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The longer the bootcamp, the better the antibodies

LA JOLLA, CA—Researchers at La Jolla Institute for Immunology (LJI) have discovered how the immune system can transform into an antibody-making machine…

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LA JOLLA, CA—Researchers at La Jolla Institute for Immunology (LJI) have discovered how the immune system can transform into an antibody-making machine capable of neutralizing one of the most elusive viruses out there: HIV.

Credit: Matt Ellenbogen, LJI

LA JOLLA, CA—Researchers at La Jolla Institute for Immunology (LJI) have discovered how the immune system can transform into an antibody-making machine capable of neutralizing one of the most elusive viruses out there: HIV.

Researchers once thought that B cells (which make antibodies) spent only weeks perfecting their weaponry against viral threats. Now LJI research shows that a “slow delivery, escalating dose” vaccination strategy can prompt B cells to spend months mutating and evolving their pathogen-fighting antibodies.

This finding, published in Nature, is an important step toward developing effective, long-lasting vaccines against pathogens such as HIV, influenza, malaria, and SARS-CoV-2. 

“This shows the immune system can do really extraordinary things if you give it the opportunity—and that in some vaccine contexts, patience really is a virtue,” says study senior author LJI Professor Shane Crotty, Ph.D.

The immune cell evolution inside you

Most pathogens look alien to the immune system. They’re unwelcome visitors covered in unfamiliar proteins. When the body’s dendritic cells see these strange proteins, they signal to “helper” T cells to start training an army.

B cells get the signal that an invader is near, and they are shown a molecular marker (called an antigen) from that invader. B cells want to make effective antibodies to neutralize the invader, so they head to a special place: germinal centers.

Germinal centers are microscopic structures that form in special “lymphoid tissues” throughout the body. Germinal centers are critical for fighting pathogens because they give B cells a place to mutate and test out their antibodies. Researchers call germinal centers the “engines of antibody evolution.” B cells that don’t mutate and improve their antibodies over time are eliminated. B cells with useful mutations get sent out into the body to wage war.

“It really is evolution,” says Crotty. “This process can work incredibly well and lead to antibodies that become a thousand times better at binding the virus.”

Germinal centers live fast, die young

Germinal centers are also the original pop-up shops. Once the threat has passed, the germinal centers collapse. No one knows yet exactly why germinal centers collapse, but there must be some kind of molecular signal that spells the end. 

For Crotty’s lab, a big question is how to get germinal centers to stay open longer. Timing is important because some pathogens can only be neutralized by rare, highly specialized antibodies.

HIV is one such tough customer. HIV is covered with an invisibility cloak of sugar molecules, and the virus can change its shape as it enters cells. This stealth and this shape-shifting power makes it really hard for immune cells to spot useful antigen targets on HIV.

As a result, germinal centers start pushing out B cells that make “low affinity” antibodies. These antibodies cannot bind and neutralize HIV in a very effective way.  Instead of throwing a wrench into the HIV machinery, the body just tosses in cotton balls. 

HIV’s shifting structure can also lead to “high affinity” antibodies that can bind really tightly—onto the wrong targets. Imagine marksmen trying to stop a raging bull by shooting it in the tail.

Crotty thinks B cells just need more time to mutate. “It takes a long time, and many cell divisions, before you just get lucky and one of the right mutations finally happens,” Crotty says. The idea is that the longer B cells can mutate and perfect themselves in germinal centers, the more likely that the B cells will luck into producing broadly neutralizing antibodies against HIV.

A slow-and-steady vaccine strategy

For years, Crotty and his collaborators in the LJI Center for Infectious Disease and Vaccine Research and the Scripps Research-led Consortium for HIV/AIDS Vaccine Development (CHAVI-ID), have worked to solve pieces of the HIV vaccine puzzle. The Crotty Lab has co-led pivotal studies into the use of promising new vaccine ingredients and how to best activate B cells against HIV.

The new study shines a light on the importance of stretching out the period where B cells can evolve in the germinal centers.

For the study, research collaborators at the Tulane National Primate Research Center gave rhesus monkeys immunizations every two days for 12 days. The series of seven shots contained an “escalating dose” of the HIV antigen (the protein on HIV they wanted the immune system to learn to target).

