could become the priority for vaccination, putting limited vaccines to more effective use.
In thinking about how a Covid-19 vaccine would play out, it helps to look at lessons from other vaccines
The Covid-19 pandemic is unprecedented in many ways, so whatever scenario emerges will be unlike anything we’ve seen before. That said, there are some historical cases that can illustrate what could happen with a Covid-19 vaccine.
The most ideal outcome would be a vaccine akin to that for smallpox, rendering robust and near-lifelong immunity to the virus. With the smallpox vaccine, smallpox has become only one of two viruses to have been eradicated in the wild .. https://www.cdc.gov/smallpox/history/history.html . “It’s obvious that we’re all aiming for a vaccine that is more like the smallpox vaccine,” Fitzpatrick said.
However, the world was very lucky with smallpox. The vaccine was unusually effective. The virus also had no known animal hosts and only spread from human to human.
That said, researchers do expect that a usable Covid-19 vaccine will emerge from the race. “I do have a lot of optimism about our ability to develop a vaccine against the coronavirus,” said Fitzpatrick. “The reason they are being tested now is because they have shown promising results in animal models.”
Even if a vaccine doesn’t prevent the disease entirely, it can still be useful if it reduces the severity of the illness. “You could imagine a scenario where something that is less than efficacious is rolled out because some benefit in the pandemic is better than no benefit,” said Omer. That would make it particularly helpful for people in high-risk groups like the elderly .. https://www.vox.com/2020/3/12/21173783/coronavirus-death-age-covid-19-elderly-seniors .. or people with preexisting health conditions.
But the lower levels of protection could also mean that an inoculated patient could still spread the virus, which means other control measures would be needed to protect high-risk groups.
On the other end of the spectrum, the race to develop a Covid-19 vaccine could be as fruitless as the effort to develop a vaccine for HIV, which has gone on for nearly 40 years.
Such an outcome would require weighing the trade-offs that may be necessary to live in a world where SARS-CoV-2 may be lurking for years. “We have to start thinking about prevention where we don’t have the magic bullet or the technological fix,” said Gregg Gonsalves, an assistant professor of epidemiology at the Yale School of Public Health.
For HIV, the lack of a vaccine to date has led public health officials to focus on treatments like antiviral drugs and to encourage less risky behavior, like using condoms. These tactics have improved the survival rate for people with the virus and reduced its spread. Similar attention to treatment and behavior could mitigate the harms of Covid-19, but it may require lasting cultural changes like wearing masks and avoiding large gatherings.
Researchers do expect that some versions of vaccines will start being deployed in the next few months in limited cases, but getting a widespread vaccine at a record pace would require a lot of the aforementioned factors to precisely fall into place. A vaccine could still arrive in time to be used to protect the majority of people. But the world will still have to endure the pandemic until then.
Even with assembly lines in place ready to ramp up production, there will likely be a scarcity of vaccines at the outset. That will require officials to ration the vaccine and make difficult decisions about whom to prioritize in their distribution.
“It’s not an easy decision to make, and I don’t envy the people who have to make it,” Durbin said.
The central focus of the vaccination campaign would be the people facing the most exposure to the virus, like health workers, followed by people in essential roles like those in grocery supply chains and first responders. Then older people and those at the highest risk of complications could be vaccinated.
An employee works at the biotech firm Stabilitech in England. Scientists there are trying to develop an oral vaccine for Covid-19. Quashing the pandemic may require billions of doses. Ben Stansall/AFP via Getty Images
One method to economize vaccines is a ring vaccination .. https://www.who.int/news-room/detail/23-09-2019-second-ebola-vaccine-to-complement-ring-vaccination-given-green-light-in-drc .. strategy. For Covid-19, it would involve vaccinating just people who were exposed to the virus rather than everyone in a population, forming a “ring” around a known carrier. Ring vaccination was used effectively in the Democratic Republic of Congo to contain the Ebola virus outbreak there in 2019. But it requires extensive contact tracing to figure out who might have been exposed. With a virus that spreads as far and as quickly as Covid-19, this tracing effort would be far more laborious than it was for Ebola, especially given that many people infected with SARS-CoV-2 can spread it without showing symptoms .. https://www.vox.com/2020/4/22/21230301/coronavirus-symptom-asymptomatic-carrier-spread .
“We would definitely aiming for a [vaccine] supply where we didn’t have to consider ring vaccination as a strategy,” Fitzpatrick said.
Another scenario isthat the distribution of the vaccine may take longer than the duration of immunity it provides. If a Covid-19 vaccine provides two years of protection but takes five years to reach most people, then the first round of immunity could fade before herd immunity is reached. That’s why it’s important to get the vaccine delivered quickly to as many people as possible.Otherwise, pockets of infection could remain and cause sporadic outbreaks until people are revaccinated.
