摘要:We once thought that only our more modern, adaptive immune system had memory. Now a breakthrough in understanding our other, more primitive, immune defences could change how we fight disease

FOR immunologists, the covid-19 pandemic has been a steep learning curve. “We’ve learned much more about the host immune response to SARS-CoV-2 in a matter of a few months than we have about many, many other viruses that we’ve dealt with for decades,” says Bali Pulendran at Stanford University in California. At every turn, the virus has confounded expectations, from why it leaves some people unscathed but kills others in days to the “cytokine storms” that wrack the bodies of those who become seriously ill. And then there was the nail-biting wait to see if vaccines were possible. But one discovery above all will have immunologists rewriting their textbooks.

This concerns a long-neglected backwater of the immune system called innate immunity. Once seen as a rather prosaic and primitive bit of human biology, it now turns out to play a pivotal, and often decisive, role in the body’s reaction to SARS-CoV-2 and the vaccines against the virus. And not just that: a better appreciation of it is also being touted as our best bet for seeing off the next pandemic.

Being vertebrates, we are the proud owners of two immune systems (see “Meet your immune system”). One is the “adaptive” system, a smart and highly effective special force that develops and deploys precision weapons against invaders. This is the now-familiar arsenal of antibodies and T-cells that have been such a focus of interest during the pandemic. It is often what people mean when they talk about “the” immune system. But it is only half of the story.

The other half is the innate immune system, which is much less sophisticated. It consists of a set of fast-acting, all-purpose defences that bludgeon invaders indiscriminately, providing covering fire while the special forces get their boots on. One of its weapons is inflammation, which is a general purpose response to pathogens, injury and stress.

The innate system is evolutionarily ancient, found in all animals and plants. Vertebrates added the adaptive system about 600 million years ago, but still rely on their innate system as a first responder; the adaptive system can take several days to fire up, whereas the innate system gets going almost instantaneously. Nevertheless, innate immunity has long been regarded as rather primitive and uninteresting. In particular, it was assumed to lack any sort of memory function.

For decades, this is what was thought to indelibly distinguish the two systems. Adaptive immunity remembers invaders for years or even decades and can respond to them at the drop of a hat. This “immune memory” is a defining feature of adaptive immunity. It is why a single exposure to some viruses such as measles confers lifelong resistance, and is also why vaccines work.

But in the past decade or so, immunologists have come to see the innate immune system in a different light. Without it, the “higher” adaptive system is a useless embellishment. Even more importantly, the innate system does actually have memory. After an encounter with a pathogen, it switches to a heightened state of alert that persists for months or even years, making us more resistant to future infections. This “trained immunity” could have been exploited to significantly soften the blow of covid-19 and is now being developed as a life-saving weapon against the next pandemic. “Innate immunity was considered the little brother, not that important,” says Mihai Netea at Radboud University in the Netherlands, who pioneered the rethink. “Now we understand how important it is.”

Immune memory

The first signs that there was more to the innate system date back a couple of decades, when immunologists began investigating the immune responses of plants and invertebrates. As Netea points out, these life forms represent 97 per cent of all biodiversity, so even if they lack sophisticated adaptive immunity, it seems unlikely that they have failed to evolve something as useful as immune memory. And so it turned out to be. Study after study showed that plants, insects and worms do remember encounters with pathogens and attack them more vigorously the second time around. The mechanism is different from adaptive immune memory and is less pathogen-specific, but the result is broadly the same: heightened protection against viruses and bacteria lasting months or even years.

The same proved to be true of mice. Stimulating their innate immune systems elicits a form of immune protection that is independent of adaptive memory. That suggested that humans could also have innate immune memory, which also looked to be true. For example, live vaccines such as measles, oral polio and the Bacillus Calmette-Guérin (BCG) vaccine for tuberculosis conferred broad protection against other, unrelated pathogens via the innate immune system. That suggests that as well as eliciting an adaptive immune memory to protect specifically against, say, TB, the jabs may also be general immune boosters.

In 2011, Netea pulled together all the evidence, coined the phrase “trained immunity” and proposed that it could lead to a whole new branch of medicine.