“That pattern mimics a natural infection more so than just a single immunization,” explains LJI Postdoctoral Fellow Harry Sutton, Ph.D., who served as co-first author of the new study with former LJI Instructor Jeong Hyun Lee, Ph.D., now a senior scientist with the IAVI Neutralizing Antibody Center at Scripps Research.

One group of monkeys wasn’t vaccinated again, but two other groups received a booster vaccine after 10 weeks.

The researchers then tracked immune responses by examining monkey lymph nodes. The team also monitored B cell development in individual germinal centers. Their work revealed that the germinal centers stayed active and B cells continued to evolve for six months after the initial seven-shot series. As Sutton points out, the study was set to end after six months, but the germinal centers may have lasted even longer if the research had gone on.

So how did the highly evolved B cells measure up? The researchers performed a genetic sequencing analysis to analyze immune cell memory and antibody binding abilities.

They found that the monkeys given the seven-shot series but never boosted had a stable and durable population of anti-HIV antibodies after six months. These non-boosted animals also had more immune cells (T follicular helper cells) ready to recognize the HIV antigen and launch B cells into battle. The boosted animals did have a second “peak” in antibody numbers after their booster shot, but they didn’t end up with the same high-quality antibodies.

The slow delivery, escalating dose strategy had paid off. The large dose of antigen had likely given the immune system enough of a “taste” of the virus that the germinal centers were ready to stay open and the B cells were prompted to evolve for as long as possible to address the perceived threat.

Next steps for better vaccines

When it comes to vaccinating against HIV, it appears that timing really is key to long-term protection. Giving vaccine boosters too early may interrupt an already effective process. “You want to get the immune response started, and then let it do its job,” says Crotty. “Let it try and undergo as much antibody evolution as it can before you come back with a booster immunization.”

Of course, a 12-day, 7-shot regimen would be impractical for most people. “If you want to give an HIV vaccine out to people in an area where they’re heavily affected by the virus, which is mainly sub-Saharan Africa, you can’t expect people to come in every two days for a vaccine for two weeks,” says Sutton. “So how can we recreate these findings using fewer vaccinations?”

The team is now looking at whether they can achieve the same antibody quality with two vaccines, versus seven. They are also studying whether they can design an mRNA vaccine that sparks the same B cell evolution by slowly producing antigen over time. This follow-up work is being supported through significant funding from the Bill & Melinda Gates Foundation.

Long-lived germinal centers may also prove important for fighting COVID-19. As Crotty explains, the original COVID-19 vaccines did an excellent job of getting the body to quickly make high-affinity antibodies against the initial SARS-CoV-2 variants. Research from the Crotty Lab suggests B cells against SARS-CoV-2 keep evolving for at least four months, giving them the chance to become even more effective.

Unfortunately, there is a decline in antibody protection against the more recent SARS-CoV-2 variants, such as Omicron and Omicron BA.1. Crotty is very interested in investigating how a long vaccine delivery method might help.

“Our new study suggests that if you want to get really good neutralizing antibodies against variants, these long germinal centers are probably the way to do it.”

Additional authors of the study, “Long-lasting germinal center responses to a priming immunization with continuous proliferation and somatic mutation,” include Christopher A. Cottrell, Ivy Phung, Gabriel Ozorowski, Leigh M. Sewall, Rebecca Nedellec, Catherine Nakao, Murillo Silva, Sara T. Richey, Jonathan L. Torres, Wen-Hsin Lee, Erik Georgeson, Michael Kubitz, Sam Hodges, Tina-Marie Mullen, Yumiko Adachi, Kimberly M. Cirelli, Amitinder Kaur, Carolina Allers-Hernandez, Marissa Fahlberg, Brooke F. Grasperge, Jason P. Dufour, Faith Schiro, Pyone P. Aye, Diane G. Carnathan, Guido Silvestri, Xiaoying Shen, David C. Montefiori, Ronald S. Veazey, Andrew B. Ward, Lars Hangartner, Dennis R. Burton, Darrell J. Irvine, and William R. Schief.

This study was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (CHAVD-ID UM1AI100663, CHAVD UM1AI144462, R01 AI125068, R01 AI136621, P01AI048240, and NIH NIAID SVEU Contract No. HHSN272201300004I) and by the Bill & Melinda Gates Foundation Collaboration of AIDS Vaccine Discovery (CAVD; OPP1115782/INV-002916).