Supply chains are critical too. If countries are willing to pool resources to ramp up vaccine production, the demand for a vaccine could be met far more rapidly than with countries working on their own. It would also prevent some of the bottlenecks that have hampered other materials needed for the Covid-19 pandemic, like personal protective equipment and reagents for tests.
Masks may be here to stay. Omar Zoheiry/DPA/Picture Alliance via Getty Images
Communication is also going to be a critical factor for the deployment of a vaccine to explain why vaccines are safe and why getting vaccinated is so important.
Even amid a deadly pandemic, it’s unlikely that people who fear vaccines will suddenly change their minds with Covid-19. “That’s not how it works. People have huge motivated reasoning .. https://www.vox.com/2018/2/27/17057990/andrew-wakefield-vaccines-autism-study,” Omer said. “There will be vaccine acceptance issues.”
Resolving this will require campaigns to convince people to get vaccinated aimed not necessarily at the people who are most opposed to vaccines, but at people who are ambivalent. Without this kind of outreach, even the existence of a highly effective vaccine won’t contain the virus.
Taken together, these scenarios highlight just how difficult it is to anticipate the pandemic’s future. But they also show why it’s important to game out what’s possible, to build for the best, and to prepare for the worst. Billions of lives and livelihoods worldwide hang in the balance.
Halting Progress and Happy Accidents: How mRNA Vaccines Were Made
"How Long Will a Vaccine Really Take?"
--- Because the tab this is sitting on is getting moldy and because just closing it hasn't felt right and because there are still deniers around it's time it's posted in full.
"Part of what made them so prone to shape shifting was that they had pockets of empty space." Like Trump cultists.
Toss in the myth tossed around by Trump cultists that Trump deserves all the credit for the mNRA vaccines. Actually Trump deserves less credit than many others deserve. See
Btw, you and the goalpost you remind me of Trump personally had little if anything to do with Warp Speed. The U.S. Fumbled the Early COVID Response in Two Major Ways [...] Now, it's interesting and it shows in the books, when Peter Marks, who is a career staffer at FDA, came up with the idea of Operational Warp Speed, because he's a sci-fi nut, he presented it to [former HHS Secretary] Alex Azar at HHS. Azar's incoming view before that meeting was that it would take too long to develop a vaccine and that they shouldn't focus on vaccines, we should focus on therapies. To Azar's credit after he heard Marks out, and Marks' plan for how to get focused on developing vaccines more rapidly, Azar supported it and decided to fund it. And the rest is history. https://investorshub.advfn.com/boards/read_msg.aspx?message_id=167413618
Arguably one could say President Bill Clinton in 1996 contributed more the the development of the mNRA vaccines than Trump did in 2020. See below. ---
The stunning Covid vaccines manufactured by Pfizer-BioNTech and Moderna drew upon long-buried discoveries made in the hopes of ending past epidemics.
A 3D plaster model of a coronavirus spike protein in the office of Dr. Barney Graham, an immunologist and virologist recently retired from the Vaccine Research Center of the National Institutes of Health. Johnathon Kelso for The New York Times
Thousands of miles from Dr. Barney Graham’s lab in Bethesda, Md., a frightening new coronavirus had jumped from camels to humans in the Middle East, killing one out of every three people infected. An expert on the world’s most intractable viruses, Dr. Graham had been working for months to develop a vaccine, but had gotten nowhere.
Now he was terrified that the virus, Middle East Respiratory Syndrome, or MERS, had infected one of his lab’s own scientists, who was sick with a fever and a cough in the fall of 2013 after a pilgrimage to the holy city of Mecca.
A nose swab came back positive for a coronavirus, seeming to confirm Dr. Graham’s worst fears, only for a second test to deliver relief. It was a mild coronavirus, causing a common cold, not MERS.
Dr. Graham had a flash of intuition: Perhaps it would be worth taking a closer look at this humdrum cold virus.
It was an impulse born more of convenience and curiosity than foresight, with little to no expectation of glory or profit. Yet the decision to study a colleague’s bad cold gave rise to critical discoveries. Together with other chance breakthroughs that seemed insignificant at the time, it would lead eventually to the mRNA vaccines now protecting hundreds of millions of people from Covid-19.
The shots were developed at record speed, arriving just over a year after a mysterious pneumonia surfaced in China, while so much else — political feuds, public distrust and botched government planning — went wrong.
They remain a marvel: Even as the Omicron variant fuels a new wave of the pandemic, the vaccines have proved remarkably resilient at defending against severe illness and death. And the manufacturers, Pfizer, BioNTech and Moderna, say that mRNA technology will allow them to adapt the vaccines quickly, to fend off whatever dangerous new version of the virus that evolution brings next.
