FOR immunologists, the covid-19 pandemic has been a steep learning curve. 鈥淲e鈥檝e 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鈥檝e dealt with for decades,鈥� 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 鈥渃ytokine storms鈥� 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鈥檚 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.
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Being vertebrates, we are the proud owners of two immune systems (see 鈥淢eet your immune system鈥�). One is the 鈥渁daptive鈥� 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 鈥渢he鈥� 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 鈥渋mmune memory鈥� 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 鈥渉igher鈥� 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 鈥渢rained immunity鈥� 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. 鈥淚nnate immunity was considered the little brother, not that important,鈥� says at Radboud University in the Netherlands, who pioneered the rethink. 鈥淣ow we understand how important it is.鈥�
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. 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-Gu茅rin (BCG) vaccine for tuberculosis 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 鈥渢rained immunity鈥� and proposed that it could lead to a whole new branch of medicine.
At first, he was ploughing a lonely furrow. 鈥淚n the first five years, probably 80 per cent of the work was coming from our group. We had to convince people that it鈥檚 an important biological process.鈥�
Game changer
But the evidence kept building. In 2015, Netea 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鈥檛 have the injection.
Eventually, one of the central dogmas of immunology 鈥� that memory is the preserve of the adaptive system 鈥� crumbled, says Pulendran. 鈥淲ork over the last five years would suggest that there鈥檚 a different form of immune memory, quite different from the immune memory that is situated in T-cells and B-cells.鈥�
鈥淚 would dare to say that it鈥檚 now accepted,鈥� says Netea. In July 2019, 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鈥檛, the immune system makes mincemeat of them long before they can make us ill. 鈥淭he virus has evolved to fight and block many aspects of our defence, and this is true for every virus you鈥檝e ever heard of,鈥� says at Icahn School of Medicine at Mount Sinai in New York. 鈥淚f it is a virus that causes disease in humans, it鈥檚 because it has evolved to block some aspect of our biology.鈥�
SARS-CoV-2鈥檚 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鈥檚 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.
鈥淔lu vaccination would have bought us time to develop covid-19 vaccines without shutting down economies鈥�
The interferons also help to start a full-scale immune response featuring the shock and awe of antibodies and killer T-cells. 鈥淭he adaptive immune response depends on the innate immune response to get started,鈥� says at the La Jolla Institute for Immunology in California. 鈥淪o if the alarm bells of the innate response are delayed, that is likely to result in a delay of the adaptive immune response.鈥�
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. 鈥淚t has free rein,鈥� says tenOever. 鈥淭hat鈥檚 what we see in the most severe covid patients: the virus replicates and spreads rapidly throughout the lungs.鈥� 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鈥檛 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 鈥� perhaps because they have a slightly compromised innate immune system to start with 鈥� never catch up. 鈥淣ow you鈥檙e in trouble because you鈥檙e not controlling the viral loads,鈥� he says. 鈥淭he antibody and T-cell responses may come up, but it may be too late.鈥�
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 鈥� from March to June 2020 鈥� 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 . 鈥淲e saw 39 per cent less covid-19 in the influenza-vaccinated people,鈥� says Netea. This suggests that the flu vaccine is somewhat protective against covid-19, possibly via trained immunity. Peer-reviewed studies from and have found similar effects.
Netea鈥檚 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鈥� second covid-19 wave, which confirm the initial result and go into more detail (the details are under review in a journal and aren鈥檛 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. 鈥淚f 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.鈥�
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 鈥渘ear-normal鈥� 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. 鈥淗ow can it be? We don鈥檛 know the answer to this,鈥� 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鈥檛 arrive. 鈥淭he innate immune system tries to fill in that vacuum and continue to control the viral loads on its own,鈥� 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. 鈥淭rained immunity works through epigenetically mediated mechanisms,鈥� 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 , so kick-starting the adaptive system and possibly laying down some trained immunity.
Pulendran proposes developing what he calls 鈥渆pigenetic adjuvants鈥� 鈥� 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. 鈥淲e 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鈥檚 where I think these epigenetic adjuvants come in.鈥�
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鈥檚 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 adding various adjuvants to an experimental covid-19 vaccine. The results are 鈥渞eally quite impressive鈥�, he says.
Ultimately, says Netea, the goal is to deploy all of the immune system, not just half of it. 鈥淏y using the power of both the innate and adaptive immune systems, hopefully we are going to be prepared for the next time.鈥�
