In the nose? In a patch? Good against many variants at the same time? With SARS-CoV-2 seeming to have taken hold, the COVID vaccines are probably here to stay, if only as a booster dose from time to time.

But the vaccines we will have in the future might not look at all like the ones we have had until now… “Pharmaceutical companies go with the product that will be the easiest to get approved by Health Canada. They don’t ask themselves ‘what will be the most effective vaccine’, but rather: what will be the easiest and least expensive approach to develop so that they can market it as soon as possible?” says Denis Leclerc, who has been working for some 20 years developing vaccines at the Quebec City University Hospital Research Centre. The most cost-effective vaccines are usually those that follow proven strategies, for which regulatory agencies have established fee schedules. When you think outside the box, proof of efficacy becomes more difficult and expensive to do, hence the industry’s tendency to stay in the same rut. We could also ask ourselves: why didn’t we develop a vaccine against the first SARS, which appeared in 2002-2003,” says Jörg Fritz, of the Department of Microbiology and Immunology at McGill University. That would have helped us against SARS-CoV-2. And why have we never developed a vaccine against seasonal coronaviruses? That would have helped us too, but I think the reason is economics: SARS is gone and seasonal coronaviruses only cause colds, so there was no money to be made on that.” Until, of course, the pandemic comes along and the emergency breaks down the blocks There were, of course, the RNA-messenger vaccines (Moderna and Pfizer) and the DNA vaccines (Janssen and AstraZeneca), which were themselves a major innovation: instead of containing inactivated viruses orbits of the virus, they simply give our cells the genetic instructions to make a viral protein, to which the immune system will react. In short, instead of making the vaccine in a factory, our cells do the work. Beyond that, however, these vaccines are not very original. They are simple injections into the arm that present the immune system with the very “classic” spike protein, which the virus uses to attach itself to our cells. The same basic ploy has been used in many other vaccines for a long time.

However, several laboratories in the world are cooking up some big innovations. Here’s a quick overview.

The ABCs of immunology: 

We often tend to evaluate the effectiveness of a vaccine by looking at whether it stimulates antibody production. It is known that the immune response is more complex than that, also having a cellular component that involves many different kinds of immune cells, but antibody concentrations in the blood remain one of the most frequently used measures of protection.

In this game, vaccines containing spike proteins, often called S proteins, are almost unbeatable. These proteins are found on the surface of viruses, they are the most easily accessible and the immune system will always produce a lot of antibodies to neutralize them – thanks to B cells, which are specialized in this.

But viruses have other proteins: SARS-CoV-2 has about a dozen, including the important nucleocapsid proteins (or N proteins), which are dotted around the lipid capsule that protects the virus’ genetic material. Once the virus has attached itself to a cell and injected its genes, its capsule remains “suspended on the cell membrane, where it can then be detected by a type of immune cell called T cells, whose job is to destroy infected cells before they release the virus. Several labs around the world are working on vaccines that, in addition to the spicule, would also contain N proteins. Denis Leclerc’s lab at Laval University is among them.

The advantage of this strategy is that it aims to stimulate T cells,” he explains. And that’s very effective against viral diseases. When you get the flu for the first time in your life, it’s not the antibodies that are going to get you through, it’s your cellular response because the antibodies take a long time to make and they’re not going to get there until the end of the infection. So if you can engage the T-cell response in addition to the antibodies, you could get excellent protection.”

In addition, N-proteins mutate much less than spicules, so you can expect more universal and long-lasting protection. And they also stimulate antibody production – it’s just that they’re different from antibodies against S proteins. “Every time there’s a viral infection, there are N proteins that get into the bloodstream because there’s so much virus being produced and so quickly, there are cells that burst, etc.,” Leclerc explains. So we produce antibodies to neutralize them and, once an antibody sticks to an N protein, it forms an immune complex that amplifies the immune response. It becomes like an alarm signal.”

Mr. Leclerc hopes to publish his first test results on animal models in the next few months.