Skeptics have seized on the rapid development of the vaccines — among the most impressive feats of medical science in the modern era — to undermine the public’s trust in them. But the breakthroughs behind the vaccines unfolded over decades, little by little, as scientists across the world pursued research in disparate areas, never imagining their work would one day come together to tame the pandemic of the century.
The pharmaceutical companies harnessed these findings and engineered a consistent product that could be made at scale, partly with the help of Operation Warp Speed, the Trump administration’s multibillion-dollar program to hasten the development and manufacture of vaccines, drugs and diagnostic tests to fight the new virus.
For years, though, the scientists who made the vaccines possible scrounged for money and battled public indifference. Their experiments often failed. When the work got too crushing, some of them left it behind. And yet on this unpredictable, zigzagging path, the science slowly built upon itself, squeezing knowledge from failure.
The vaccines were possible only because of efforts in three areas. The first began more than 60 years ago with the discovery of mRNA, the genetic molecule that helps cells make proteins. A few decades later, two scientists in Pennsylvania decided to pursue what seemed like a pipe dream: using the molecule to command cells to make tiny pieces of viruses that would strengthen the immune system.
The second effort took place in the private sector, as biotechnology companies in Canada in the budding field of gene therapy — the modification or repair of genes to treat diseases — searched for a way to protect fragile genetic molecules so they could be safely delivered to human cells.
The third crucial line of inquiry began in the 1990s,when the U.S. government embarked on a multibillion-dollar quest to find a vaccine to prevent AIDS.That effort funded a group of scientists who tried to target the all-important “spikes” on H.I.V. viruses that allow them to invade cells. The work has not resulted in a successful H.I.V. vaccine. But some of these researchers, including Dr. Graham, veered from the mission and eventually unlocked secrets that allowed the spikes on coronaviruses to be mapped instead.
In early 2020, these different strands of research came together. The spike of the Covid virus was encoded in mRNA molecules. Those molecules were wrapped in a protective layer of fat and poured into small glass vials. When the shots went in arms less than a year later, recipients’ cells responded by producing proteins that resembled the spikes — and that trained the body to attack the coronavirus.
The extraordinary tale proved the promise of basic scientific research: that once in a great while, old discoveries can be plucked from obscurity to make history.
“It was all in place — I saw it with my own eyes,” said Dr. Elizabeth Halloran, an infectious disease biostatistician at the Fred Hutchinson Cancer Research Center in Seattle who has done vaccine research for over 30 years but was not part of the effort to develop mRNA vaccines. “It was kind of miraculous.”
A Wily Virus
Dr. Anthony S. Fauci, the top government scientist investigating H.I.V., gave a lesson on the biology of AIDS to President Bill Clinton and Vice President Al Gore at the White House in 1996. NIAID
In December 1996, President Bill Clinton invited Dr. Anthony S. Fauci to the Oval Office to brief him on that era’s grave pandemic, AIDS, which by then had killed more than 350,000 people in the United States and six million more globally.
Dr. Fauci, the top government scientist investigating the virus, was feeling oddly hopeful. For the first time since the virus emerged, annual AIDS deaths in the country had fallen, thanks to several new drugs that were tested and approved after years of intense public pressure by patient activists.
But the most valuable tool remained missing from their arsenal: a vaccine. And the president was impatient.
As the men walked out to the Rose Garden, Dr. Fauci recalled, the president turned to him and said: “You’ve known about AIDS as a disease since 1981. How come you guys don’t have a vaccine yet?”
Dr. Fauci, taken aback, told the president that research efforts thus far had been largely uncoordinated. Then he made a bold pitch: a research facility where scientists from different disciplines could talk to one another and collaborate, with the goal of putting vaccines into arms rather than proving that their own discipline had the answers.
Mr. Clinton turned to his chief of staff, Leon Panetta. “You think we can do that?” he asked.
“You’re the president of the United States,” Mr. Panetta recalled saying. “You can do whatever the hell you want.”
Dr. Fauci figured they were flattering him. Vaccine research was hardly exciting science and had long taken a back seat to efforts to cure cancer and heart disease. But five months later, Dr. Fauci got a call from one of the president’s speechwriters. Mr. Clinton was going to give a commencement address at Morgan State University .. https://www.presidency.ucsb.edu/documents/commencement-address-morgan-state-university-baltimore-maryland .. in Baltimore and wanted to announce the vaccine research center. Could Dr. Fauci supply a description? “I was completely shocked,” Dr. Fauci said.
Dr. Barney Graham in his home office in Smyrna, Ga. Johnathon Kelso for The New York Times
One of the first scientists to be recruited to the new effort was Dr. Graham. A bearded virologist with a calm demeanor, who at 6-foot-5 towered over most of his colleagues at Vanderbilt University in Nashville, he had begun his career as a clinician. But in 1982, when he was just starting as chief resident at the hospital, he had a shattering experience.
