Typically found only in West and Central Africa, this virus is causing a outbreak in more than a dozen countries from Europe —including Spain—, USA, Middle East and Australia.

“Viruses are with us, they are reaching us and the important thing is to know how to act”, he tells SINC Mariano Estebanvirologist of National Biotechnology Center (CNB-CSIC). Esteban is one of the world’s leading experts in the study of the biology of viruses.

His research has focused on understanding the molecular biology of these pathogens, with the aim of developing procedures that allow the control of infectious diseases. Of note are his findings on the biology of the vaccine virus, which was used as a vaccine to eradicate smallpox.

Esteban developed, together with Juan García Arriaza (also from CNB) and the Spanish pharmaceutical biofactory, one vaccine against covid-19. Their platform, which precisely uses an attenuated variant of the smallpox virus, has successfully completed pre-clinical trials in three animal models: mouse, hamster and monkey. The results were published in the journal Frontiers in Immunology and now it’s in the absence of human trials.

This is a very widespread family of viruses in nature and it is necessary to know how to diagnose and differentiate one from the other.

After the coronavirus comes another zoonotic virus, monkeypox. What mechanisms do we have to protect ourselves?

First, techniques for rapid identification of causal agents must be used. Keep in mind that this monkey virus is very similar to human smallpox and also very similar to other viruses that affect rats and cows, camels, buffalo…

It is a very widespread family of viruses in nature and it is necessary to know how to diagnose and differentiate one from the other. O National Center for Microbiology of the Carlos III Health Institute (ISCIII) uses technologies already developed through the WHO Advisory Committee on Smallpox Virus Research and that they are now using in the cases that were detected.

What recommendations does this WHO commission make?

I am one of its oldest members. For the past 23 years, we’ve come together as a way of keeping an eye on smallpox cases.

Basically, what is established is that if a single case of human or monkey smallpox appears, the immediate action is to make a ring or a fence to prevent it from spreading. That is, as soon as an infected person is detected, it is necessary to look for close contacts, expand the reach a little and isolate these individuals quickly.

Monkeypox is transmitted by direct contact by viral particles that are produced during the first 12 to 24 hours, which is the viral replication cycle. The infected person can spread it through drops of salivary secretions, nasal secretions or nasopharyngeal mucosa. Also by contact with the skin lesions of an already infected person, because in these vesicles there is a large amount of virus. This disease has an R0 [número de reproducción] than five, which means that approximately one infected person can infect another five.

Fortunately, the number of cases is small and control and monitoring can be done easily. At the same time, the genomes of the viruses are being sequenced to discover the variation between them and whether they come from Central Africa, where the virus is more lethal, or from West Africa, which is much more attenuated.

So what you need to do is establish that fence and maintain surveillance and monitoring.

With this disease, would that be easier since there are still few cases?

Yes, fortunately, the number of cases is small and this control and monitoring can be done easily. At the same time, the genomes of the viruses are being sequenced to discover the variation that exists between them: whether the viruses come from central Africa, where they are more lethal because they have a 10% mortality rate, or from the western part, which has 1 %.

What we do know about the UK cases is that they are associated with the more attenuated West African virus. It seems that the ones from Portugal also have the same genetics and, probably, the ones from Spain are also from the virus from that area of ​​Africa. ISCIII is now doing the full sequencing and we’ll know soon.

What vaccines can be used against this virus?

Among the vaccines is Accam 2000, which is second generation. It is an active vaccine, that is, it is inoculated by breaking the epidermis, which is the traditional method, and produces an attenuated viral infection and a characteristic lesion. This is why people who have been vaccinated against smallpox have a mark on their arm or thigh.

In contrast, the third-generation Imvanex, based on the modified Ankara virus (MVA), is administered intramuscularly and causes no injury. Being a non-replicating virus, it does not produce progeny and does not leave a mark. This vaccine is licensed by FDA and the EMA for human and monkey pox. The US has been accumulating doses of this vaccine for years.

Studies of these vaccines have been published [Accam 2000 e Imvanex]. As smallpox no longer exists, tests were done on monkeys and both proved effective.

How effective are these human versus monkey smallpox vaccines?

Studies of these vaccines have been published. As smallpox no longer exists, the tests were done on monkeys and both were effective.