DOI: 10.1038/s41586-022-05216-9

###


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Government

Biden’s Secret Promise To OPEC Backfires: Shellenberger

Biden’s Secret Promise To OPEC Backfires: Shellenberger

Submitted by Michael Shellenberger,

In early September, United States Secretary of…

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Biden's Secret Promise To OPEC Backfires: Shellenberger

Submitted by Michael Shellenberger,

In early September, United States Secretary of Energy, Jennifer Granholm, told Reuters that President Joe Biden was considering extending the release of oil from America’s emergency stockpiles, the Strategic Petroleum Reserve (SPR), through October, and thus beyond the date when the program had been set to end. But then, a few hours later, an official with the Department of Energy called Reuters and contradicted Granholm, saying that the White House was not, in fact, considering more SPR releases. Five days later, the White House said it was considering refilling the SPR, thereby proposing to do the exact opposite of what Granholm had proposed.

The hand of Russia's President Vladimir Putin (right) is now strengthened within the OPEC+ cartel controlled by Saudi Arabia's Crown Prince Mohammed bin Salman (left), which today decided to cut production by 2 million barrels.

The confusion around the Biden administration’s petroleum policy was cleared up yesterday after a senior official revealed that the White House had made a secret offer to buy up to 200 million barrels of OPEC+ oil to replenish the SPR in exchange for OPEC+ not cutting oil production. The official said the White House wanted to reassure OPEC+ that the US “won’t leave them hanging dry.” The fact that this offer was made through the White House, not the Department of Energy, may explain why a representative of the Department called Reuters to take back the remarks of Granholm, who has shown herself to be out-of-the-loop, and at a loss for words, relating to key administration decisions relating to oil and gas production.

The revelation poses political risks for Democrats who, in the spring of 2020, killed a proposal by President Donald Trump to replenish the SPR with oil from American producers, not OPEC+ ones, and at a price of $24 a barrel, not the $80 a barrel that the Biden White House promised to OPEC+. At the time, Trump was seeking to stabilize the American oil industry after the Covid-19 pandemic massively reduced oil demand. Trump and Congressional Republicans proposed spending $3 billion to fill the SPR. Senate Democratic Leader Chuck Schumer successfully defeated the proposal, and later bragged that his party had blocked a “bailout for big oil.”

Even normally strong boosters of the Biden White House viewed the Democrats’ opposition to refilling the SPR as a major blunder. “That decision,” noted Bloomberg, “effectively cost the US billions in potential profits and meant Biden had tens of millions of fewer barrels at his disposal with which to counter price surges.” Moreover, observed Bloomberg, it will take significantly more oil today to fill the SPR than it would have two years ago. In spring 2020, the SPR contained 634 million barrels out of a capacity of 727 million. Now, the reserve is below 442 million barrels, its lowest level in 38 years.

The decision looks even worse in light of the decision by OPEC+ today to cut production, which will increase oil prices. The Biden administration in recent days has been pulling out the stops trying to persuade Saudi Arabia and other OPEC+ members, a group that includes Russia, to maintain today’s levels of oil production. Last Friday, the Biden administration sought a 45-day delay in a civil court proceeding over whether Saudi Arabia’s Crown Prince Mohammed bin Salman should have sovereign immunity for the murder of Washington Post columnist Jamal Khashoggi, for which bin Salman has taken responsibility.

The behavior by the Biden White House displays a willingness to sacrifice America’s commitment to human rights for the president’s short-term political needs. Instead of pleading with OPEC+ to maintain or increase high levels of oil production, the Biden administration could have simply allowed for expanded domestic oil production. Instead, Biden has issued fewer leases for on-shore and off-shore oil production than any president since World War II. As such, the pleadings by Biden and administration officials have backfired. The perception of the U.S. in the minds of OPEC+ members has weakened while the influence of Russian President Vladimir Putin has strengthened.

Why is that? Why did the Biden administration decide to spend so much political capital trying, and failing, to get Saudi Arabia and other OPEC+ members to expand production when it could have simply expanded oil production domestically? What, exactly, is going on?