A homeless man arrived in the emergency room with delirium, skin lesions and multiple infections in his lungs, liver and spleen. Looking at his chart, Dr. Graham was stunned at the collapse of the man’s immune system, and suspected a new virus that was spreading among drug users and gay men. He was right: The man had AIDS.
Soon patients with the same array of symptoms filled the hospital — often young men, skeletal and desperately ill, filling the staff with despair.
“It was scary — horrible,” Dr. Graham said. However mysterious the virus, he vowed to find a way to prevent it from spreading. “I want to be a virologist,” he told the head of an infectious disease department. “What do I do?”
The Vaccine Research Center opened its doors in 2000 at the National Institutes of Health’s campus in Bethesda, Md., with an annual budget of $43.9 million in today’s dollars and a staff of 56. Among them was Dr. Graham. It now has a staff of 444, with a budget of about $180 million.
To complement that research, the N.I.H. spent more than $1.5 billion over the same period on a network of clinical trial sites across the country for experimental H.I.V. vaccines. About 85 H.I.V. shots have been tested. None have worked.
H.I.V. Failures
A human T-cell, depicted in blue, under attack by H.I.V., in yellow. NIAID
[Spend a minute looking at that image. The ugliness of it eats into you.]
Vaccines protect people by giving the immune system a preview of an invading microbe so it can prepare a strong defense against the real thing.
But H.I.V. proved impossible to vaccinate against, for a long list of reasons. Other viruses might use one or another protective mechanism to evade the immune system. But H.I.V. seemed to use all of them, Dr. Graham said: “If we could figure out how to make an H.I.V. vaccine, all the problems with other viruses would be solved.”
Some of the researchers at the center decided to try a new, more theoretical approach, though it was a long shot. They would map the detailed atomic structure of H.I.V.’s spike, a protruding protein that allows the virus to invade human cells. They would then try to identify the part of the spike that was most vulnerable to antibodies, components of the immune system that recognize viruses and can block spikes from entering other cells. Ultimately, the goal was to make a vaccine that showed the body a harmless version of that same section of spike.
They knew it would be difficult. H.I.V. spikes constantly change shape, taking one form before invading a cell and a different one when the virus slips in. A vaccine would ideally use only the shape that elicited powerful antibodies against an initial form of the spike, to have the best shot at keeping the virus out. But the scientists struggled for years to determine which shape to choose. Mapping the spike was like trying to grab Jell-O.
In 2008, a 27-year-old named Jason McLellan from outside Detroit applied to join a group at the Vaccine Research Center working on just that problem. When he was growing up, his father managed a grocery store and his mother ran the home. He attended Wayne State University on a full scholarship, becoming the first in his family to earn a college degree.
He would go on to graduate school to study X-ray crystallography, the difficult and painstaking art of making tiny crystals of proteins and then blasting them with X-rays to figure out their three-dimensional structure.
But by the time he was hired by the center, Dr. McLellan had tired of chasing the shape of one molecule after another, never knowing what it added up to. He wanted to work on molecules that would matter to human health, like H.I.V.
Peter Kwong, chief of the structural biology section at the National Institutes of Health, studies the rare human antibodies that could attack H.I.V. Shuran Huang for The New York Times
Within six months, though, Dr. McLellan was flummoxed by H.I.V. and wanted to apply its lessons to another pathogen.
So he approached his boss, Peter Kwong, with an unconventional proposal: Let’s start working on a more manageable virus.
It was time, Dr. McLellan said, to take aim at “something important, but something more tractable.”
Dr. Kwong was not keen on taking his eyes off H.I.V. With the virus killing more than one million people globally every year, Dr. Kwong believed that he had an obligation to stay focused.
Still, Dr. Kwong put his protégé’s proposal for pursuing other targets to a vote of his entire team, just as he did matters of whom to hire and what equipment to buy. The result was almost unanimous, Dr. Kwong recalled: “Try other things.”
Dr. McLellan didn’t have to look far. He had been working in a spillover area on another floor from Dr. Kwong’s lab, and was seated close to Dr. Graham, who for years had studied not only H.I.V., but respiratory syncytial virus, or R.S.V. .. [ https://www.health.nsw.gov.au/Infectious/factsheets/Pages/respiratory-syncytial-virus.aspx ], a disease that can kill young children. They got to talking, and Dr. McLellan began studying the structure of a protein that helps the virus fuse with cells.
Over the next years, their success in stabilizing that protein opened the door to several R.S.V. vaccines now in clinical testing.