At first, he was ploughing a lonely furrow. “In the first five years, probably 80 per cent of the work was coming from our group. We had to convince people that it’s an important biological process.”

Game changer

But the evidence kept building. In 2015, Netea published game-changing results from a clinical trial in Guinea-Bissau showing that low-birthweight infants given the BCG vaccine had stronger innate immune responses to other pathogens, and much lower mortality than infants who didn’t have the injection.

Eventually, one of the central dogmas of immunology – that memory is the preserve of the adaptive system – crumbled, says Pulendran. “Work over the last five years would suggest that there’s a different form of immune memory, quite different from the immune memory that is situated in T-cells and B-cells.”

“I would dare to say that it’s now accepted,” says Netea. In July 2019, he published another piece laying out his vision for using trained immunity to develop revolutionary and life-saving new therapies against hard-to-cure diseases such as immune disorders, cancer and infectious diseases caused by viruses.

And then along came covid-19. During the early stages of the pandemic, immunologists were keen to understand what tricks the SARS-CoV-2 virus uses to evade our immune defences. This is something that all disease-causing viruses do to some extent; if they don’t, the immune system makes mincemeat of them long before they can make us ill. “The virus has evolved to fight and block many aspects of our defence, and this is true for every virus you’ve ever heard of,” says Benjamin tenOever at Icahn School of Medicine at Mount Sinai in New York. “If it is a virus that causes disease in humans, it’s because it has evolved to block some aspect of our biology.”

SARS-CoV-2’s trick turned out to be evasion of the innate immune response, specifically a group of proteins called interferons. These are released inside a cell when it senses the presence of foreign RNA, a reliable sign of viral attack. As the name suggests, interferons interfere with viral replication. They also activate certain genes of the innate immune system and alert neighbouring cells to the threat. Interferons are thus a critical node in the innate immune system’s antiviral defences. They are also responsible for making those people who get symptoms feel unwell, causing them to hunker down under the duvet instead of going out and spreading the virus.

“Flu vaccination would have bought us time to develop covid-19 vaccines without shutting down economies”

The interferons also help to start a full-scale immune response featuring the shock and awe of antibodies and killer T-cells. “The adaptive immune response depends on the innate immune response to get started,” says Shane Crotty at the La Jolla Institute for Immunology in California. “So if the alarm bells of the innate response are delayed, that is likely to result in a delay of the adaptive immune response.”

That is what makes SARS-CoV-2 so dangerous. With the interferon response hobbled and the adaptive immune system AWOL, the virus can run amok. “It has free rein,” says tenOever. “That’s what we see in the most severe covid patients: the virus replicates and spreads rapidly throughout the lungs.” Without backup from the adaptive system, the innate system may go into overdrive to try to fill the gap, leading to a potentially deadly cytokine storm.

According to Crotty, the virus isn’t tricksy enough to fool all of the people all of the time. We may lose the early battles, but the vast majority of us eventually mount enough of an immune response to win the war. Yet a significant minority of people – perhaps because they have a slightly compromised innate immune system to start with – never catch up. “Now you’re in trouble because you’re not controlling the viral loads,” he says. “The antibody and T-cell responses may come up, but it may be too late.”

The fact that SARS-CoV-2 gains a toehold by sabotaging the innate immune system suggests that trained immunity may be worth pursuing as a therapeutic strategy. Similar to how a vaccine primes adaptive immunity, trained immunity could stiffen the innate immune response.

This was the opportunity that Netea and his colleagues had been waiting for. After the first wave of covid-19 in the Netherlands – from March to June 2020 – they obtained health records from more than 10,000 hospital employees. The records showed whether the employees had caught covid-19, and also whether they had been given a flu shot in late 2019 or early 2020. A comparison of the two data sets revealed something significant. “We saw 39 per cent less covid-19 in the influenza-vaccinated people,” says Netea. This suggests that the flu vaccine is somewhat protective against covid-19, possibly via trained immunity. Peer-reviewed studies from Italy and the US have found similar effects.

