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The persistence of memory in B cells: Hints of stability in COVID immunity

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Enlarge / The immune response involves a lot of moving parts.

There’s still a lot of uncertainty about how exactly the immune system responds to the SARS-CoV-2 virus. But what’s become clear is that re-infections are still very rare, despite an ever-growing population of people who were exposed in the early days of the pandemic. This suggests that, at least for most people, there is a degree of long-term memory in the immune response to the virus.

But immune memory is complicated and involves a number of distinct immune features. It would be nice to know which ones are engaged by SARS-CoV-2, since that would allow us to better judge the protection offered by vaccines and prior infections, and to better understand whether the memory is at risk of fading. The earliest studies of this sort all involved very small populations, but there are now a couple that have unearthed reasons for optimism, suggesting that immunity will last at least a year, and perhaps longer. But the picture still isn’t as simple as we might like.

Only a memory

The immune response requires the coordinated activity of a number of cell types. There’s an innate immune response that is triggered when cells sense they’re infected. Various cells present pieces of protein to immune cells to alert them to the identity of the invader. B cells produce antibodies, while different types of T cells perform functions like coordinating the response and eliminating infected cells. Throughout this all, a variety of signaling molecules modulate the strength of the immune attack and induce inflammatory responses.

Some of those same pieces get recruited into the system that preserves a memory of the infection. These include different types of T cells that are converted into memory T cells. A similar thing happens to antibody-producing B cells, many of which express specialized subtypes of antibodies. Fortunately, we have the means to identify the presence of each of them.

And that’s the focus of a major study that was published a couple of weeks ago. Nearly 190 people who had had COVID-19 were recruited, and details on all these cells were obtained for periods as long as eight months after infection. Unfortunately, not everyone donated blood samples at every point in time, so many of the populations were quite small; only 43 individuals provided the data for six months after infection, for example. There was also a huge range of ages (age influences immune function) and severity of disease. So the results should be interpreted cautiously.

Months after infection, T cells in this population still recognized at least four different viral proteins, which is good news in light of many of the variants in the spike protein that have been evolving. T cells that specialize in eliminating infected cells (CD8-expressing T cells) were present but had largely been converted to a memory-maintaining form. The number of cells declined over time, with a half-life of roughly 125 days.

Similar things were seen with T cells that are involved in coordinating immune activities (CD-4-expressing T cells). Here, for the general population of these cells, the half-life was about 94 days, and 92 percent of the people who were checked six months after infection had memory cells of this type. A specialized subset that interacts with antibody-producing B cells seemed to be the relatively stable, with almost everyone still having memory cells at over six months.

So overall, as far as T cells go, there are clear signs of the establishment of memory. It does decline over time, but not so rapidly that immunity would fade within a year. However, for most of the cell types examined, there are some individuals where some aspects of the memory seems to be gone at six months.

The B side

Like T cells, antibody-producing B cells can adopt a specialized memory fate; cells can also specialize in producing a variety of antibody subtypes. The first paper tracked both antibodies and memory cells. Overall, the levels of antibodies specific to the viral spike protein dropped after infection with a half-life of 100 days, the number of memory B cells increased over that time, and stayed at a plateau that started at about 120 days post-infection.

A second paper, published this week, looked at the trajectory of the antibody response in much more detail. Again, it involved a pretty small population of participants (87 in this case), but monitored for over six months. A bit under half of them had some long-term symptoms after their initial infections had cleared. As with the earlier study, the levels of antibodies they found declined in the months following the infection, dropping by anywhere from a third to a quarter, depending on the antibody type. Intriguingly, people with ongoing symptoms tended to have higher levels of antibodies across this period.

But when the team looked at antibody-producing memory cells, they noticed that the antibodies were changing over time. In memory cells, there’s a mechanism by which parts of the genes that encode the antibody pick up a lot of mutations over time. By continuing to select those cells that produce antibodies with a higher level of affinity, this can improve the immune response in the future.

That seems to be exactly what is happening in these post-COVID patients. At the first sampling time, the researchers identified the sequences of many of the genes that encode antibodies against coronavirus proteins. At the time of the second check months later, they were unable to find 43 of these initial antibody genes. But 22 new ones were identified, arising from the mutation process—by six months, the typical antibody gene had picked up between two and three times the number of mutations. In some cases, the authors were able to identify the ancestral antibody gene that picked up mutations to create the one present at six months.

The system seems to be working. One of the early antibodies was unable to bind some of the variants of the spike protein that have evolved in some coronavirus strains. But the replacements with more mutations could, suggesting it was higher affinity and for the spike protein than the earlier version. While the average antibody had similar affinities at the early and late time points, specific antibody lineages saw their ability to neutralize the virus increase.

