COVID Immunity: The Road Ahead

This month it’s smiles all round as the world is finally rid of leaded petrol. After 20 years of campaigns and close collaboration between international groups, Algeria, the last country still pumping leaded fuel, finally switched fully to unleaded. But why did we use leaded petrol in the first place, and how was it putting us at risk? Eva Higginbotham spoke to the United Nations Environment Program’s Rob de Long...

Rob - So some decades ago the whole world was using leaded petrol because in the early 20th century, around the 1920s, it found out if you add some lead to fuel, it will increase its octane, which means that it will prevent pre ignition in the cylinders and the engine will just run much better. So when they found that out, basically all fuel in the world, all petrol in the world they started adding lead. And in the 1960s and 70, the whole world, all the fuel used was this leaded fuel.

Eva - And what's the problem with adding lead?

Rob - The problem with adding lead is that it doesn't combust in the engine, but it works as a catalyst. So it goes out with the exhaust into the atmosphere. And of course, where our cars are driving, people are breathing, so everybody was breathing these small lead particles that were nicely dispersed through car exhausts. And breathing in that lead, it goes in your lungs and even through your lungs, into your blood. And in the sixties and seventies, or fifties and sixties I would say, it was found that this lead in your blood is really bad for your body and has multiple health impacts. Actually, doctors say that there's not a single part in your body that is not negatively affected by the fact that you will lead in your blood.

Eva - So we tried to move away from lead because it was having bad health effects on the people who live nearby.

Rob - That's not the only reason. So it was indeed having serious health effects, but it was also preventing the mental development of children's brains. And so that was also known to restrict the mental development, and children growing up in an environment where leaded petrol was used were shown to have between 5 and 10 IQ points less. And a third reason is that in the seventies, filters were invented that can filter out the exhaust, they're called catalytic converters, and are now standard in every car. But those catalytic converters cannot run with leaded petrol, and so those filters that can filter 80 to 90% of pollution from cars could only work when we would switch to fuel without that.

Eva - So how did that transition get started, moving from everyone having leaded petrol, to away from that?

Rob - You can imagine it was a major transition. Every single car in the world was going around on leaded petrol and now we had to go to unleaded petrol. And that worked quite quickly in the developed world - in the eighties and seventies, eighties, and nineties, most of the developed countries banned the adding of lead to fuel and soon they were unleaded. However, at the beginning of the 21st century, there were still more than 100 countries using leaded petrol, and almost all of them were in low and middle income countries where these programs had not been started.

Eva - If you need the lead to make the engines work better, how have we now gotten away with not using it?

Rob - There are different ways to compensate for removing the lead. The most common way is you change the refinery process - that needs some investment. And the fuel that you produce - a fuel is a mixture of different components, the components are slightly different - and you can then increase the octane with changing the refinery process, increase the quality of the fuel, increase the octane level. There's also other possibilities. You can add another additive instead of lead, ethanol or manganese. So there are different ways that developed countries managed basically to completely eliminate leaded petrol and keep the same quality of fuel.

Eva - And what were some of the challenges in getting to the final transition of no one using leaded petrol?

Rob - Well there were a number of challenges for low and middle income countries, the global south ,to follow the developed countries. Some of these challenges were one, there was a lack of awareness among consumers. So people have been driving around using leaded petrol for decades, and now this product came, unleaded, it was costing slightly more. They were known to it, and there was no communication about why they should take this. Another issue was that there was resistance from local oil traders and the chemical industry to stop using this additive. People were making a profit out of it, and they were trying to stop it. And there were these myths going around -  when you had a very old fleet of vehicles, you couldn't use this new modern fuel, your cars would break down. Your engines would break down. In many countries we worked with over the years, ministers and decision-makers said, well, unleaded is nice for the developed countries, but in our case, when we have an old fleet, our cars can't take it. These are all not true. These are myths. And we debunked them with publications and showing that actually it did work, but it took a bit of time and a bit of effort. In addition to that, the producers of the additive, they actually bribed some government officials to keep buying the lead additive and keep adding it to fuels. And so some of these countries, their refineries, they created huge stockpiles. So those were a number of challenges we had to overcome in the past years to get the whole world to move to unleaded petrol

Eva - What sort of benefits can we expect moving forward then?

