Dr. Manel Juan:" “There are no good vaccines or bad vaccines”

Interview with Dr. Manel Juan, head of the Immunology Service

"There is no humoral immune response without a cellular response", says Dr. Manel Juan.

How is the immune system trained to fight a new virus such as SARS-CoV-2?

When the virus enters it is detected by “innate” mechanisms, which are diverse and constitute the body’s first line of defence. However, the most important ones that are relevant to the entry of this virus (and others) are the type 1 interferons, which have an antiviral capacity to control the virus. In many cases, these interferons are sufficiently effective and, accompanied by other components of the "innate immunity" they mean that most infected people show no symptoms (the famous "asymptomatic individuals").  What happens is that with these type 1 interferons we have a series of variabilities, which have become more obvious with COVID-19 and mean that, in some people, especially the older you get, they are slow to activate. Therefore, at a given time, because they are slow, there is a high viral load and a strong response is required, which is what the disease generates through hyperinflammation.  In some cases, all this ends, because this inflammation causes respiratory problems and even death. However, in individuals who have had no symptoms or recover (even after having been seriously ill), it is because the immune system has worked and, in general, an "adaptive or specific" response is added to the “innate system, with the production of antibodies and T cells, which are what give us the most lasting and effective immunity. This is what is we call the immune “memory”.

Antibodies and the T cells are involved in the adaptive immune response. Are T cells what we refer to as the cellular response?  

Yes, and we call the antibodies “humoral”.

Does this occur firstly because of the type 1 interferons?

The interferons generate an environment that allows for this specific recognition of the cellular and humoral responses. 

And are these two paths? The humoral response and the cellular response?

Not quite. There is no humoral immune response without a cellular response. This separation does not exist. In order for antibodies to be produced, there has to be a cellular response. There is a slight possibility of a humoral response occurring on its own, but this is not important nor is it effective in the SARS-CoV-2 virus. In other infections, there can be a humoral response that is significant enough on its own.

These two paths have been separated in the media, and this can give rise to such doubts. What kind of response do vaccines generate?

Both. Because they cannot generate antibodies without the cellular response.  There are cases of people who do not create antibodies, and in fact there are extreme cases of people who cannot make antibodies because they have no B cells for genetic reasons, but they are not badly affected by the SARS-CoV-2 infection. To make an analogy with an orchestra, the violins (which are responsible for carrying the melody of a symphony) could be represented by some of the effector cells… However, the conductor’s role is always played by the T cells, whilst the percussion instruments (drums or cymbals), which are also important but perhaps not essential, would be the antibodies.  Without the percussion instruments, the music can be heard quite well, although we do not have the complete symphony and part of the rhythm of the music may be lost.

When talking about the effectiveness of vaccines, what is meant by this efficacy of for example 91%?

That when we have studied the possibility of people within the clinical trial groups generating disease after reinfection, in terms of the virus being able to enter again, it ensures that 91% of them will have no symptoms. 

So, what is this popular distinction that has been made between “good” and “bad” vaccines?

We would not be talking about a pandemic if people were not getting ill. If we were all in the group that has an innate response without any symptoms, we would still have a pandemic because the virus would be circulating again, but no one would get ill and very few people would be concerned.  What ALL vaccines guarantee is that practically no one gets ill. So, they are equally effective. The fact that some people make more antibodies than others or that one person has a humoral response that can even detect the virus, is of no importance from the point of view of the disease. We are simply faced with the possibility that you can detect the virus and that you can even pass it on to other people.  But that happens with all of them. Because the types of vaccine we are using right now do not guarantee that the virus will not enter or will not be able to replicate initially in the mucous membranes. There is a vaccine that is being developed by Dr. Luis Enjuanes at the CSIC (Spanish National Research Council), which is inhaled. Administration via inhalation can guarantee more localized protection, which will even avoid the virus reaching your mucous membranes. This will thus prevent you passing the virus on to another person. The vaccines currently in use reduce this likelihood and do generate this local protection, but less than a normal infection and less than can be achieved with these inhaled vaccines if they become available, since they are more localized. However, there are no better or worse vaccines. 

Let's continue talking about vaccines. New variants have appeared now, which I understand is a common process.

Yes, it’s natural. 

So, it means that viruses adapt to their environment…

In fact, they simply mutate, not because they want to adapt to the environment. Any variant that has a selective advantage spreads and occupies the place previously taken up by other variants in circulation: it is natural selection. The virus mutates just like we mutate.

Now we have British and Indian variants. They appear to be scarier. 

They all appeared scary when they emerged, didn’t they? And the media and some scientists have become specialized in stoking a climate of fear about this.

At present, we believe they are more contagious, but they don't appear to cause more serious disease.

No. Basically, because these variants are in the interaction zone with the cell receptors. And so, the antibodies, despite not being the anti-infection response melody, allow us to avoid transmission, since they can block the entry to other cells. This does not mean that you get ill; in order for that to occur, your innate immune system and the T cells have to fail, and the variants do not destroy the T cells. To top it off, the lymphocytes that produce the antibodies that undergo a process called somatic hypermutation can make a large number of variants and, through the same process they use for recognition, they make increasingly good variants. So, when there is a variant that is not easily recognized, these lymphocytes will rapidly undergo somatic hypermutation and adapt to the new variant.

