Evidence is mounting that a garden-variety virus that sometimes causes mono in teens is the underlying cause of multiple sclerosis, a rare neurological disease in which the immune system attacks the brain and spinal cord, stripping away protective insulation around nerve cells, called myelin.

It’s still unclear how exactly the virus—the Epstein-Barr virus (EBV)—may trigger MS and why MS develops in a tiny fraction of people. About 95 percent of adults have been infected with EBV, which often strikes in childhood. MS, meanwhile, often develops between the ages of 20 and 40 and is estimated to affect around one million people in the US. Yet, years of evidence have consistently pointed to links between the childhood virus and the chronic demyelinating disease later in life.

With a study published today in Science, the link is stronger than ever, and outside experts say the new findings offer further “compelling” evidence that EBV isn’t just connected to MS; it’s an essential trigger for the disease. The study found, among other things, that people had a 32-fold increase in risk of developing MS following an EBV infection in early adulthood.

“It’s a great paper,” Dr. Ruth Dobson, a preventive neurology professor and MS expert at Queen Mary University of London, told Ars in an interview. “The evidence just adds up and adds up and adds up… Whilst we don’t understand biologically how EBV drives MS and we think about causation theories, really we have the rest of the building blocks in place,” said Dobson, who was not involved in the new Science study. “It’s another piece of evidence that really solidifies this theory” that EBV triggers MS.

New findings

For the study, researchers led by Harvard neuroepidemiologist Dr. Kjetil Bjornevik mined an exceptionally rich repository of blood serum samples taken from a cohort of more than 10 million active-duty military personnel between 1993 and 2013. The samples were taken from relatively healthy, fit, and young military personnel in the course of standard screenings for infections, particularly HIV.

In the cohort, there were 801 members who developed MS and had banked up to three serum samples prior to their diagnosis. This gave the researchers the unique opportunity to go back in time and examine serum samples from MS patients years before they developed the disease. The researchers could also compare samples from the 801 MS patients to samples from 1,566 cohort members who did not develop MS and could serve as controls.

Of the 801 people who developed MS, all but one had antibodies indicating an EBV infection by the time of their MS diagnosis. And most of those EBV infections occurred earlier in their lives. At the start of the 20-year period, only 35 of the 801 MS patients started out as negative for EBV. By the end of the period, 34 of those 35 developed anti-EBV antibodies—aka seroconverted—prior to their diagnosis.

Bjornevik and colleagues compared those 35 initially EBV-negative personnel with 107 control-group members who also initially tested negative. They found that the rate of seroconversion in the 35 who would go on to develop MS was significantly higher than the rate in the control group—97 percent of the 35 seroconverted prior to diagnosis while only 57 percent of the control group seroconverted during the 20-year period. From that data, the researchers calculated that those who seroconverted had a 32-fold increased risk of developing MS.

It’s unclear why the one MS patient did not appear to seroconvert during the study. The authors speculate that, given gaps in sampling, it’s possible the person did seroconvert between the last sample and the diagnosis. It’s also possible that the person was misdiagnosed with MS or was infected with EBV but for some reason didn’t seroconvert. It’s also possible that the person had a rare type of MS that was triggered by something besides EBV. Regardless, the authors reasoned that the one outlying case didn’t weaken the strong connection between MS and EBV.

But EBV wasn’t the only virus the researchers scrutinized. In fact, they screened serum samples for antibodies targeting more than 200 viruses. The screening indicated that the risk of MS did not increase following infection with any other virus besides EBV. Moreover, when the researchers compared the overall antiviral antibody responses in MS patients to those in controls, they found the overall antibody responses were similar. This suggests that there wasn’t some sort of underlying immune dysregulation that spurred the development of MS after an EBV infection. Last, they screened serum samples for markers of nerve damage that show up early in MS, finding them only after a person had an EBV infection.

https://arstechnica.com/?p=1825773

Researchers have now reported data from early (and small) clinical trials of four candidate COVID-19 vaccines.

So far, the data is positive. The vaccines appear to be generally safe, and they spur immune responses against the novel coronavirus, SARS-CoV-2. But whether these immune responses are enough to protect people from infection and disease remains an important unknown.

The four candidates are now headed to larger trials—phase III trials—that will put them to the ultimate test: can they protect people from COVID-19 and end this pandemic?