And what antivirals have been developed against smallpox?

There are two against smallpox, which also treat monkeypox. Both are FDA-approved, and are tecovirimat, which inhibits the spread of the virus from cell to cell, and brincidofovir. The latter acts by inhibiting the action of DNA replication. Smallpox viruses are DNA viruses of 197,000 base pairs or nucleotides.

In contrast, SARS-CoV-2, which is the largest RNA virus that infects humans, is 30,000 nucleotides long. Unlike these RNA viruses, which introduce mutations and produce different variants, DNA viruses such as monkeypox are very stable, with a very low mutation rate of one or two nucleotides per year.

For SARS-CoV-2, it was not possible to develop any really effective antiviral, we still have a pending.

DNA viruses such as monkeypox are very stable, with a very low mutation rate of one or two nucleotides per year.

For you who are on this WHO surveillance committee, it’s not strange that this happened, is it?

Viruses are with us, they are reaching us and the important thing is to know how to act. We’ve been tracking this family of viruses for a long time. Keep in mind that in the Democratic Republic of Congo in central Africa, 10,000 cases have been detected since 2020, with 342 deaths. And in January and February of this year there were more than 700 cases and 37 deaths in this area.

In other words, this monitoring continues. What happens is that the cases were mostly confined to Africa. Now there have been leaks due to the importation of animals.

You are an expert on these viruses…

I’ve been working with this smallpox virus family for 50 years, I think I’m the longest working Spaniard. In Spain, we have some of the best groups in the world working with them to study their biology and use them as a developmental system. In addition to my laboratory for viruses and vaccines at CNB, there are also those of Antonio Alcamí and Margarita del Val, both from the Severo Ochoa Molecular Biology Center. And Rafa Blasco, from INIA. It is important to highlight that here we have world reference groups in this area and my laboratory is the oldest of all.

In the vaccine they developed against the coronavirus, they just used an attenuated variant of the smallpox vaccine as a platform, right?

Yes, our SARS-CoV-2 vaccine is based on a highly attenuated variant of the one used in the smallpox eradication program, called Modified Vaccinia Virus Ankara (MVA), into which we have incorporated genes encoding SARS-CoV-2 proteins to induce broad and lasting immune responses against covid-19.

The vaccine has successfully completed preclinical trials in three animal models: mouse, hamster and monkey. The results were published in the journal Frontiers in Immunology and this one lack of human testing.

What we want is to be able to carry out clinical trials to see what the effect of our vaccine is. It could be very interesting to see what the effect would be on both SARS-CoV-2 and monkeypox virus, because we use the same platform: the MVA vector.

Now could be a good time to see what effects your vaccine could have against the smallpox virus and the smallpox virus?

What we want is to be able to carry out clinical trials to see what the effect of our vaccine is. It could be very interesting to see what the effect would be on both SARS-CoV-2 and monkeypox virus because we use the same platform. The MVA vector is the same vaccine platform that has already been approved for use against the smallpox virus.

The truth is that it would be interesting to carry out clinical trials, if we have this capacity, because the vector was produced by a Spanish company [Biofabri]which I think we could do this kind of experimentation with, but they’re separate considerations that I’m not going to get into right now.

After eradicating smallpox, there was talk of destroying the virus, but it was decided to keep it for research, correct?

There are currently two centers authorized to maintain smallpox stocks: one in Atlanta, USA, at the Center for Infectious Diseases (CDC) and another in Novosibirsk. [Siberia, Rusia].

What the WHO advisory committee does is tell these two centers what research can be done on the smallpox virus so that we can move towards better procedures to protect humanity. For example, if smallpox reappeared due to bioterrorism. The meetings of this committee have this objective: to know that we have the necessary mechanisms of action.

The WHO General Assembly has not considered the option of destroying smallpox virus stockpiles, which are in two centers, one in the US and one in Russia. With them, they continue to investigate better procedures to protect humanity.

And do we have these mechanisms?

In these years, we have advanced in knowledge and research is needed to improve control procedures. We have vaccines and antivirals, at least two, and it would be a question of developing more antivirals that can cover a broader spectrum of action.

This is why smallpox virus stocks are not destroyed. The WHO General Assembly has not considered this option for now and it is now even more complex given the situation in Russia with the war in Ukraine.

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