Netea’s team also took innate immune cells from people vaccinated and unvaccinated against flu and exposed these to SARS-CoV-2 in an assay they use to detect trained immunity. Again, cells from flu-vaccinated people showed clear signs of being more resistant to the virus. He also now has data sets from the Netherlands’ second covid-19 wave, which confirm the initial result and go into more detail (the details are under review in a journal and aren’t yet public). Taken together, Netea says these lines of evidence strongly point to trained immunity to SARS-CoV-2.

Indeed, Netea says that, knowing what we know now, it would have been a good idea to do mass flu immunisation at the start of the pandemic. “If in March last year, we vaccinated the population very quickly with an influenza vaccine, we would have bought enough time to develop specific vaccines without shutting down our economies.”

Flu vaccines are no substitute for the highly effective SARS-CoV-2 vaccines, but even if they provide 40 per cent protection, they would have allowed us to go about our daily lives in a “near-normal” way, he says.

Netea and his colleagues have also been looking at whether the BCG jab can give any protection against covid-19, but again, the results are under wraps for now.

There are other hints that trained immunity is already helping to fight covid-19. In Israel and other places that have vaccinated large proportions of society, there is emerging evidence that people are surprisingly well protected after a single dose of vaccine, says Pulendran. This is despite clinical trial data showing that the booster shot is required to stimulate a full antibody response. “How can it be? We don’t know the answer to this,” he says.

High alert

One possibility is trained immunity. So far, covid-19 vaccines have generally been given to older people, who are also routinely immunised against flu and shingles, and possibly had a BCG shot many years ago. These earlier vaccines may have trained the innate immune system into its heightened state of alert.

Trained immunity may also make the initial innate response to the covid-19 vaccine stronger, in turn spurring a bigger adaptive response. In principle, trained immunity could also diminish the risk for deadly cytokine storms. This innate immune overreaction probably arises when the adaptive response is slow or doesn’t arrive. “The innate immune system tries to fill in that vacuum and continue to control the viral loads on its own,” says Crotty.

Pulendran and his team are currently examining the immune responses to covid-19 vaccines to look for signs of trained immunity. They have also been probing what happens inside innate immune cells when they are exposed to a threat, to reveal the underlying mechanisms the drive trained immunity, with a specific eye on epigenetic changes. These are chemical tags added to DNA to control which genes are expressed. “Trained immunity works through epigenetically mediated mechanisms,” says Netea.

Pulendran is now looking at the role of epigenetic changes in innate immune cells in response to the flu jab and also in the context of exposure to viruses other than SARS-CoV-2. That work is now under review.

According to Pulendran, our growing understanding of trained immunity means we can start using it to our advantage. He proposes a new take on an old trick in vaccine design: adjuvants. These are compounds added to boost vaccine effectiveness. Adjuvants have been used for over a century, but until recently were more alchemy than science, based on trial and error. We now know that some adjuvants work their magic by stimulating the innate immune system, so kick-starting the adaptive system and possibly laying down some trained immunity.

Pulendran proposes developing what he calls “epigenetic adjuvants” – therapeutic agents that are specifically designed to train the innate immune system to be more resistant to viruses. He envisages an inhalable aerosol that could be delivered to the lungs to make cells of the respiratory tract more hardy. “We know that we can make vaccines in 12 months, but I would say that is 12 months too long. Is there something else that we could be doing in the intervening time to control the pandemic? That’s where I think these epigenetic adjuvants come in.”

They will take time to develop and test, but there are things we can already try. Up until now, adjuvants have barely featured in the design of vaccines against covid-19. That is understandable given the urgency and the bias towards the adaptive response, says Netea. It is also possible that the newer vaccine technologies such as mRNA used by Moderna and Pfizer/BioNTech, and the chimpanzee adenovirus used by Oxford/AstraZeneca, automatically stimulate the innate immune response already. But deliberate addition of adjuvants has to be worth a try, he says.

To that end, Netea’s group is in the middle of an experiment to see whether using the BCG jab as an adjuvant can improve the already impressive efficacy of the Pfizer/BioNTech vaccine. Pulendran recently published early results from a study adding various adjuvants to an experimental covid-19 vaccine. The results are “really quite impressive”, he says.

Ultimately, says Netea, the goal is to deploy all of the immune system, not just half of it. “By using the power of both the innate and adaptive immune systems, hopefully we are going to be prepared for the next time.”