And though they never expected it, their happenstance collaboration would prove critical for understanding the scary new virus that would emerge more than a decade later.
A Pipe Dream
Dr. Drew Weissman, third from right, and Dr. Katalin Karikó, third from left, in 2001. via Katalin Karikó
In the 1950s, the molecule at the heart of the mRNA vaccines was cloaked in mystery. Midcentury biologists knew that blueprints for making proteins — DNA — resided in the middle of cells, and that other structures within cells, called ribosomes, actually produced the proteins. But they didn’t know how the genetic blueprints found their way to the cellular factories.
[EEKS LOL Yeeks will never hold exactly the same meaning again.]
The scientists figured out that X carried copies of segments of the DNA code to ribosomes, cellular machines that could read the code and pump out its corresponding proteins. The scientists named the molecule messenger RNA, or mRNA.
But for all of their initial excitement, those heavyweights of the field didn’t do much more with mRNA. The molecule was nearly impossible to isolate from cells because it would fall apart as it was being removed.
“Molecular biologists were much more excited about DNA and proteins,” said Doug Melton, a Harvard biologist who in 1984 figured out how to make mRNA in a lab. “mRNA was just annoying because it was so easily degraded.”
For decades, few scientists paid attention to these delicate molecules. They might never have made it into the Covid vaccines if not for a chance meeting between two academics at a Xerox machine at the University of Pennsylvania.
A transmission electron microscope image of messenger RNA connecting ribosomes. Omikron/Science Source
Dr. Drew Weissman, a physician and virologist so taciturn that his family liked to joke he had a daily word limit, was desperate for new approaches to an H.I.V. vaccine. Earlier in his career, he had spent years in Dr. Fauci’s lab at the N.I.H. testing a treatment for AIDS that turned out to be toxic.
One day in 1998, he was at the copy machine in Penn’s department of medicine when a woman approached him. Katalin Karikó, a 44-year-old scientist from Hungary, was as exuberant as Dr. Weissman was withdrawn. She had come to the United States two decades earlier when her research program at the University of Szeged ran out of money. But she’d been marginalized in American research labs, with no permanent position, no grants and no publications. She was searching for a foothold at Penn, knowing that she would be allowed to stay only if another scientist took her in.
Her obsession was mRNA. Defying the decades-old orthodoxy that it was clinically unusable, she believed that it would spur many medical innovations. In theory, scientists could coerce a cell to produce any type of protein, whether the spike of a virus or a drug like insulin, so long as they knew its genetic code.
“I said, ‘I am an RNA scientist. I can do anything with RNA,’” Dr. Karikó recalled telling Dr. Weissman. He asked her: Could you make an H.I.V. vaccine?
“Oh yeah, oh yeah, I can do it,” Dr. Karikó said.
Up to that point, commercial vaccines had carried modified viruses or pieces of them into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions — encoded in mRNA — that would allow the body’s cells to pump out their own viral proteins. This approach, Dr. Weissman thought, would better mimic a real infection and prompt a more robust immune response than traditional vaccines did.
It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were not impressed, either. His lab had to run on seed money that the university gives new faculty members to get started.
By that time, it was easy to synthesize mRNA in the lab to encode any protein. Drs. Weissman and Karikó inserted mRNA molecules into human cells growing in petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick.
“Their fur got ruffled, they hunched up, they stopped eating, they stopped running,” Dr. Weissman said. “Nobody knew why.”
For seven years, the pair studied the workings of mRNA. Countless experiments failed. They wandered down one blind alley after another. Their problem was that the immune system sees mRNA as a piece of an invading pathogen and attacks it, making the animals sick while destroying the mRNA.
Eventually, they solved the mystery. The researchers discovered that cells protect their own mRNA with a specific chemical modification. So the scientists tried making the same change to mRNA made in the lab before injecting it into cells. It worked: The mRNA was taken up by cells without provoking an immune response.
Their paper, published in 2005,was summarily rejected by the journals Nature and Science, Dr. Weissman said. The study was eventually accepted by a niche publication called Immunity .. https://www.sciencedirect.com/science/article/pii/S1074761305002116 . Just as mRNA itself had been ignored, no one cared that they could get cells to accept mRNA. It seemed of academic interest, at best.
Fatty Coats
Katalin Karikó of BioNTech. “I said, ‘I am an RNA scientist. I can do anything with RNA,’” she recalled telling Dr. Drew Weissman in 1998. Hannah Yoon
Despite the naysayers, Drs. Karikó and Weissman believed their discovery could change the world. They now knew how to protect mRNA once it was inside a cell. But to work as a vaccine or a medicine, the fragile molecules would need to be shielded in the bloodstream to prevent degradation on their way to cells.
