It’s pretty annoying having  to go in for your flu shot.

And your COVID shot. And then the doctor asks when was  your last tetanus shot and you’re   sat there going when was my last tetanus shot?

Should I get it just in case? And then they bring up hepatitis  and you’re like come on, man… It would be real nice if they  could package all that into a   single jab so you didn’t have to think about it. But they can’t.

Except that they’re getting closer. Scientists have created a vaccine – in  mice – that works against respiratory   germs of all sorts, both viruses  and bacteria, and even allergens. It’s a universal vaccine.

Universal for respiratory diseases, anyway. And it could be a game-changer  for pandemic preparedness. So, how did they do it, and when can I get mine? [♪ INTRO] To talk about vaccines, first we  have to talk about the immune system.

Keep in mind, by the way, that the immune system  is wildly complicated, so some of what I’m about   to say is a simplification for the sake  of this video not being 30 minutes long! The immune system has two modes of defense:   innate, which is fast and broad, and  adaptive, which is slow and specific. The innate immune cells are first  to the scene when there’s a threat.

They indiscriminately fight any invaders. They attack first and ask questions later. For example, cells called macrophages  engulf pathogens so they can’t go anywhere,   while neutrophils attack  germs with toxic proteins.

That can mean collateral damage to tissues. Even so, we need this quick response mode,   because the last thing you want when pathogens  sneak into an open wound is bureaucracy. It’s all about speed.

Macrophages are also doing recon, so  they can present pieces of invaders,   called antigens, to the cells  of the adaptive immune system. It’s basically their way of saying “Hey look,  there’s something new and dangerous in the body. Could you make super-specific  weapons targeting just this guy? ‘Kay thanks!” This handoff from innate to adaptive  takes time, a few weeks usually.

But then, the adaptive immune cells can  mount a very specific and generally more   effective response with less collateral damage. And this lasts for a while, because cells become   specialized to kill particular  invaders, and can remember them. Which is where vaccines come in: they  can leverage this immune system memory.

Most current vaccines work by  introducing antigens to the body. These molecules are presented  to two specific members of the   adaptive immune system: B cells and T cells. B cells pump out antibodies that  react with specific antigens,   like the ones provided by the vaccine.

And T cells have specific  receptors on their surface to   help them identify antigens and kill  any cells that have been infected. As they develop, B and T cells  cut and paste specific regions   of their DNA to design the best tools  to recognize and fight a specific germ. That’s right: these cells  are editing their own DNA.

For B cells, it’s the antibody genes,   while T cells edit their antigen receptor  genes to recognize and stick to the antigen. So a vaccine prepares B and T cells to respond to  a later infection, based on the memory of the antigen. It works because of the  adaptive immune system’s memory.

But scientists have started exploring whether  a more integrated vaccine approach could be   possible, one which involves both the  adaptive and innate immune system. See, we used to think the immune memory super  power was just an adaptive immune system thing,   but it turns out, innate  immune cells can learn too. Which is actually not that surprising:  plenty of organisms lack adaptive immune   systems but still respond more effectively  to germs they’ve been exposed to before.

Although innate immune cells can remember stuff  too, their training is a little different. There’s no gene editing. Instead, they change up little flags on  their DNA that determine how that DNA   is used and changes the cell’s  behavior over months or years.

This primed response in innate immune cells  is more generalized compared to adaptive ones,   so there’s a path forward for using that response  to create a “ready-for-anything” type of vaccine. The story of that vaccine  starts with tuberculosis. And I’ll get to how that works  right after this quick break.

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And right now, SciShow viewers can save 20% off  an annual subscription at brilliant.org/scishow. What I mean by that is the  Bacillus Calmette-Guerin vaccine. It contains a live but weakened species of a   bacterium closely related  to the one that causes TB.

This vaccine works pretty well at  preventing severe forms of TB in children. What’s more, it’s been known since at least  the early 2000s that the BCG vaccine somehow   has a protective effect against certain other  diseases too: not just bacteria, but viruses. Which is weird, because bacteria and  viruses are totally different things.