The challenge

While early trials looking at safety and immune response required dozens or hundreds of volunteers, researchers will now have to recruit tens of thousands. Ideally, volunteers will be in places that still have high levels of SARS-CoV-2 circulating. The more likely it is that volunteers will encounter the virus in their communities, the easier it is to extrapolate if a vaccine is protective. As such, researchers are planning to do a significant amount of testing in the US and other parts of the Americas, which have largely failed at controlling the pandemic.

There has been much debate about the use of “human challenge trials,” in which researchers would give young, healthy volunteers at low risk from COVID-19 an experimental vaccine and then intentionally expose them to SARS-CoV-2 in controlled settings. This could potentially provide a clearer, faster answer on vaccine efficacy. It’s certainly an appealing idea given the catastrophic pandemic—and it’s an idea that has gained traction in recent weeks. An advocacy group called 1Day Sooner has collected the names of more than 30,000 people willing to participate in such a trial, for instance.

But experts remain divided on the idea. The main concern is that there is no “rescue” treatment for COVID-19 that can fully protect a trial volunteer from severe disease and death if an experimental vaccine fails. Though young, healthy people have less risk than older people and those with underlying health conditions, some still suffer severe disease and death from COVID-19—and it’s unclear why. Opponents also note that challenge trials may not be faster or necessary, given the high levels of disease spread in the US and elsewhere.

Though the debate on challenge trials is ongoing, it’s unclear if researchers will end up needing or using them. Meanwhile, traditional phase III trials are now underway—and they have generated plenty of enthusiasm from the public. According to a report this week, more than 138,600 people have signed up through the National Institutes of Health to participate in vaccine testing. If all goes well, we could have data from these trials by the end of the year.

So how do the four top vaccine candidates work, and what do we know about them?

mRNA-1273: Moderna, NIAID

mRNA-1273 is a messenger RNA (mRNA) vaccine made by the biotechnology company Moderna, which was working with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The idea behind the mRNA vaccine platform is that it delivers snippets of a target virus’s genetic code—in this case, code in the form of mRNA—into human cells. Those cells can then translate that code into viral protein. From there, the immune system can mount a response to the protein, which can be activated if the target virus ever tries to invade.

In the case of mRNA-1273, researchers used a fatty nanoparticle to package up mRNA that codes for the SARS-CoV-2 spike protein, which is usually found jutting out from SARS-CoV-2 viral particles.

Vaccines using genetic material—RNA or DNA—are new and untested. So far, there are no approved vaccines using this type of platform. It’s unclear if they will be successful here or elsewhere and—if they are—how easy it will be to manufacture such a vaccine on a global scale. (For background on the different types of vaccine platforms, see our vaccine primer.)

On July 14, researchers published results from a phase 1 trial, which primarily looks at safety in a small group of people. The study, appearing in the New England Journal of Medicine, included 45 healthy volunteers between the ages of 18 and 55 and tested three dose levels of the vaccine. That is, there were three groups of 15 people, with each group getting either a low, medium, or high dose of the vaccine (25 micrograms, 100 micrograms, or 250 micrograms dose). Each participant got two shots of their dose, 28 days apart.

The vaccine was generally found to be safe. More than half of the participants had mild to moderate side effects, mainly including fatigue, chills, headache, myalgia, and pain at the injection site. Side effects were more common after the second dose, regardless of the strength, but those who received the two higher-dose vaccinations reported more side effects. Two people (one in the 100-microgram group and the other in the 250-microgram group) had severe skin redness at the site of the injection. Two people in the 250-microgram group experienced lightheadedness and fainted.

All participants produced antibodies against SARS-CoV-2, with antibody levels jumping up after the second shot. Those who got the higher doses had slightly higher levels of antibodies. The researchers compared participant antibody levels to those seen in 41 people who had recovered from a COVID-19 infection. Those vaccinated all had antibodies in the same range as the recovered people.

The researchers also tested specifically for neutralizing antibodies—that is, antibodies that don’t just bind to a virus particle but can completely disable it. Researchers found that the vaccine prompted higher levels of neutralizing antibodies than was seen in most of the people who recovered. For instance, 57 days after the first dose, people in the 100-microgram group had neutralizing antibody titers ranging from 163 to 329, while the range was about 60 to 200 in the patients who had recovered from COVID-19.