As it turned out, a team of biochemists in Vancouver[Ah, know it well] had spent years quietly revolutionizing ways of ferrying genetic material into cells. It was a partnership as improbable as any that helped lead to mRNA vaccines.
The team’s ringleader was a lanky man named Pieter Cullis who had intended to become an experimental physicist, not a biochemist. But he came to feel that the biggest discoveries in physics had been made decades earlier, and went in search of emptier scientific pastures.
He found one in the field of biological membranes: the outer layer of fats, called lipids, that encases the trillions of cells in the body, separating the watery outside from the inside. Dr. Cullis wondered if he could design his own lipid membranes to encase drugs or genetic material and transport it to cells.
In the 1990s, mRNA-based medicines were on hardly anyone’s radar,but gene therapy was in vogue as a technique to modify certain genes to treat or cure disease. For those drugs to successfully deliver a new gene to a patient, they needed a FedEx package of sorts. And Inex, a firm co-founded by Dr. Cullis, set out to find one.
The project was grindingly difficult. He was working with fat globules one hundredth the size of a cell. Human cells had a system of elaborate defenses to prevent anything but food from entering. And some versions of his lipids were extremely toxic and had electric charges that could rip cell membranes apart.
The big breakthrough came when he and his team figured out how to manipulate the positive charge on the fatty coats, said Thomas Madden, who worked with Dr. Cullis at Inex. The fatty bubbles would be charged when scientists loaded DNA inside, but the charge and toxicity disappeared once they were injected into the bloodstream.
But technical challenges remained, and the Vancouver chemists decided there was more money to be made in other sorts of drugs. Dr. Cullis shifted focus, licensing the lipid technology for some applications to a new company, Protiva, whose chief scientific officer was a soft-spoken biochemist named Ian MacLachlan.
In 2004, Dr. MacLachlan’s team made another crucial step forward .. https://link.springer.com/article/10.1007/s11095-004-1873-z : He encased the genetic material inside fatty coats in a way that would allow drug companies to increase production, and changed the ratios of lipids to keep more of the precious cargo from escaping. The team also worked to ensure that cells did not simply break up the genetic material as soon as it arrived.
Seeing those advances as critical to making mRNA-based medicine, Dr. Karikó tried to convince Dr. MacLachlan twice over the coming years to work together.
---- The Coronavirus Pandemic: Key Things to Know Cards 4 of 4
Omicron in retreat. Though the U.S. is still facing overwhelmed hospitals and nearly 2,000 Covid-19 deaths a day, encouraging signs are emerging. New cases are plummeting in several parts of the country, and recent studies of wastewater are helping scientists learn more about the Omicron variant.
Free tests and masks. The Biden administration’s new website allowing each U.S. household to order up to four free at-home tests is live. The White House also announced that it would make 400 million N95 masks available free of charge at health centers and pharmacies across the U.S.
Around the world. Austria is nearing the approval of a vaccine mandate for almost all adults, putting it on the path to be the first European country with such a wide-reaching mandate. In France, where a presidential election looms in April, officials set a timeline to lift restrictions over the next few weeks.
Staying safe. Worried about spreading Covid? Keep yourself and others safe by following some basic guidance on when to test, which mask to pick and how to use at-home virus tests. Here is what to do if you test positive for the coronavirus. ----
But business disputes got in the way. The first time, she cornered him at a conference and begged him for his lipids. He said no because her university insisted on getting the rights to Protiva’s intellectual property, Dr. MacLachlan said. The second time, around when Dr. Karikó began working for BioNTech, Dr. MacLachlan flew to their offices in Mainz, Germany, to try to make a deal. Dr. Karikó visited Vancouver, too. But Dr. MacLachlan said the company’s offer was not serious. “Our shareholders would’ve crucified us,” he said.
Protiva was also engaged in an intellectual property fight with a new firm co-founded by Dr. Cullis. Disenchanted, Dr. MacLachlan quit the company and bought a motor home to travel with his family.
Eventually it was Dr. Cullis’s teams that worked with vaccine makers on wrapping an mRNA shot in lipids — a major departure from the scientists’ original goals. “We were not going in that direction at all,” Dr. Cullis said.
Wobbly Spikes
Jason McLellan of the University of Texas at Austin, whose expertise is studying the shape of proteins. Sergio Flores for The New York Times
The work on mRNA and the lipid coats were two pieces of the puzzle that came together in 2020 in the Covid vaccines. But the third component was figuring out the precise mRNA code that would direct cells to make the most effective version of the coronavirus’s spike protein.
And that crucial bit of information came out of the longstanding collaboration between Drs. McLellan and Graham, who had been working together ever since their days sitting near each other at the Vaccine Research Center.