President Joe Biden greets the Saudi Crown Prince on July 15, 2022.

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Tyler Durden Thu, 10/06/2022 - 22:20

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Government

What Really Divides America

What Really Divides America

Authored by Joel Kotkin via UnHerd.com,

The Midterms aren’t a battle between good and evil…

Reading the…

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What Really Divides America

Authored by Joel Kotkin via UnHerd.com,

The Midterms aren't a battle between good and evil...

Reading the mainstream media, one would be forgiven for believing that the upcoming midterms are part of a Manichaean struggle for the soul of democracy, pitting righteous progressives against the authoritarian “ultra-MAGA” hordes. The truth is nothing of the sort. Even today, the vast majority of Americans are moderate and pragmatic, with fewer than 20% combined for those identifying as either “very conservative” or “very liberal”. The apocalyptic ideological struggle envisioned by the country’s elites has little to do with how most Americans actually live and think. For most people, it is not ideology but the powerful forces of class, race, and geography that determine their political allegiances — and how they will vote come November.

Of course, it is the business of both party elites — and their media allies — to make the country seem more divided than it is. To avoid talking about the lousy economy, Democrats have sought to make the election about abortion and the alleged “threat to democracy” posed by “extremist” Republicans. But recent polls suggest that voters are still more concerned with economic issues than abortion. The warnings about extremism, meanwhile, are tough to take seriously, given that Democrats spent some $53 million to boost far-Right candidates in Republican primaries.

Republicans are contributing to the problem in their own way, too. Rather than offering any substantive governing vision of their own, they assume that voters will be repelled by unpopular progressive policies such as defunding the police, encouraging nearly unlimited illegal immigration, and promoting sexual and gender “fluidity” to schoolchildren. They ignore, of course, the fact that their own embrace of fundamentalist morality on abortion is also widely rejected by the populace. And even Right-leaning voters may doubt the sanity of some of the GOP’s eccentric candidates this November.

In short, both major parties stoke polarisation, the primary beneficiaries of which are those parties’ own political machines. But most Americans broadly want the same things: safety, economic security, a post-pandemic return to normalcy, and an end to dependence on China. Their divisions are based not so much on ideology but on the real circumstances of their everyday life.

The most critical, yet least appreciated, of these circumstances is class. America has long been celebrated as the “land of opportunity”, yet for working and middle-class people in particular, opportunity is increasingly to come by. With inflation elevated and a recession seemingly on the horizon, pocketbook issues are likely to become even more important in the coming months. According to a NBC News poll, for instance, nearly two-thirds of Americans say their pay check is falling behind the cost of living, and the Republicans hold a 19-point advantage over the Democrats on the economy.

A downturn could also benefit the Left eventually. As the American Prospect points out, proletarianised members of the middle class are increasingly shopping at the dollar stores that formerly served working and welfare populations. Labour, a critical component of the Democratic coalition, could be on the verge of a generational surge, with unionisation spreading to fast food retailers, Amazon warehouses, and Starbucks.

To take advantage of a resurgent labour movement, however, Democrats will have to move away from what Democratic strategist James Carville scathingly calls  “faculty lounge politics”: namely, their obsession with gender, race, and especially climate. For instance, by demanding “net zero” emissions on a tight deadline, without developing the natural gas and nuclear production needed to meet the country’s energy needs, progressives run the risk of inadvertently undermining the American economy. Ill-advised green policies will be particularly devastating for the once heavily Democratic workers involved in material production sectors like energy, agriculture, manufacturing, warehousing, and logistics.

To win in the coming election and beyond, Democrats need to focus instead on basic economic concerns such as higher wages, affordable housing, and improved education. They also need to address the roughly half of all small businesses reporting that inflation could force them into bankruptcy. Some progressives believe that climate change will doom the Republicans, but this is wishful thinking. According to Gallup, barely 3% of voters name environmental issues as their top concern.

Racial divides are also important — though not in the way that media hysterics about “white supremacy” would lead you to believe. Florida Governor Ron DeSantis’s decision to fly undocumented immigrants to Martha’s Vineyard was undoubtedly a political stunt, and one arguably in poor taste. But it succeeded in its main goal: highlighting the enormous divide between the border states affected by illegal immigration and the bastions of white progressivism who tend to favour it.