The immune system has ways of preserving the spike protein to select for improved antibody variants after infections are cleared, and that may be part of what’s going on here. But in a number of participants (under half of those tested), there were still indications of active SARS-CoV-2 infections in the intestine, even though nasal tests came back negative. So it’s possible that at least some of the improved binding comes from continued exposure to the actual virus.

The big picture

Let’s emphasize again: these are both small studies, and we really need to see them replicated with larger populations and more consistent sampling. But at least when it comes to antibodies, the consistencies between these two studies are a step towards building confidence in the results. And those results are pretty good: clear signs of long-term memory and that the immune system’s ability to sharpen its defenses seems to be working against SARS-CoV-2.

Beyond that, the T cell results, while more tentative, also seem to hint at a long-term immunity. But there, the results aren’t as consistent, with different aspects of T cell immunity persisting in different patients. The researchers divided the different aspects into five categories, and found that fewer than half their study population still had all five categories of memory present after five months. But 95 percent of them had at least three categories present, suggesting the persistence of at least some memory. The problem is that, at this point, we don’t really understand what would provide protective immunity, so it’s difficult to judge the meaning of these results.

Science, 2021. DOI: 10.1126/science.abf4063
Nature, 2021. DOI: 10.1038/s41586-021-03207-w (About DOIs).

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NASA selects SpaceX as its sole provider for a lunar lander

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Enlarge / Rendering of SpaceX’s Starship vehicle on the surface of the Moon.

NASA

In an extraordinary announcement on Friday, NASA said that it has selected SpaceX and its Starship vehicle to serve as the lunar lander for its Artemis Program. This is NASA’s plan to return humans to the Moon later this decade.

About a year ago, NASA gave initial study and preliminary development contracts for Moon landers to SpaceX, Dynetics, and a team of aerospace heavyweights led by Blue Origin. The cost of SpaceX’s bid was about half that of Dynetics, and one-fourth the amount received by Blue Origin. That frugality, at least in part, led NASA on Friday to choose SpaceX as the sole provider of landing services during the down-select phase.

“We looked at what’s the best value to the government,” said Kathy Lueders, chief of the human exploration program for NASA, during a teleconference with reporters on Friday.

NASA said it will award SpaceX $2.89 billion for development of the Starship vehicle and two flights. One of these missions will be an uncrewed flight test of Starship down to the lunar surface and back. The second mission will be a crewed flight—the first one of the Artemis program—down to the Moon.

Starship offered several advantages, NASA officials said. It has a spacious cabin for astronauts, two airlocks, and ample payload capability to bring large numbers of experiments to the Moon and return samples to Earth. Significantly, the NASA engineers also praised the vehicle’s innovative design and future-looking technology that might also one day be used on Mars.

Ultimately, the selection criteria were based on a company’s technical proficiency, management, and cost. SpaceX scored well in all three. But budget appears to have been the biggest factor. The space agency has had difficulty securing funding from Congress for the lunar lander aspect of the program. For the current fiscal year, NASA said it needed $3.3 billion in funding to meet the goal of landing humans on the Moon by 2024. Congress provided just $850 million, and as a result, NASA acknowledged that 2024 was no longer a realistic target.

Making Artemis affordable

At the direction of the Trump administration, NASA formally created the Artemis Program about two years ago to send humans back to the Moon in a sustainable way and establish a base there. The goal was to move beyond the flags-and-footprints forays of the Apollo Program and gain the knowledge needed to eventually send humans to Mars. The Biden administration has endorsed this basic goal, and it’s working to update the Artemis Program with a more realistic timeline given the budget predilections of Congress.

Friday’s announcement is part of that process of making Artemis more affordable. A sole-source award to SpaceX for the Human Landing System will certainly not be particularly popular in Congress, where traditional space companies such as Lockheed Martin and newer entrants like Blue Origin have more established lobbying power. But it sends a clear message from NASA and the White House to budget writers in the House and Senate.

This award effectively says that NASA is serious about getting to the Moon with the funding it has. And if Congress were to fully fund the Human Landing System program, NASA could bring on a competitor. Ideally, of course, there should be competition. This approach has worked well for NASA’s commercial cargo and crew programs. But NASA is getting a small fraction of what it needs to run a lunar lander competition.

In addition to this development award, NASA said it would soon move to procure “recurring landing services” from industry. This contract will be for operational missions to the lunar surface, and it seems like SpaceX would have a significant advantage in winning the award. However, there may be an opening here, if Congress provides more funding for the Human Landing System, for either Dynetics or the Blue Origin-led team to play a role in human landings.