As Dr. McLellan prepared to open his own lab at Dartmouth in 2013, he and Dr. Graham discussed what the new lab should focus on. His mentor had a surprising answer: coronaviruses. It was a class of viruses that usually caused nothing worse than a cold, attracting scant interest from funding bodies. Devoting a lab to them would be a gamble.
But MERS had recently begun spreading in camel barns and slaughterhouses in the Middle East. Only 11 years earlier, another deadly coronavirus, SARS, had emerged in Southern China. And for a young researcher trying to make his mark, the lack of attention to coronaviruses meant less direct competition for research grants and signature findings.
“As we were talking about it, it seemed like we were maybe on a 10-year clock for new spillover events,” Dr. McLellan said.
MERS, like all coronaviruses, had a curious feature reminiscent of the shape-shifting proteins on H.I.V.: squirmy spikes on its surface that latch onto human cells. They had thwarted all efforts to make a vaccine. The MERS spike was especially fearsome, so much so that the scientists struggled to reproduce and isolate it in the lab. It was large, covered in a thick bush of sugars and highly unstable.
“It was pretty much a nightmare,” Dr. McLellan said.
Making matters more difficult, Dr. Graham had failed to secure samples from anyone infected with MERS in the Middle East.
After years of Western scientists parachuting into lower-income countries for studies that excluded local researchers, especially during the AIDS crisis, governments had “become very protective of their samples,” Dr. Graham said.
When a young Lebanese-American flu researcher in his lab, Hadi Yassine, recovered from an illness after a trip to Mecca, Dr. Graham thought he might have been infected with MERS. But it turned out to be a cold virus known as HKU1.
It was then that Dr. Graham had his insight: The world’s most boring coronaviruses may hold critical lessons about the most dangerous ones.
Like other coronaviruses, HKU1 had the dreaded spike — and, with some modifications, it held steadier than the one on the MERS virus. Within a few years, the team — which now included Andrew Ward, an expert, at the Scripps Research Institute, in freezing proteins to hold them still under an electron microscope — had published intricate images of the HKU1 spike in Nature .. https://pubmed.ncbi.nlm.nih.gov/26935699/ . It was the first time scientists had visualized a human coronavirus spike protein in the initial form it took before latching onto cells.
“You can consider it luck,” Dr. Yassine said recently of his long-ago cold, “or you can consider it a blessing.”
Now, the team set out to use what they had learned about the spike on the common cold virus to steady the proteins on their real adversary, MERS. Making a vaccine depended on it.
A MERS coronavirus particle. NIAID
The trouble was, any spikes they made in the lab — by adding genetic instructions to mammalian cells in a flask — were rarely stable and kept changing shape, making them much less effective for use in a vaccine.
The scientists needed to lock the spike in place. It was a complex task, so Dr. McLellan turned to the map he had built of the cold virus spike for clues.
Working alongside Dr. McLellan on that problem in his Dartmouth lab was Nianshuang Wang, a postdoctoral fellow from China, who believed that SARS and MERS presaged worse coronavirus outbreaks to come.
Dr. Wang’s job, like those of many junior scientists in American research labs, was to put in the lonely hours at the lab bench needed to realize his boss’s improbable ideas. The biggest discoveries often depended on those researchers, many of them ambitious students from outside the United States, who work on launching their own careers even as they play background parts in someone else’s.
In this case, Dr. Wang was working on a virus he knew well. The son of peasant farmers from a small village in eastern China, he as a child had become interested in the scientific concepts behind animal life, and later helped a Chinese team make crucial discoveries about MERS. Having read about Dr. McLellan’s R.S.V. research, Dr. Wang applied to join his Dartmouth lab, and was soon assigned the task of holding the MERS virus’s ungainly spike proteins still.
Part of what made them so prone to shape shifting was that they had pockets of empty space. So Drs. McLellan and Wang first tried filling them with a molecular glue — “cavity filling,” Dr. McLellan called it. Next they tried inserting two molecules that, when close enough, formed a bond, cementing a moving part of the spike to a steadier one. But both of those methods failed.
A third approach produced excellent results. Using their map of HKU1 as a rough guide, they zeroed in on a particularly loose joint of the spike and added two stiff amino acids. Those changes made the entire thing more rigid.
By the time they refined the method, however, the MERS epidemic was long over, and interest in coronaviruses had faded. Rejected by five prestigious scientific journals, the study ended up buried in a less prominent publication and a 2017 patent filing.
That was Dr. Wang’s only first-author journal article to come out of some three years of work — far short of what he needed for the prestigious academic job in the United States that he craved.
The lack of recognition stung, Dr. Wang said: It had been punishing, often boring work that had starved him of time with his wife and young daughter and left the family without much money.
