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DR ŽUGIĆ, HEAD OF IMMUNOBIOLOGY DEPARTMENT AT ARIZONA UNIVERSITY: 'Corona will be like the flu – we will get seasonal jabs.'
Foto: Privatna Arhiva

INTERVIEW OF THE WEEK -

DR ŽUGIĆ, HEAD OF IMMUNOBIOLOGY DEPARTMENT AT ARIZONA UNIVERSITY: 'Corona will be like the flu – we will get seasonal jabs.'

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'I would be very surprised if we weren't protected from the original coronavirus strain infection for years, even decades. However, how protected from various coronavirus mutants we end up being will also depend on the type of mutation and our immune systems.'

"I expect the immunity to SARS-CoV-2 after vaccination or recovery from the infection to last for years, possibly decades. I would be very surprised to see a different outcome. However, the virus won't stay put either – it will change to avoid the existing immunity, so that we are probably in for seasonal SARS-CoV-2 epidemics as well as seasonal vaccinations, similar to the flu virus," Professor Janko Nikolić Žugić, a famous immunologist, Head of the Immunobiology Department at Arizona University in Tucson, and scientist working on coronavirus immunity with his team, said in an interview with Kurir.

What do you base the claim regarding decades on?

"I'd like to put this into perspective of what is known about humoral immunity duration with regard to antibodies. Some very good studies have shown that our immune systems can produce antibodies that outlive us many times. Antibody longevity is measured in terms of half-life, i.e. the period of time it takes to lose 50 percent of antibodies out of 100. In smallpox, the half-life is 90 years. So, if in 90 years you lose a half of the antibodies, you will never lose the protection you have. In chicken pox, the half-life did not go down at all in women, and in men it stood at 370 years. There is no reason for the coronavirus immunity to be short-lived."

How many subjects did you use in your study?

"The entire antibody longevity study had around 6,500 subjects, of whom 200 or so were positive for the coronavirus, because there weren't many of them back then. At the time of publication, the longest-term samples that we had were seven months post contracting the disease. There were people who registered for testing more or less by accident, those who suspected they had had something, those with a confirmed PCR test, as well as people who were in hospital with a severe Covid. Those with Covid had a slightly higher maximum response. But, there was no reduction in the levels of antibodies in any group. Importantly, we did the test on three separate segments of the coronavirus and confirmed it in functional terms as well."

What are these segments?

"We measured the antibodies on the spike protein domain, which is used by the virus to bind to the ACE2 cell receptors and enter cells in this way; on another segment of the spike protein, located on the other side of the molecule; and on the nucleocapsid protein, which plays an important role in virus replication. And fourthly, we looked at whether the antibodies can block the virus from entering cells – the so-called neutralization test. That is an important measure of a person's immunity and ability to defend themselves."

What did you conclude?

"In three of these measurements, including the neutralizing antibodies, there really was no loss of immunity. The nucleocapsid antibodies were the only ones to go down, which isn't key to the defence and is probably an effect of previous infections with common cold coronaviruses, which 96 to 98 percent of these people had had. The claims that the coronavirus antibodies are lost fairly quickly contradict everything we know about B lymphocytes (B cells), which produce these antibodies. When infection occurs, B lymphocytes produce the first wave of antibodies as fast as possible. They are not the best that we can produce in terms of quality, and aren't long-lasting either – as the cells producing them are short-lived – but they are the first line of defence."

How soon after the infection does that occur?

"If you used supersensitive measurements, you could find them as early as day five in some people, and on day 14 in everyone. They are IgM and IgG antibodies. Around weeks four to six, the production wave is peaking, and then it starts to drop. Based on this drop, comparatively short-term studies predict that we will be left without antibodies around the third month."

So how are we protected in the long term then?

"These studies have completely overlooked the fact that, even as the first wave and emergency response are under way, a much higher-quality response is being prepared in the background. The other B lymphocytes, themselves far longer-lived, are producing antibodies which bind to the virus between 100 and 1,000 times better."

How much longer-lived are they?