Rob - Studies have shown that switching to unleaded petrol saves an estimated 1.2 million premature deaths every year. So this is a major environmental success and health success. But also the impacts were also economic impacts, there were impacts even on crime rates - stopping with leaded petrol crime rates dropped dramatically 20 years after we stopped exposing our children to leaded petrol and affecting their brains. So there are many, many major impacts of this campaign that we today basically closed because there is no more leaded petrol in the world. At least no more automotive leaded fuels.

Researchers from Switzerland are jumping on their nanogenerator, for joy. The team from Eidgenössische Technische Hochschule (ETH) Zürich and Swiss Federal Laboratories for Materials Science and Technology (Empa) Dübendorf designed an A4 sized prototype of wooden flooring capable of powering small electronics and LED light bulbs. Group leader Guido Panzarasa starts us off with his vision for the nanogenerator… 

Harry - Do you hear that? Yeah, that's the sound of my floorboards creaking, um, which is an ominous sign in this case. It's because the boiler leaked a little while ago and it's bloated the floorboards right up. It's not a good sound, but what happens if that sound instead could correlate with something nice, let's say savings. What happens if your floor, when walked upon could actually produce energy? Well, it could, it's called triboelectricity. Guido Panzarasa is here to explain to me exactly what that is.

Guido - From a physical point of view, the phenomenon is the same that produces a static electricity. The same kind of effect that happens when you pat a cat backwards. That's because when the 2 disimilar materials are put in contact and then separated electrons accumulate on one material, which generates an electric field, which in turn produces an electrical current. These currents can be collected and used for practical purposes.

Harry - Triboelectric materials are materials that are able to build this static energy. Is wood a good. Tribo electric material?

Guido - No. Wood is quiet terrible as a triboelectric material. It means that wood doesn't have a strong tendency, neither to attract or to lose electrical charges. Wood needs to be treated. The approach was to take advantage of the structure typical of wood.

Harry - In essence, Guido took two sheets of wood and laid them on top of one another. One of these planks was soaked in a common silicon that's known for soaking up electrons whilst nanocrystals that prefer to lose electrons were grown in the other. When the two materials are separated or press firmly together, they're in a state of equilibrium. They don't produce an electric charge. It's only when they rub against each other. It's also worth mentioning that these materials are sourced sustainably in keeping with the theme of wooden flooring. In the team's prototype the small A4 sized plank of flooring was actually able to power LEDs, small electronics, even a household lamp. But, don't be mistaken. This isn't a substitute for other renewable energy sources, but it could improve energy efficiency around the house. There's only one question left to ask, are these smart houses going to continuously cause me static shocks?

Guido - Oh no, no, no. The electricity generation mechanism will be hidden inside of the wood flooring itself. There will be absolutely no risk of getting electrocuted while walking on the triboelectric wooden floor.

It seems likely that the new coronavirus will continue to circulate for the foreseeable future, despite vaccination. So why are we seeing a situation where, despite vaccination, or even having caught the virus, people remain vulnerable to infection? Adam Murphy spoke to Peter Openshaw, an immunologist at Imperial College London, to find out...

Peter – It's a war between the immune system and the virus, and other viruses breakthrough having infected previously and having induced an immune response. A virus I've been working on for about 30 years called respiratory syncytial virus causes bronchiolitis, but it can still reinfect people throughout their lives, even though 96 of people have been infected by the age of three. So it's not that unusual. The one thing the immune system does is remember, the other thing it does is forget if it's not repeatedly reminded.

Adam – And that's just post vaccination with COVID-19. Can we expect it to keep happening, that more and more people become more susceptible as time goes on?