Self-funding Starship

SpaceX has largely self-funded development of the large Starship vehicle for about five years, with the intent of using it to settle humans on Mars one day. Starship is a fully reusable upper stage that will launch atop the Super Heavy rocket. SpaceX is in various states of testing and developing both of these vehicles at its facility in South Texas.

As part of the Artemis Program, SpaceX has proposed launching a modified version of its Starship vehicle to lunar orbit. Shortly afterward, a crew of NASA astronauts would launch inside an Orion spacecraft on top of a Space Launch System rocket, both of which were developed by NASA. Orion would rendezvous with Starship in lunar orbit, board the vehicle, and go down to the surface. Starship would then lift off from the lunar surface and link back up with Orion, and the crew would come back to Earth in the smaller capsule.

Left unsaid is the reality that SpaceX is also planning to launch humans on Starship from Earth. It does not seem like all that much of a stretch to question the need for the much more costly Orion and Space Launch System rocket, when lunar crews could simply launch in a Starship into low-Earth orbit, undergo refueling there from another Starship, and then go to the Moon and back. But NASA knows that Congress—which is heavily invested in Orion and the SLS rocket, and their jobs across all 50 states—would not support a SpaceX-only program.

The choice of SpaceX was applauded by some industry officials on Friday. “The selection of SpaceX as the sole-source developer of the Human Lander System is a sign of how far both the company and their relationship with NASA has come over the last ten-years,” said Lori Garver, a deputy administrator for NASA under President Obama. “SpaceX’s involvement in Artemis is sure to elevate public interest and will hopefully lead to our soonest possible return to the Moon.”

For years, space industry leaders like Garver have advocated for NASA to increase support for commercial space companies that have sought to drive down the costs of spaceflight. After all, SpaceX’s bid for the entirety of its Human Landing System, $2.9 billion, is about what NASA spends each year on the Space Launch System and associated ground systems development. Now, the space agency appears to be boldly embracing such a future.

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Arkansas representatives pass bill to allow creationism in schools

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Enlarge / The Arkansas state capitol.

Last week, the Arkansas state House of Representatives passed a bill that would amend state education law to allow teachers in public schools to teach creationism as “a theory of how the earth came to exist.” As it stands, the act promotes blatantly unconstitutional behavior as made clear by a precedent set in a 1982 case involving the Arkansas Board of Education. Despite that, the bill passed 72-21, and it already has a sponsor in the state Senate.

The body of the bill is mercifully short, consisting of two sentence-long amendments to the existing Arkansas code:

A teacher of a kindergarten through grade twelve (K-12) science class at a public school or open-enrollment public charter school may teach creationism as a theory of how the earth came to exist.

This section is permissive and does not require a teacher to teach creationism as a theory of the earth came to exist.

But those two sentences are enough to land teachers and their local school system in a world of trouble, in that the permission given runs afoul of a lot of legal precedent. In a key case that involved Arkansas itself, McLean V. Arkansas Board of Education, a group of plaintiff’s banded together to challenge a state law that mandated the teaching of “creation science” in public schools. The judge in that case correctly recognized that creation science was actually religious in nature, and therefore it violated the constitution’s prohibition against the establishment of state religion.

That ruling wasn’t appealed, meaning the legal precedent only applied to Arkansas. But later in that same decade, a similar case from Louisiana made it to the Supreme Court, and it reached the same conclusion. The prohibition against creation science has applied nationally since.

These precedents only apply to the teaching of creationism as science; there are other contexts, like a comparative religion class, where it might be appropriate to teach this idea. But the bill’s use of “theory” clearly indicates that it’s intended to insert the concept into science classes.

While the state might end up being sued if this law passes, it’s just as likely that a teacher in Arkansas will exercise this permission and the suit will end up targeting the teacher and the school board they work for. If the local school board loses (which it would), there is a good probability it will end up liable for the legal fees of whoever sues. Thus, the legislation serves as an invitation for local school districts throughout the state to rack up enormous legal bills.

Although the legal history of creationism is available to anyone with a working Internet connection, the bill passed with 72 representatives, all Republicans, voting in favor. Of the chamber’s 22 Democrats, 21 voted against it, and one other didn’t vote.

It’s not clear whether these legislators are simply unaware of the legal precedents or if they are simply using this bill as an opportunity to signal their cultural affiliations. We’ve contacted its two sponsors to find out. As of the time of publication, neither had responded.

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SARS-CoV-2 variant found in Brazil: More infectious, may limit immunity

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Enlarge / COVID-19 has taken a terrible toll on Brazil.

Almost from the moment it made the jump to humans, the SARS-CoV-2 virus has been picking up mutations and creating new lineages as it expands into different populations. In practical terms, the vast majority of these mutations make absolutely no difference; the resulting virus has the same properties as the unmutated form it’s derived from.