Playing on all fronts at once

Image by Arek Socha from Pixabay 

When we are dealing with a virus that mutates fairly rapidly, we know that it will eventually escape the antibodies generated by our vaccines. One possible strategy is then to develop vaccines that contain several versions of the spike protein or several different variants of the same virus. This is called a “multivalent vaccine”. This is the approach used in flu vaccines, which typically contain two, three, or four strains of influenza – with not always very convincing results.

But antibodies still retain a certain degree of effectiveness, albeit diminished, against mutated spicules. And there are not an infinite number of possible mutations either, since some of them render the virus inoperative altogether. So if we present a sufficiently varied array of S proteins in the right way, perhaps we can obtain a cocktail of antibodies that will be reasonably effective against all variants, even future ones?

That’s the calculation of the U.S. military, which has mounted several different versions of the SARS-CoV-2 spike on a particle called ferritin. In a study published in late December in Science – Translational Medicine, the vaccine was tested on macaques with impressive results. The monkeys produced antibodies that responded not only to several variants of SARS-CoV-2 but also to SARS 2002-03 – even though the latter is not a close relative of COVID.

“That’s something we need to try to move toward,” comments Fritz of the multivalent approach in general. We already know that one of the reasons children seem to be less vulnerable to COVID is that they have had seasonal coronavirus infections on average more recently than adults, and that gives them cross-immunity [Editor’s note: immunity to one virus that also protects, in part, against other related viruses).”

On the scene of the crime

The idea of administering a vaccine through the nose is not new: intranasal flu vaccines have been available for several years now. And in principle, they should even offer the best of all since they generate immunity directly where the virus strikes, unlike intramuscular injections – let’s just say that the shoulder is not a very common entry point for respiratory viruses. But this kind of vaccine has never lived up to its promise of superior efficacy, at least not for influenza vaccines, where intranasal don’t work any better than “conventional” ones. The Quebec Immunization Committee no longer recommends them over other vaccines.

The nasal passages are not such good places to vaccinate, because the nose is a part of the body that is immunosuppressed,” explains Denis Leclerc. And that’s normal because there are always a lot of things that go through there, microbes, pollens, dust, etc. (The immune system must therefore be more sensitive to these things. The immune system must therefore be more tolerant in the nasal passages,

Because otherwise, the inflammation would be permanent there). So if you’re going to vaccinate through the nose, you have to go with something potent.”

Proteins and bits of the virus are not enough: many of these flu vaccines contain attenuated viruses, which are weakened but still able to replicate. This is enough to start an immune response in the nose, but it comes with contraindications – especially for immunosuppressed people, so paradoxically those who need it most.

It is also possible to use an adjuvant, a substance that will stimulate the immune system in the respiratory tract. This has been done before with influenza vaccines, but it was largely abandoned because it caused too many side effects.

However, the pandemic has renewed interest. It is hoped that intranasal vaccines, by stimulating immunity directly at the site of infection, will eventually be better at curbing transmission of COVID than injectables, which also reduce contagion for a time, but mainly protect against severe forms. This week, the team of Yale virologist Akiko Iwasaki posted a study on a non-adjuvanted intranasal vaccine that could be used as a booster dose (after a first intramuscular dose). The results show a very good local immune response and “complete protection” in mice, but as they have not yet gone through the review process leading to full publication in the scientific literature, they should be treated with caution.

In the skin

Not in the shoulder or nose: another possible strategy is to insert the vaccine just under the skin using patches or devices with microneedles. The administration is painless and does not require as much technical skill as intramuscular injections.

Often, says Denis Leclerc, “it takes the form of a small square. You clean the skin, stick it on and leave it there for an hour. The vaccine is on microneedles that will dissolve in the dermis. And because it’s right under the skin, that’s the place in the body where you have the most dendritic cells (a type of immune cell, so you can expect a good response).”

Studies have shown promising results in recent years, including for polio [ and rabies. India also licensed the first intradermal vaccine for COVID in August, but it is administered with a device, not a patch. The microneedles insert DNA coding for the spike protein under the skin. In this respect, it is therefore similar to the Janssen and AstraZeneca vaccines – it is the “delivery” method that changes. In clinical trials, it has shown % efficacy 67 against symptomatic infections.

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