Peter – It's likely that people will become repeatedly boosted and will accumulate some pretty good immune responses over time. If we think that most of the common cold Corona viruses infect during childhood, and that is typically quite a mild infection - it just causes a bit of a common cold - and then when people are re-exposed in later life, they don't typically get very severe disease, because they've already got that immunological memory, which has been built up from that childhood exposure. This game of developing memory and maintaining or losing it is just a lifelong feature of our immune system.

Adam – Do you think we can see that sort of thing happening with COVID? That is, we will become susceptible again, but it won't be the same thing - it'll be something more cold-like than COVID.

Peter – That's what we think is probably happening, yes. This is the first time we've actually been able to watch a virus like this evolve in real time using all the tools that we have at our disposal in terms of modern immunology. It's actually quite an exciting time for immunologists and virologists to be watching all of this actually playing out - there's been a revolution really in our understanding of the immune system.

Adam – How does this work between patient groups, for example in old people versus young people or in people whose immune systems don't work as well? Do they get the same sort of benefits long term, or I suppose fewer detriments than benefits?

Peter – Yes. Well, there are people with weakened immune systems, either because they've got chronic disease or because they're on drugs that suppress the immune system, particularly people who've had transplants, who've had cancer chemotherapy - they won't develop such a good immune memory because immune memory depends on forming new cells. And if those are not being formed, because somebody is on chemotherapy, then immune memory won't develop. There's actually quite a large number of people who suffer from chronic illness, who won't develop such good immune memory. And during old age establishing good immune memory is also sometimes not so secure. So we may need to revaccinate people in order to boost their immune responses, and also maybe direct the immune response into the lining of the nose and lung, which is where we really need it. Of course, vaccines induce very good antibody in the bloodstream, but don't really inform the immune system that where it needs to focus is in the lining of the nose and lung.

Adam – You were talking there about who to vaccinate next. There's been that sort of tension between the joint committee for vaccination and immunisation (JCVI) and the government on whether we vaccinate 12 to 15 year olds or older children with health problems? Where would you fall in that line?

Peter – I think the JCVI are absolutely right to be focusing on those who will most benefit from vaccination. But remember that the brief that they've been given is really to consider the benefit to the individual, not the wider public health implications, or say, the priority that there is to get kids back into school and to try to reduce the circulation of virus in schools, because that will result in school absentees, both for the children and for the staff. So it's not part of the remit of the JCVI to consider that, and I think it's very important to appreciate that when they have made their judgment it's based really on the proven facts in relation to the individual benefit. They are quite reasonably concerned about these reports of inflammation of the heart, the myocarditis or pericarditis inflammation around the heart, which is very, very rare indeed, and actually reasonably common after COVID infection. It seems that that inflammation is probably related somehow to the actual spike protein. It's pretty mild and self-limiting actually after vaccination - I would be much more concerned that it may be more long lasting and severe if we just let the infection rip through teenagers.

The vaccines we have against COVID-19 continue to work spectacularly well to protect people against severe diseases. But, as we’ve been hearing, they are less good at preventing infection and their effectiveness does drop with time. So can we improve on them to combat some of these weaknesses? That’s the goal that Pablo Penaloza-Macmaster from Northwestern University in Illinois has set for himself with what he dubs “Covid vaccine 2.0”, the next generation of Covid vaccinations, as he explained to Chris Smith...

Pablo - Most SARS-CoV-2 vaccines are based only on the spike antigen, which is the surface protein of SARS-CoV-2. And these vaccines are tremendously effective. But as you were saying, there's evidence of breakthrough infections. So we wanted to go one step further and we asked a very simple question. What if we teach the immune system, not only how the outside of the virus looks, but also how the inside of the virus looks? And for this, we gave mice this vaccine that not only expresses the outside protein of the virus, but also the inside or the guts of the virus. And what we saw is that these mice were better protected against breakthrough infections.

Pablo - And there's two reasons why we chose the nucleocapsid or the inside protein. Number one, because it is highly expressed in the coronavirus life cycle. So it's a perfect target for early detection by the immune system. But number two also because it is very stable, through many different variants and even other strains of coronaviruses, it doesn't mutate as much as the spike protein. That's the first part.