But there have been a number of cases where variants surge in frequency. Early on in the pandemic, this was often the product of the variant moving into a previously unexposed population—a matter of chance rather than a feature of the virus. Separating out these cases from instances where mutations make the virus more dangerous is a serious challenge. But this week, an international team of researchers has published evidence showing that a variant first characterized in Brazil is likely to represent a significant additional threat.

There’s a lot of uncertainty about the details, but the virus appears to be more infectious and more likely to infect those who have immunity to other viral strains, and it might even be more lethal. And as of when the paper was written, the lineage had been detected in over 35 countries.

The second wave

Earlier this year, we described the situation in the Brazilian city of Manaus, which the first wave of coronavirus infections had hit hard. But that was followed by a long period of low infections, despite an indifferent response to the pandemic by the Brazilian government, leading some to suggest that the city might have reached a level of infection sufficient to provide herd immunity.

That hopeful thought was brought to an end in December, when a second wave of infections started up in the city, straining its health care systems and causing another surge in deaths. The infection rates were so high that it raised the suspicion that there might be a new strain of virus that could evade the immune response generated by infections that occurred during the first wave.

Brazilian healthcare workers responded to the rise in cases by sequencing the genomes of some of the viruses causing the second wave of infections. Prior to this second wave, only seven viral genomes had been obtained from Amazonas, the state where Manaus is located. The new effort increased that number by 184, although not all of these were complete genomes.

The genomes revealed the presence of a lineage researchers call P.1, which is an offshoot of a strain that had been present during the first wave. Since then, P.1 had picked up a large number of mutations, including 17 individual mutations that altered the amino acid sequences of the proteins it encodes, one insertion of new bases, and three deletions of bases. That’s a substantial number of changes and suggests a high level of mutations picked up since March. Timing estimates suggest that P.1 originated in November, just before the start of the large second wave in Manaus.

Over the course of the second wave, the P.1 variant went from not being detectable in the samples taken to accounting for 87 percent of viruses sampled just seven weeks later. Viral genomes from elsewhere in Brazil indicated it was also spreading rapidly within the country, showing up in cities that were on popular flight routes from Manaus first. This indicates that P.1 likely originated in the city.

What is this thing?

Tests for the virus that use polymerase chain reaction (PCR) involve a cyclical amplification of the virus’s genome. As a result, if you start with more viral genomes, you’ll reach a detectable level of signal in fewer cycles. This is thought to mean that the cycle count needed for detecting the virus provides a rough measure of the viral load carried by the person the sample came from. In the case of the P.1 strain, tests showed a fairly consistent, if small, indication of increased viral load.

Because the samples came at different times after infection, however, the researchers can’t tell whether this is indicative of higher maximum levels of the virus or a longer infection duration. Neither is especially good.

To try to understand how P.1 might have influenced the second wave of infections in Manaus, the researchers developed an epidemiological model that allowed them to track two different strains of the virus. The first strain was set up with the typical properties of SARS-CoV-2. For the second, they were able to adjust the properties of the virus, such as the immunity provided by prior infections and its transmissibility. This let them determine which properties were consistent with the dynamics of the second wave in Manaus.

Overall, the model suggests that P.1 is very likely to be more transmissible than prior strains of SARS-CoV-2, and it’s likely to be roughly about twice as infectious. There’s also an indication that it can evade the immune response generated by past infections to some extent. The model suggests there’s at least a 10 percent chance that the variant can evade immunity, but it’s unlikely to be more than a 50 percent chance.

There was some evidence of enhanced lethality due to infection by the P.1 strain. But the timing of the strain’s rise was such that the evidence came from a period where the hospitals were on the verge of being overwhelmed. So the authors are treating this possibility cautiously.

What might be causing these changes? At least 10 of the mutations seen in the P1 strain affect the virus’s spike protein, which the virus uses to latch on to cells it infects. At least eight of those mutations seem to have been selected for over the course of the strain’s evolution, suggesting they assist in making it more infectious. Three of the specific changes have also been seen in another lineage of virus that has caused concerns, and at least one of them has been shown to interfere with antibodies that attack the virus.

So while this data isn’t really a decisive indication that P.1 poses a distinct threat to us, it’s all certainly consistent with that concern. And it would help explain why Manaus had two distinct waves of infection that seem to have hit a substantial fraction of the city’s population. Still, as the authors of the new paper point out, we don’t fully understand the consequences of mutations that alter proteins targeted by antibodies. Until we get a grip on that, we won’t really know how worried we need to be about P.1 and other variants.

Science, 2021. DOI: 10.1126/science.abh2644  (About DOIs).

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