Under Biden, the Democrats have essentially embraced “open borders” — illegal crossings are at record levels, and few of the migrants who make it across the border are ever required to leave. This policy reflects a deep-seated belief among elite Democrats that a more diverse, less white population works to their political favour. Whether they are right to think so, however, is far from clear. Black people still overwhelmingly back the Democrats, but Asians (the fastest-growing minority) and Latinos (the largest) are more evenly divided, and have been drifting toward the Republicans in recent years.

Here, too, class is a key factor. Many middle and upper-class minorities are on board with the Democrats’ anti-racist agenda. But many working-class Hispanics and Asians have more basic concerns. After all,  notes former Democratic Strategist Ruy Teixiera, these are the people most affected by inflation, rising crime, poor schools, and threats to their livelihoods posed by draconian green policies.

Culture too plays a role. Immigrants, according to one recent survey, are twice as conservative in their social views than the general public and much more so than second generation populations of their own ethnicity. Like most Americans, they largely reject the identity politics central to the current Democratic belief system. Immigrants and other minorities also tend to be both more religious than whites; new sex education standards have provoked opposition from the Latino, Asian, African American and Muslim communities.

The final dividing line is geography, always a critical factor in American politics. For decades, the country seemed to become dominated by the great metropolitan areas of the coasts, with their tech and finance-led economies. But even before the pandemic, the coastal centres were losing their demographic and economic momentum and seeing their political influence fade. In 1960, for example, New York boasted more electoral votes than Texas and Florida combined. Today, both have more electoral votes than the Empire State. Last year, New York, California, and Illinois lost more people to outmigration than any other states. The greatest gains were in Florida, Texas, Arizona, and North Carolina. These states are high-growth, fertile, and lean toward the GOP.Likewise, regional trends suggest that elections will be decided in lower density areas; suburbs alone are  home to at least 40% of all House seats. Some of these voters may be refugees from blue areas who still favour the Democrats. But lower-density areas, which also tend to have the highest fertility rates, tend to be dominated by family concerns like inflation, public education and safety, issues that for now favour Republicans.

Put the battle between Good and Evil to one side. It is these three factors — class, race, geography — that will shape the outcome of the midterms, whatever the media says. The endless kabuki theatre pitting Trump and his minions against Democrats may delight and enrage America’s elites — but for the American people, it is still material concerns that matter.

Tyler Durden Thu, 10/06/2022 - 21:40

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International

Switzerland, Not USA, Is The ‘Most Innovative’ Country In The World

Switzerland, Not USA, Is The ‘Most Innovative’ Country In The World

The World Intellectual Property Organization (WIPO) has released its 2022…

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Switzerland, Not USA, Is The 'Most Innovative' Country In The World

The World Intellectual Property Organization (WIPO) has released its 2022 Global Innovation Index. It evaluated innovation levels across 132 economies focusing on a long list of criteria such as human capital, institutions, technology and creative output as well as market and business sophistication, among others.

The 2022 index has found that innovation is still blossoming in some sectors despite the global economic slowdown and coronavirus pandemic, especially in industries to do with public health and the environment.

As Statista's Katharina Buchholz reports, Switzerland topped the rankings with a score of 64.6 out of 100, the 12th time it has been named the world leader in innovation. The United States come second while the Sweden rounds off the top three.

You will find more infographics at Statista

One of the biggest winners of the ranking was South Korea, which climbed up from rank 10 in 2020 to rank 6 in 2022.

China is now the world's 11th most innovative nation, up from rank 14 in 2020 and 2019 and rank 17 in 2018.

China was also named the most innovative upper middle-income country ahead of Bulgaria (overall rank 35), while India (overall rank 40) came first for lower middle-income countries, followed by Vietnam (overall rank 48).

Notably, China is now on a par with the United States in terms of the number of top 100 Science & Technology clusters

Finally, WIPO notes that on the one hand, science and innovation investments continued to surge in 2021, performing strongly even at the height of a once in a century pandemic. On the other hand, even as the pandemic recedes, storm clouds remain overhead, with increasing supply-chain, energy, trade and geopolitical stresses.

Tyler Durden Thu, 10/06/2022 - 20:40

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