"As we mentioned, up to 370 years, even to infinity. Going by what we know about immunology, I would be surprised if we turned out not to have a very long-lasting response to this coronavirus. Immunity to SARS-CoV-1 is claimed in the literature to last up to three years, possibly six. However, it was recently found that nearly everyone who has had it has an antibody response 17 years later. I expect the same to hold for SARS-CoV-2. I would be very surprised if we weren't protected, even from some mutations. In addition to B lymphocytes, we have a good T cell response. Even if the spike protein changes, our T lymphocytes (T cells) will be there to protect us, at least from severe forms of the infection."

Does this mean that those who have had the disease or have been vaccinated are also protected from the UK strain of the coronavirus?

"The appearance of new virus mutants/strains shows that we are entering the 'race against the virus' phase – the virus is now pressured by the immune system and works to avoid it. This is not a surprising turn of events. For the time being, the UK strain, as well as the South-African one, seem to spread faster, but don't appear to cause a more severe form of the disease. Current estimates say that those who have had the 'original' coronavirus will be immune to these variants, which is predicted to be the case with those who have been vaccinated as well. As the virus changes, there is a possibility that new variants bypass the existing immunity. We need to look into this experimentally and, based on the findings, prepare new vaccines that can protect us from new strains in the future. This could be achieved by analysing the immunity and identifying the virus segments necessary for replication, which the virus cannot change without harming itself. This is a very important ongoing task, worked on across the globe, including by our group."

What are T lymphocytes (T cells) really?

"T lymphocytes are white blood cells which regulate, and participate in, the immune response to an infection. T lymphocytes have an important role with respect to viruses. We have two trillion lymphocytes (B and T lymphocytes) in our bodies. Of these, only between a few thousand and a few tens of thousands are specific to individual viruses, including the coronavirus. Aging affects T cells first, as they are produced in the thymus – a gland located in the chest, whose mass drops nearly tenfold by puberty, resulting in a tenfold reduction in the production of new T lymphocytes."

Is the high number of T lymphocytes the reason why children aren't as affected by the coronavirus?

"That is certainly not the only reason. We still don't understand many details about this virus and children's resilience to it."

T lymphocytes aren't effective beyond the age of 40?

"That is not entirely true. In some people they work well even in their 90s. However, between the ages of 40 and 50, another tenfold drop in production takes place. Maintaining previously produced T lymphocytes is fairly successful over many decades, but this process is disrupted in the last third of life in a fairly large percentage of people. It's not so much that these cells aren't powerful in and of themselves, it's that there aren't enough of them. You see 50-year-olds with a significant drop in the so-called naïve T cells – those that have just been produced. Around the ages of 65, 70, or 75, we have a third of the number we used to have when we were young."

Is that enough to defend us?

"That's a great question. The loss of T lymphocytes is serious, but it's not the only problem. Additional problems are associated with response coordination. T lymphocytes need to get to the place where the virus entered the body as fast as possible. In the case of the coronavirus, that's the upper respiratory tract – the mouth, nose, and lungs. The immune response is initiated in the lymph nodes servicing these areas. This coordination is lost due to degenerative changes in the lymphoid organs."

Are T lymphocytes the cause for the coronavirus spreading to other organs?

"It's because of them that we are fighting a losing battle right from the start, as the virus is not stopped fast enough. The immune system is a very destructive force, made to wipe out viruses and bacteria, and its actions need to be carefully restricted. If it continues acting destructively when, for example, there isn't a lot of virus present, the so-called immunopathological reaction follows, i.e. the immune system destroys cells that are not that sick or are not sick at all, simply because they are located next to the diseased/virus-infected cells. The immunopathological aspect is probably one of the explanations why this virus is so troublesome in some people and why the multiple organ syndrome – the attack against many organs – occurs."

The notion of the 'twilight of immunity' refers to this drop in T lymphocytes?

"Yes, it is a combination of insufficient production of immune cells, insufficient maintenance of the immune cells produced, and insufficient coordination of their response to the infection. B lymphocytes go through the same thing, but at a much later time than T lymphocytes. The number of naïve B lymphocytes, which constitute the default response to a new infection, goes down between the ages of 50 and 60. Nonetheless, a great many people over 65 retain a strong immunity. As is the case with aging in general, the aging of the immune system depends to a considerable extent on the individual. The good news is that the immune system can be stimulated into working better in old age, even rejuvenated to a point."