In 2023, a research team based at Stanford  University showed the BCG vaccine improved   outcomes for vaccinated mice infected with  the viruses that cause flu and COVID-19. They also described how the adaptive and innate   immune systems synergized to have  this long-term immunity effect. Turns out, communication was a two-way  street: the innate immune cells presented   Mycobacterium antigens to the adaptive  immune system, as was already known.

But, T cells could then provide  critical signaling molecules to   help stimulate innate immune cells to  respond to microbes, including viruses. The effect wasn’t even limited  to innate immune cells. The cells lining the inner  surface of the lungs learned too.

These cells can also alter mucus  secretion in response to attack,   and also produce some of their  own anti-microbe molecules! Around the same time, another team  reported on the same phenomenon:   BCG-induced immunity to COVID-19 in mice. They also showed that a T cell-secreted protein  affected innate immune cells’ antiviral response.

Again with the lung epithelium joining the fight. The BCG results gave the Stanford team  the idea to focus on a holistic vaccine:   one that could integrate innate  and adaptive immune responses. But BCG itself wasn’t a great  candidate as a universal vaccine,   because those results in  mice came from injections.

Not like the intramuscular  injection of your flu shot,   but directly into the bloodstream,  which doesn’t work so great in humans. So instead, the team decided to develop  a vaccine that could be inhaled,   and would help fight off the  gamut of airborne pathogens. Your flus, your COVIDs,  maybe even the common cold.

And by 2026, they had something promising. Their vaccine had molecules that  target some important receptors   present in innate immune cells  known as Toll-like receptors. These link to key pathways  controlling innate immune responses.

The vaccine also had ovalbumin,  an antigen found in egg whites   that should wake up resident T cells in the lung. These vaccine components were put into fatty  capsules which were sprayed up the noses of mice. A few weeks later, after several doses,   the team checked how the mice’s immune  systems responded to various microbes.

And it worked! The vaccine was able to enhance  protection against several   different respiratory viruses and bacteria. Bacterial levels in vaccinated  mice were significantly lower,   over 100-fold in the case of one species.

And the virus that causes  COVID-19 was 700 times lower. Meanwhile, markers of immune  cell activation went up. The team studied how this robust, broad  and durable response was accomplished.

As with the BCG vaccine, innate  immune cells and lung epithelium   were both better at responding to threats. This was mostly down to the work  of resident T cells in the lung. T cells helped to maintain the innate  immune response for at least three months.

Basically, the adaptive immune system helped  to keep the innate immune cells switched on,   instead of their usual short-term MO. As a bonus, the vaccine immune response  suppressed certain kinds of hypersensitivity,   like the type of asthma  caused by house dust mites. Which could make this an all-in-one  vaccine for germs and allergies!

So, could this work in humans? Maybe, but it needs development! One issue is that we’re bigger than  mice, and have much longer airways.

So we can’t as easily breathe a  vaccine straight into our lungs. We’d likely need different technology  to get the vaccine where it needs to go. We’d also need to monitor the side-effects  of a long-term boosted innate immune system.

Because immune hypervigilance can lead to chronic  inflammation, and that’s not healthy either. But if it works, it’ll be a huge  step for pandemic preparedness,   because the vaccinated population  will have a better baseline immunity. It could make a respiratory pandemic less likely,   if the results are as good as the ones in mice,  and if enough of the population is vaccinated.

You heard me: No COVID sequel! The authors have described this as “integrated  organ immunity,” leveraging both the adaptive   and innate immune systems, including  the lung epithelium to fight invaders. It’s an all-hands-on-deck situation where  the whole lung gets involved in defense.

It still has to scale up from mice to humans. But can you imagine? One vaccine for every respiratory  disease, even the ones we don’t have yet?

It could be a while, but once it’s  approved, I’ll be first in line. [♪ OUTRO]