So, viruses mutate, but we too can defend ourselves better.

Yes, if we are vaccinated, because what we do with the vaccine is to create a lot more lymphocytes.  An article in Nature shows that there are long-lasting responses. This means that if there is a second round of infection there may be cells that last for decades. Based on this, as we already knew from the epidemiology of other coronaviruses, it is most likely that we will be protected for years and that our immune system will be able to adapt, despite the variants. In fact, if this did not occur (protection lasting decades), it would make the news. Of course that just might happen, but it's not likely.

And what about the fact that people are now saying that total immunity will require a third or fourth dose?

That is all based on the fact that antibody levels drop. However, as we noted, these antibodies are not the elements that give us the highest level of immunity.  This is the whole problem. We are confusing issues. Going back to the example of the drum, antibodies are only used for the percussion…and a symphony can be played without percussion instruments. On the other hand, it is very complicated to play a symphony without violins, which would be the lymphocytes.

You say that the antibody levels drop, but does the T cell response persist?

The data we have at present show that it persists, yes. We can compare this with other viruses and other situations and we see that in general it lasts for at least 10 years. Moreover, if there are long-lived cells, which we have seen can be antibodies, it is because there must be T cells to maintain these antibodies. Everything indicates that the protection will be long-lasting. Let's go back to the example of the drums: the antibodies are the noise that the drum makes, but the drum continues to exist. It doesn’t play, it doesn’t do anything, but it still exists. There are B cells that are able to respond and now we know that they can last for years. However, what happens is that, if it's not this drum’s turn to make a noise, you don't hear it. When we say, “These individuals retain the antibodies,” it may be that they are still in contact with components of the virus (they can remain in the lymph nodes). But what is logical is that the antibodies remain whilst the infection lasts; for a few months.

Do we know how the virus works in order to attack it with some form of treatment?

This would have been the solution. If, right from the start, one of these drugs had been useful in treating the virus, we would not have raced to develop vaccines. In fact, very few antiviral drugs are produced, and they usually have a large number of side effects.  If an antiviral drug had existed, it would have been used. But it is a different virus, and no one had been concerned about the coronaviruses up to now. These drugs could definitely be very useful. However, the downside is that they have lots of side effects, because the virus is something that is intrinsic to us: RNA particles in this case that infect us and use our cell machinery. No one has been able to develop a drug to treat COVID-19 yet. We have antibodies, but they are very expensive and hard to make and administer to large numbers of people. Antivirals will be developed. They will come, but it will be a long time before they become effective.

If the population is vaccinated and no longer develops the disease, producing these treatments and creating the profiles of these drugs will be increasingly complicated.

Unfortunately, it is very likely we shall do this so badly that in Africa there will no doubt be millions of people becoming infected naturally, without vaccines. The question is, “Could we have done this better?” I am convinced we could have. Vaccinating people earlier. Vaccinating elderly people directly who were dying. As we have seen, we already know how to make vaccines without generating side effects (to make safe vaccines), but we can definitely make useless vaccines. So, we had two options: either that it would not work, or that if it worked we would protect them. This is literally what I said to a colleague.  And he replied, “What do you think we could do?” “I would vaccinate people and, if it works, you’ll have won, you’ll already have vaccinated a few people.” But that is not in line with the regulations we currently have for developing vaccines, very “protective” regulations, which aim to avoid us harming people…but people died during the months when we were unable to obtain the vaccines. 

The starting point for the COVID vaccines was cancer research. Could this now have a knock-on effect on cancer treatment?

All this will make it easier for it to be applied more to cancers. All clinical research is carried out based on the obtaining of informed consent. It will be much easier to convince someone by saying, “We’ll give you a vaccine like the COVID-19 one.” This type of patient is already very convinced, because in general they are in danger of dying and they see this as a solution. However, it is harder to develop good vaccines against cancer than against infections. 

Are they also mRNA vaccines?

Yes, yes. It is the same principle. The only difference is that, instead of inserting the viral sequence, you inject the sequence of the tumour mutations.

The idea is to activate the immune system against the tumours. In other words, would the immune system be able to distinguish between good cells and tumour cells?

In fact, that is what it does as a matter of course. In other words, it has been calculated and seen that, based on the mutations that can cause cancer, every 5 and 15 years everyone should suffer from cancer. However, fortunately, what happens is that we do not see this because the immune system possibly eliminates them. If not, people would develop cancer several times over the course of their life; we are talking about six or seven times!!! However, the eighth time the immune system "fails" in this defence against cancer...and that is when we see the cancer.

So, every 5 and 15 years you can develop cancer…

This is intrinsic to our capacity to mutate.  It is intrinsic to biology; it is the basis of evolution. These same mutations in reproductive cells generate variants that later adapt better to the environment. However, they also occur in somatic cells. This is unavoidable. But we can help avoid problems when they appear, and that is what we are trying to do by boosting the immune system.