Vaccines: 'Anything is better than the coronavirus.'

How safe are the RNA vaccines?

"It all comes down to how much time we have to be careful. This is known as personalized medicine in the US – providing someone who should be vaccinated with state-of-the-art treatment beforehand, identifying immune defects they might have and establishing whether they are susceptible to autoimmune diseases. And then, based on all that, choosing one vaccine over another. The mRNA vaccine makes a single virus (spike) protein and stimulates the human body less. The viral RNA, if it were to be administered unaltered and in high doses, certainly could result in a cytokine storm in some people. However, this RNA is silenced to a considerable extent. In my opinion, the Novavax vaccine will hit the market by February or March. It is much more conventional, protein-based, with adjuvants added, and has been tested better and used longer."

In Serbia, you can choose which vaccine you wish to take. Which one would you choose?

"For people in good health, without any health issues or suspected conditions, I'm sure that the Moderna and Pfizer vaccines will be a good option. I don't know enough about adenovirus vaccines, e.g. Sputnik V or AstraZeneca – I haven't seen the results of the testing so I cannot comment. I expect that both are safe. I think a possible problem there might be that repeated vaccination won't be effective, as adenoviruses are quite immunogenic – we produce adenovirus antibodies, which then prevent revaccination from stimulating the coronavirus immunity again. That said, it's a good thing that all these vaccines were made so quickly in such circumstances. Having something is more useful than nothing, and I hope that vaccines will change our lives for the better."

Why women are attacked less: 'Women have better immunity.'

Why are men more vulnerable to the coronavirus and die more than women?

"We still don't know. On the one hand, it is a well-known fact – it is mentioned in our published rhesus monkey studies – that women maintain their immune system better as they age, and that the number of their T lymphocytes drops slower than men's. However, women also have a much higher incidence of autoimmune diseases. So, you get a stronger immune system, but one prone to auto-aggression – attacking its own tissues. This is why multiple sclerosis and many other autoimmune diseases occur more often in women."

They never knew: 'As many as 12 percent of people had innate immune defects.'

"Interferons are made by every cell when it becomes infected with an RNA virus, such as the coronavirus. It was found that around 12 percent of men and around eight percent of women with a severe form of Covid were genetically unable to mount a good interferon response. According to the same study, published in the Science magazine last summer, something even more unexpected occurred in three percent of the people involved – they formed antibodies to their own interferons and launched an autoimmune response to their own defence system. The coronavirus has revealed immune defects that people never knew they had."

A dilemma solved: 'You are not a spreader if you have antibodies.'

Let's solve the dilemma – if someone has antibodies and the coronavirus gets to them, can they transmit it while being protected themselves?

"In my opinion, no. It could happen that someone has a certain quantity of the virus on their hands, shakes someone else's hand, and then the other person touches their face and gets infected. But, that 'spreader' would have to have been in contact with someone who is infected and who has literally sneezed onto their hands. In order to be truly infectious, the virus needs to replicate in a person transmitting it, be secreted into the saliva, and then spread around in high concentrations after the cells in the mouth and nose disintegrate. And that cannot happen to someone who has antibodies."

Then why do we have people who have had Covid twice, even three times?

"The percentage of actually documented reinfections is very low, around one person in 10,000 of those who have had the infection. That is about the same incidence as that of people with an innate immune system defect. Although this hasn't been proven yet, I suspect, based on all available information, that it's people with immune defects. Of course, going back to our discussion about mutations, all this can change if the virus undergoes extensive mutations. However, the likelihood of someone recovering from Covid and then getting a severe form again is low in that case too."

It's never too late: 'Vitamin D every day.'

Is it already too late for vitamin D and boosting the immunity?

"It's never too late for vitamin D. It is one of the few vitamins which, when taken, have beneficial effects at any age. The same is the case with defending oneself against malignant diseases. Ideally, the daily intake should be between four and five thousand units."

What else can be done to help the immunity?

"People need to have a healthy lifestyle. Working out, sleeping well, and eating a balanced and healthy diet, with lots of vegetables – a very important item – are essential."

Jelena S. Spasić

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