But any lingering resentment disappeared when, in early 2020, a few months before leaving Dr. McLellan’s new lab at the University of Texas at Austin for a pharmaceutical company, Dr. Wang helped unearth his old findings to make a coronavirus vaccine.
“A small little thing can actually change the field, and even change the world,” Dr. Wang said. “That was the first thought for me.”
‘Back in the Saddle’
Building 40 of the Dale and Betty Bumpers Vaccine Research Center in Bethesda, Md. NIAID
At 5:30 a.m. on Dec. 31, 2019, Dr. Graham, who regularly started his days before dawn, was working in his home office when he saw a news release from ProMed, a listserv for infectious disease experts around the world. A new pneumonia was spreading in Wuhan, China. At 5:54, he sent an email to his lab group: “We should keep an eye on this.”
A week later, he heard that the frightening new disease was caused by a coronavirus, the same class of pathogen that he had trained his focus on years earlier when most other scientists were ignoring them.
He called his old collaborator Dr. McLellan, whose lab had been splitting time between coronaviruses and other pathogens. When his cellphone rang, Dr. McLellan was browsing in a ski shop in Park City, Utah, while waiting for his snowboarding boots to be heat-molded. When he saw the caller ID, he thought Dr. Graham was calling to wish him a belated Merry Christmas.
Instead Dr. Graham told Dr. McLellan the grim news. “We need to get back in the saddle,” he said. “This is our time.”
Dr. McLellan texted his lab to let them know the news. Several days later, when Chinese researchers posted the virus’s genetic sequence online, they got to work.
Using what they had learned working on Dr. Yassine’s cold virus and MERS, the team zeroed in on the spikes and came up with genetic sequences within days, incorporating the crucial cementing technique that Drs. McLellan and Wang had refined.
And on Feb. 15, Dr. Graham and Dr. McLellan published a paper .. https://www.biorxiv.org/content/10.1101/2020.02.11.944462v1 .. detailing the spike’s structure on a website for scientific manuscripts. The study was later published in Science.
“That meant a lot,” Dr. McLellan said. “Because we published where to put the stabilizing mutations, other companies could use it.”
The team’s stabilizing technique was crucial to the mRNA vaccines made by BioNTech (which by then had partnered with Pfizer) and Moderna, as well as certain non-mRNA vaccines.
Once Moderna and BioNTech scientists had genetic sequences for the spike, they then synthesized the mRNA molecules in their labs, applying the same chemical tweak that Drs. Weissman and Karikó had learned 15 years earlier. They wrapped their genetic cargo in protective fatty coats like those first dreamed up by the Canadians. They poured the resulting clear liquid into tiny glass vials and shipped them off for the first human tests.
From left: Dr. Graham, President Biden, Dr. Francis Collins and Kizzmekia Corbett. The scientists were explaining the role of spike proteins to Mr. Biden during a visit to the Viral Pathogenesis Laboratory at the N.I.H. last year. Pete Marovich for The New York Times
For Moderna’s all-important clinical trials, the government once again relied on its past investments in H.I.V. On March 3, 2020, as the coronavirus was spreading, Dr. Fauci called Dr. Larry Corey, a virologist at the Fred Hutchinson Cancer Research Center and the director of the government’s 21-year-old network of clinical trial sites for testing H.I.V. vaccines. “It’s time to pivot,” Dr. Fauci said.
At about 100 sites, the program would simultaneously test four vaccines: the mRNA shot from Moderna, as well as non-mRNA formulations from Johnson & Johnson, AstraZeneca and Novavax. (Pfizer decided to test the BioNTech vaccine on its own.)
“We wanted them all to succeed,” Dr. Corey said.
The team recruited 30,000 volunteers, a daunting task. It required enrolling 2,000 people a day — far more, Dr. Corey said, than had ever been attempted for a trial.
By November, the first results were in from the trial of Pfizer-BioNTech’s mRNA vaccine.
It was the culmination of decades of fundamental discoveries that had once been shrugged off as uninteresting. To get here, hundreds of researchers had tried, failed, reversed course and made incremental progress in different fields, never knowing for sure that any of their efforts would ever pay off.
If these Covid vaccines worked, Dr. Graham knew, they could pave the way for other new shots against diseases as varied as the common cold, flu and cancer — and even against that most elusive virus, H.I.V.
He was in his home office on the afternoon of Nov. 8 when he got a call about the results of the study: 95 percent efficacy, far better than anyone had dared to hope.
“It works!” he told his wife. Two of his grandchildren, 5 and 13, approached his office desk and hugged him from the front. His wife and son hugged him from the back. And the virologist began to sob.
Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and The Science That Saved Them.” @ginakolata • Facebook
Benjamin Mueller is a health and science reporter. Previously, he covered the coronavirus pandemic as a correspondent in London and the police in New York. @benjmueller
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