A vaccine to dominate them all (flu viruses)?


If you read my article yesterday, you will have been left with the firm impression that it is impossible to manufacture a unique vaccine, a wildcard that, like Tolkien’s ring, can dominate all influenza viruses regardless of whether they are orcs or dwarves. . But no, it is not. Possible, yes; easy, no. We already have one in evidence that could reach your preferred arm in a few years.

As I told you yesterday, the problem with immunization against influenza is that the vaccines are directed against a spike in the shape of a tree on the surface of the virus, consisting of two proteins called hemagglutinin (H) and neuraminidase (N), which have a amazing ease to change form.

Illustration of the influenza virus preparing to infect a cell to which it binds through its hemagglutinin protein. Image of CSIRO / Wikipedia.

Illustration of the influenza virus preparing to infect a cell to which it binds through its hemagglutinin protein. Image of CSIRO / Wikipedia.

The action of the vaccines is based on creating an immunological memory that prepares the response against future attacks of the same enemy. Stimulating the immune system with a dead virus (I have already told here that – and why – I am in favor of describing viruses as living beings, but if they do not agree, they change “dead” to “inactivated”) or with those proteins loose, we create that memory that will later repel a real attack with fierceness. If we do not create that memory before, the organism will also react against the invader, but suffering from the disease it causes.

Thus, and given that the profile recorded by the vaccine in the immunological memory is determined by H and N, when they change it is as if the organism faces an almost completely new virus, although everything below those variable spikes is basically the same as before.

The question then is: would not it be possible to direct the vaccine against something that does not change so much in the flu virus? The answer is yes, yes it is, but finding the perfect strategy is complicated. Numerous research teams around the world are working on the creation of a universal flu vaccine, which can protect us once and for all (or at least, for a good number of years) not only against the seasonal of each year , but against rarer strains of those that cause pandemics such as the so-called “Spanish flu” of 1918.

As I told you here a couple of years ago, experts fear that at any moment a strain of an exotic type of flu, such as H9N2 or H10N8, may suddenly sprout, which suddenly turns our week of malaise and sick leave into a very serious threat for the lifetime. And the possibility of having an immunization that acts in the long term would allow the vaccine to be applied to children, when the response is stronger, and not as now at an advanced age when the immune system already suffers from the same ailments as the rest of the body. .

Thus, the current attempts of researchers to design a universal vaccine against influenza are summarized in these two lines:

1. Use the base of the skewers, less variable than the head

The H and N proteins of the influenza virus vary widely in their heads, the part most exposed to the outside, but not so much in their stems, the part that is attached to the envelope of the virus. Some research groups are trying to get the immune system to react against the base of the spikes; but since it is less accessible than the head, it is less exposed to the recognition of our body’s antibodies, so the challenge is to find a way to make it more visible to the immune system.

A US team is trying with nanoparticles covered in spikes that have had their heads cut to leave their stems exposed. Using in this way a skewer based on the H1 protein, the scientists have managed to completely protect mice and partially ferrets (two animal models widely used for influenza studies) against a lethal infection of another virus, H5N1, called bird flu. With a similar idea, but with the stems of H1 in small groups as they appear in the virus, the Crucell Vaccine Institute in Leiden (The Netherlands) has also managed to neutralize H5N1 in mice and monkeys.

Particles of the influenza virus to the electron microscope. Image of Pixnio.

Particles of the influenza virus to the electron microscope. Image of Pixnio.

2. Use internal antigens of the virus

An antigen is everything against which our organism is capable of producing antibodies, Y-shaped molecules whose ends fit the shape of the antigen like the pieces of a puzzle. Our veins and arteries are continuously patrolled by an immense legion of lymphocytes, cells of the immune system. One of its types, B cells, is specialized in producing a type of antibody capable of recognizing and binding a specific antigen, carrying this antibody on the surface. When by chance a B cell encounters the antigen that matches its antibodies, it captures it and swallows it, breaking it into pieces that it then exposes again on its surface.

This cell then waits for the help of other so-called Helper or Th ( helper) T cells. When a Th cell recognizes the pieces of antigen exposed on the B cell envelope, it produces a series of molecules called lymphokines that force the B cell to multiply. Some of the cells resulting from this multiplication become memory cells, which are left waiting, prepared to respond to a future infection (this is one of the mechanisms that take advantage of vaccines), while others become plasma cells , capable of producing mass antibodies that are released into the blood.

Once circulating through the blood, these antibodies will wait to find their target antigen to bind to it, coating the virus and neutralizing it. Often, the viruses thus coated with antigens will then be swallowed and eliminated by other types of cells called phagocytes.

I have explained this so that you understand what the problem is: viruses also carry antigens inside them, but since they are hidden when the virus circulates through the body, they can not trigger this response known as humoral, so called by antibodies who travel freely because of humor or blood flow. But luckily, our immune system has another answer called cell. Some cells swallow the virus and break all its components, including the internal ones, into pieces that are then exposed on its surface. Certain T cells will recognize these pieces to trigger the antibody response, as I explained above, but other cytotoxic T or Tc calls are also activated that kill the cells infected by the virus.

Therefore, the internal antigens of the virus can also trigger the cellular response. But in general vaccines are designed to cause a strong humoral memory response, and instead are ineffective in the cellular response. Currently many research on vaccines are looking for precisely this, increase the cellular response to improve the immune reaction and offer longer term protection.

Vaccine against the flu. Image of CDC.

Vaccine against the flu. Image of CDC.

Thus, if it were possible to design a vaccine capable of starting a strong cellular response against an internal antigen that varies little over time and between some viruses and others, we would have the single ring, the universal flu vaccine. To provoke a greater cellular response, vaccines with weakened live virus are tested instead of dead viruses or loose pieces as in the current ones, with the idea that they will trigger a good cellular response.

Although the prospect of injecting a live virus may sound alarming, attenuated virus vaccines are very common and work wonderfully; The viral triple that is applied to children against measles, mumps and rubella is a vaccine of attenuated viruses, as well as that of yellow fever that we travelers put on. An additional advantage of vaccines with attenuated viruses is that some can be administered through the mouth or nose; The oral polio vaccine could be distributed massively in developing countries, and is a decisive factor in the effort towards the eradication of this disease.

In fact, there is already the nasal flu vaccine attenuated against influenza, but it has not been very effective. This week, a new design that looks very promising has been published in the journal Science . Researchers in China and the United States have obtained a mutant virus that has everything that is desirable in a vaccine flu: it multiplies well, which allows it to be very visible to the immune system, but it barely produces symptoms and instead triggers a strong cell response. T; In addition, it is hypersensitive to interferon, a natural antivirus of our body that the normal influenza virus eludes. He still has a long way to prove its usefulness, but for the moment it has worked very well in mice and ferrets.

I have left for the end the vaccine that is closest to becoming a reality. The company Vaccitech, a spin-off from the University of Oxford, has mounted internal flu antigens in a fake virus that is used as a vehicle. The objective of this vaccine is to fight absolutely all types of influenza A, the most worrisome and the one that causes the greatest number of deaths.

Of the three phases of clinical trials that must be covered before a pharmaceutical product reaches the market, Vaccitech is now in the second. In the first one they already proved that the vaccine is safe, after demonstrating its effectiveness in animals. Currently phase II is testing whether it is able to protect against influenza in combination with seasonal vaccines. This stage will end in October 2019. If everything works as expected, phase III would undertake the final tests before the vaccine becomes available, which could occur within 5 to 7 years. Maybe this is a race we can win before the next big flu pandemic arrives.