Last, the researchers looked at responses from T-cells—which can attack cells infected with virus—and found that the vaccine did generate certain types of T-cell responses against SARS-CoV-2.

Overall, the results are encouraging but not conclusive. Researchers don’t yet know what immune responses or levels of antibodies are necessary to prevent a SARS-CoV-2 infection and/or disease. And, being only six months into the pandemic, it’s unclear how long any such protective immune responses would last.

According to a listing on the NIH’s registry for clinical trials, Moderna plans to begin a phase III trial of mRNA-1273 on July 27. Moderna wants to enroll 30,000 people in the trial, looking at efficacy as well as further safety and immune response data.

AZD1222 (ChAdOx1 nCoV-19): Oxford University, AstraZeneca

On July 20, researchers published results from a phase I/II trial of AZD1222, a candidate vaccine made by researchers at the University of Oxford and the international pharmaceutical company AstraZeneca.

AZD1222 (also called ChAdOx1 nCoV-19) is a viral vector-based vaccine. With this platform, researchers can package bits of a dangerous virus into a far less dangerous virus. The mostly harmless viral parcel then gets delivered to the immune system, which can learn to seek and destroy the dangerous virus based on the smuggled fragments.

In the case of AZD1222, genetic material of the SARS-CoV-2 spike protein is packaged into a weakened type of adenovirus that infects chimpanzees. Human-infecting adenoviruses normally cause mild infections, often considered common colds. The chimpanzee virus, which doesn’t typically infect humans, is made even more harmless by engineering that prevents it from replicating in human cells. In early tests, AZD1222 protected monkeys from developing pneumonia after researchers exposed them to high doses of SARS-CoV-2.

The clinical trial results, published in The Lancet, show that AZD1222 is generally safe and spurred immune responses in humans. The trial involved 1,077 participants (aged 18 to 55), 543 of which were randomly assigned to get AZD1222, and the remaining 534 were given a meningococcal vaccine as a control. Researchers divided the participants into four groups and ran different types of tests on their immune responses. Ten of the participants who received AZD1222 were in a “boost” group that got a second vaccine shot after 28 days. The other participants who received AZD1222 only received one dose.

Mild side effects from AZD1222 were common, including pain, feeling feverish, chills, muscle ache, headache, and malaise. Some participants were preemptively given paracetamol (acetaminophen/Tylenol) to lessen these effects. No serious side effects were reported.

In 127 participants vaccinated with AZD1222, all produced antibodies against SARS-CoV-2. The levels were within the range seen in people who had recovered from COVID-19. The researchers conducted two separate tests to look for neutralizing antibodies in 35 vaccinated participants. In one test, 32 (91 percent) were positive for neutralizing antibodies 28 days after vaccination and, in the other test, 100 percent were positive. The ten participants who got a booster shot all produced neutralizing antibodies, some which were at levels higher than those typically seen in the COVID-19 recovered patients. The researchers also reported that AZD1222 induced T-cell responses.

Researchers have already begun a phase III trial of AZD1222 at sites in Brazil, the UK, and South Africa. They also plan to test the vaccine in the US soon. AstraZeneca said it will use two doses in trials moving forward in order to maximize immune responses.

https://arstechnica.com/?p=1693804

While cancerous cells look a lot like normal human cells, they’re still different enough that the immune system regularly attacks them. Obviously, this attack sometimes bogs down, allowing cancer to thrive and spread. Figuring out how to get the immune system back on track has been a major focus of research, and success in the area has been honored with a Nobel Prize.

Despite these successes, many patients aren’t helped by the newer immune-focused therapies, raising questions of what else we still need to figure out to help cancer patients. A new paper highlights something we may have missed: a class of immune cells that appears to be primed specifically to attack cancer. But the finding raises questions about what it is on cancer cells that the immune cells are recognizing and why they fail to keep cancer in check.

Finding cancer killers

The start of this work was pretty simple: a large international team of researchers grew a mix of immune cells called “T cells” in the presence of cancerous cells and looked for cells that grew rapidly. This rapid growth is typically a sign that the immune cells have been activated by something they recognize—in this case, the cancer. They identified one particular lineage of T cells that grew well and named it MC.7.G5, confirming yet again that most scientists don’t belong in the creative industries.