Pablo - The second part, the other piece of data, is that we have shown that SARS-CoV-1 vaccines made in 2003-2004 for the original SARS-CoV-1 also seemed to protect against SARS-CoV-2. And we have also shown in mice that some common cold coronavirus infections seem to protect mice against other coronaviruses. So what this suggests is that the vaccine does not have to be a hundred percent matched with the virus. You could have vaccines that are only 75% match, and that will still confer protection. And the follow up rationale is that it is possible to maybe make an arsenal or stockpile of vaccines based on the available known sequence of coronaviruses. And then in the future, in the case of a pandemic, we could deploy the ones that are more antigenically matched to the pandemic.

Chris - So in essence, using other parts of the virus to educate the immune system rather than just the outer coat, these spike proteins, might give the immune system more to get hold of when it's dealing with the virus. Why didn't we do that in the first place then? Why did the first generation of vaccines we're all using focus exclusively on that spike protein?

Pablo - The reason why is because data from the original SARS-1 and also MERS have pinpointed to the spike or the surface protein of the virus as being the Achilles heel. So we didn't want to take any risks. We went to the best target. And we're not saying that spike-based vaccines are worse than the nucleocapsid based vaccines. We're saying that if you combine them, it's a lot better, but if you compare them side-by-side - spike-only versus nucleocapsid-only - then the spike-only does a lot better. So people were just trying to make a vaccine very fast with the educated guess, which is based on the other coronaviruses. So that's why people focused on the spike protein.

Chris - And now you've taken it a step further. How much better is it in head-to-head trials when you do this? Admittedly, this is in mice. This is not in humans with COVID-19, but you know, we can learn a certain amount this way, can't we. How much better is it when you have the extra bit of the guts of the coronavirus, as you put it, in there alongside the spike, compared with just using a vaccine that uses the spike?

Pablo - If you compare in distal sites, for example, if you compare in the brain, it seems to be more than 10-fold better at protecting the mice from the breakthrough infection. And now we're actually trying to make it better by incorporating other vaccines. So basically, we're just trying to increase the coverage of the vaccine.

Chris - In essence then, what you might have your hand on is the ability to deal with the problem we've highlighted quite a few times in this programme, which is that at the moment we have a tool which is really good at stopping people ending up in hospital. But what it's not doing is stopping the virus circulating through society, which at the end of the day is what we really want to achieve. And with the better immunity conferred by these enhanced vaccines that you're potentially developing, we might have a way of doing that.

Pablo - Precisely. We think so.

Chris - I'm intrigued by your idea that it might also be possible to come up with a sort of pan-coronavirus vaccine, something that can counter all coronaviruses and all variants, both the knowns and the unknowns as yet. What evidence have you got that that might be achievable?

Pablo - We vaccinated mice with a SARS-CoV-1 vaccine from 2003. That is the original SARS-1. And we observed that these mice were protected against a SARS-2 challenge. That's one of the experiments. The other one is that we have infected mice with common cold coronaviruses, and then they're protected against related but different coronaviruses. So what this means is that the vaccine does not have to be 100% matched. You could have some genetic similarity, but it doesn't have to be a 100% match. So what that means is that you could potentially make a stockpile of vaccines based on the known sequences of coronaviruses, because we know a lot of different sequences. We have sequenced so many different coronaviruses. So, as long as in a future pandemic, if we pick up the right one, the right arsenal, and we take them out of the freezer - they're already made - and we take the one that is closest, genetically speaking, to the future pandemic, then we may be able to have a quick immediate response to a future pandemic.

Chris - Would you see this being realisable for this pandemic or is it too far away right now? And can we do this this time or is this going to take a lot more development?

Pablo - I honestly don't know. I think the most important thing right now is for the whole world to get vaccinated with the vaccines that we currently have available because although they don't prevent infection, they do prevent severe disease and death. So to me, that's the most important thing. So I would focus mostly on getting the whole world vaccinated.