One notable thing about the MC.7.G5 cells quickly became apparent: MC.7.G5 didn’t simply grow well in the presence of cancer cells; it killed them. So, the authors tested a variety of different cancer types (lung cancer, melanoma, colon, breast, and more). These cells don’t have much in common. They’re activated by different mutations, start out with different populations of proteins on their surface, and have many other differences from one another. So it wasn’t clear what the T cells could possibly be recognizing on their surfaces in order to attack them. Yet attack them they did.

To find out, the researchers did an experiment that wouldn’t have been possible just a decade earlier: they used a gene-editing construct to eliminate every single protein-coding gene that we know of in the genome. Lots of individual populations of a cancer-cell line had a single gene knocked out and then were tested to see whether the MC.7.G5 immune cells could still kill them. If any cancer cells were left alive, then the gene edited in them would be essential for producing the molecule used by the immune cells to recognize cancer.

The experiment identified a series of genes involved in putting a single protein on the surface. But, of course, that protein is also present on normal cells. How could it possibly be responsible for the cancer cells being recognized as distinct?

Fortunately, we know a lot about the family of molecules that the protein, MR1, belongs to, as well as a bit about MR1 itself. The larger family includes the molecules that help the immune system recognize self from non-self by binding to bits of the cell’s proteins and presenting them on the cell’s surface for the immune system to check out. If either these molecules or the proteins they present look different, the immune system attacks. So, that makes a degree of sense as something that can trigger the immune system to go after the cancer cells.

MR1, however, doesn’t work like that. Instead, it brings some of the cell’s metabolites to the surface. And the researchers confirmed that it has to bind to something in order to make it to the surface. They hypothesize that it’s a metabolite that’s specific to cancer cells, but they have no idea what it might be.

Stay on target

While there are still some question marks about what causes these immune cells to pick out cancerous cells, there’s no shortage of evidence that they do so effectively. The researchers tested the immune cells against resting and dividing normal cells and got no response. MC.7.G5 didn’t kill healthy cells that were stressed or damaged. So, there’s no indication that the immune cells accidentally go off target and kill healthy cells.

The researchers also confirmed that the cancer-killing T cells are defined by the standard receptor that T cells normally use to recognize infected cells. They made a copy of this receptor’s genes and inserted them into T cells from an unrelated individual. They also killed cancerous cells from at least two different sources.

Finally, the authors injected lymphoma cells into immune-compromised mice, then added the cancer-killing T cells. In control mice without the cancer-killing cells, the lymphoma took over the bone marrow, eventually accounting for about 80 percent of the cells there. With the cancer-killing cells injected at the same time, the bone marrow in the mice consistently had far fewer cancer cells (consistently less than 10 percent of the total cells). This indicates that the immune cells can help keep cancer in check but may not be able to consistently eradicate it.

Does that mean, as the BBC has claimed, that these cells “May treat all cancer”? Well, to begin with, the T cells were seemingly unable to eliminate cancer in mice. That’s more significant than it seems, in that lots of potential treatments seem to work well in mice, but few ever advance to the point of clinical trials in humans, much less end up being used as treatments. This is a case when mouse assays are helpful for knowing what deserves a closer look but far from the last word on a topic.

Do we all have cancer killers?

These cancer-killing immune cells were also obtained from at least two individuals, suggesting that they may be present in all humans. Yet humans regularly suffer from cancer, so there’s clearly something that keeps them from doing their job. At this point, we don’t have the slightest clue as to what that something might be.

Then there’s the issue of what the cells are recognizing that allows them to identify cancer cells. Whatever it is, it’s not widely present on healthy cells. But the body has a dizzying number of specialized cell types, so we’ve barely scratched the surface of testing whether these cells might attack some healthy cell types. However, if the authors are right about a couple of things, there’s a very good chance the cells might.

The authors suggest that the target of the cancer-killing cells is a metabolite presented on the surface by the protein MR1. And, because the gene-editing screen didn’t pull out any metabolic enzymes, they suspect that the metabolite is essential for cancer cell viability. It’s difficult to understand how something central to cancer cell viability, produced using the same genes found in normal cells, isn’t ever produced by normal cells.

None of this is to say that this discovery won’t end up being important. But we really need much more information before we’re in a position to judge whether it is or not.

Nature Immunology, 2020. DOI: 10.1038/s41590-019-0578-8  (About DOIs).

https://arstechnica.com/?p=1647381