[Music] And so basically hepatitis B virus is a cancerogenic virus. The problem is that about 15 to 40% of people with chronic hepatitis B develop liver cirrhosis and liver cancer. [Music] Biological with Florian Cramer. [Music] Hello and welcome to Viral Logical. This episode was recorded on January 31st of 2026 in New York City. Today we are going to talk about hepatitis B and hepatitis B virus. This virus is part of the hepatna viridae. It has four zero types and a number of different genotypes. The disease severity and complications and treatment success is somewhat influenced by the genotype. So there are differences between the different circulating viruses. In terms of molecular biology, the virus is pretty interesting. It has a double-stranded DNA genome that's circular. In a way it's only partially double-stranded, but I guess it's a little bit too much to go into the details there. Basically the DNA or the genome would be called covalently closed circular DNA or a CCC DNA. The virus particle itself is pretty small. It's only 42 nanometers in diameter. The structure of the viruline includes the genome on the inside. Then we have a nuclear capsid, a structure which looks like a small sphere. That's a regular shape. Then we have a lipid envelope. Then this lipid envelope we have the surface antigen or HBSHE. Hepatitis B surface antigen. The genome of the virus is actually pretty interesting. This is not a retro virus. It can switch between RNA and DNA. So basically from DNA to RNA and then back to DNA. It has reverse transcript, the virus polymerase has reverse transcript this activity. Again, it's not a retro virus like HIV, but it can basically do the same thing. The other important thing about Hepatitis B virus is that it can persist in cells in the nucleus as a basically mini chromosome. That allows it to cause chronic infections. That's highly problematic, as we will see. Hepatitis B virus is a human virus, but there's a lot of related viruses around closely related viruses circulating apes and primates. But there's also similar viruses in birds, for example. The idea is that this mammalian bird viruses split about 300 million years ago. That's quite a long time ago. These viruses or the human version of the virus has co-involved with humans. And has also evolved in different human populations. This virus has been found in relatively old samples. It's now possible to take bones, for example, from people who died during the Stone Age and then sequenced their genome from the bones. Which is pretty cool. And if you do that, you of course sequenced DNA, right? And if these people had infections with Hepatitis B virus, that DNA is there too. And so from these sequencing data sets that exist from these old bones, and partially also from frozen bodies, from the Stone Age, from the Bronze Age, from Middle Ages, we can reconstruct the genome of Hepatitis B virus that caused infections back then. And that's pretty interesting. And basically also shows us that there were some genotypes of Hepatitis B virus that were circulating back then that are not around anymore. That seemed to be extinct. And then there's other genotypes which are very similar or identical to what is circulating in humans right now. The disease itself, Hepatitis, which is basically liver inflammation, liver infection, I has been recognized early on. It's described by the Babylonians, for example, by Hippocrotis. Then there's more recent historic descriptions by Lurman, for example, in 1885. There was an outbreak in Bremen in Germany. It seems there was a small-box vaccination campaign. Typically, small-box vaccine was produced on cows, but it seems in that case human material of a vaccine virus, which was used as vaccine for small-box was used, and that seemed to have been contaminated with Hepatitis B virus. And so when the vaccinated people didn't have an outbreak in this vaccinated people with Hepatitis, and that's well described. There's also a historic description from 1909 where Hepatitis outbreak was associated with needles used for syphilist treatment. And again, back then, the needles were used and not probably not sterilized between different patients, and that can explain how a Hepatitis B virus was spread between these people. There was also a pretty big outbreak during World War II in U.S. soldiers, and that was traced back to contaminated yellow fever vaccine that involved about 330,000 soldiers, so that's a really, really big outbreak. In the 1950s, people started to differentiate between different types of Hepatitis. We know now that there are several different Hepatitis viruses, viruses that can cause Hepatitis, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, and then Hepatitis E virus. Hepatitis D virus is something interesting and we'll talk about that later. But so there are several types, right? And in the 1950s, it was already determined that there at least two. There was a type A, and basically people figured out that Hepatitis was transmitted through the oral fecal route, so basically through feces, through contaminated waters, through contaminated food. And then they had determined that the other type of infection was serum related, so basically transmitted through human material. So that was called serum Hepatitis. In the 1960s, Baruch Bloomberg then discovered basically the virus. He discovered an antigen that he called Australia antigen, and that was this surface antigen of the Hepatitis B virus. And it was called Australia antigen because he founded in part of or Aboriginal people from Australia. He also got the Nobel Prize in 1976 for the discovery. And in the 1970s David Dane could visualize the virus using electron microscopy and using specimens from human serum, and the particles were then also called Dane particles. And already in 1971, the FDA had a blood test up and running, which was important because they needed to really screen blood transfusions for the presence of the virus to make sure that the blood supply was safe. So a little bit about disease, how do you get infected with this virus? Basically through blood, blood products, needles, and here intravenous drug uses an issue, sexual contacts, and also during birth. So it can be transmitted from infected moms to their babies, and that is a big issue. Historically, in the 1980s, for example, there were also infections through the tooth. So when you get it at two, and you know, you use a needle to kind of pierce this skin that can basically lead to hepatitis B infections if the needles are not keen. The whole group of puncture was another way to get infected, but the hygiene has changed quite a bit, and people are now well aware that this equipment has to be sterilized, and so that's not very common anymore. The virus is a very long incubation time between 30 and 180 days, and once symptoms start, typically start with body aches, mild fever, nausea, vomiting, fatigue, abdominal pain, and then because the liver is infected, you get often jaundice. Basically, you see yellow skin, you develop yellow skin, the eyes can become yellow, also there's a symptom that your urine can become pretty dark, that is because belly rubin is then secreted through the urine, because the liver can't metabolize it anymore. After these initial symptoms, people often develop jaundice. Symptoms for that are yellowing of the skin, often yellow eyes. Basically, the liver is damaged. Often people also have relatively dark urine, because belly rubin, which is usually metabolized by the liver, is now secreted.
created through the kidneys because the liver doesn't work properly anymore and then also relatively bail or almost whitish tools because the gallbladder is not working anymore. In the small fraction of individuals, this can also lead to liver failure, which is of course a little bit more dangerous than just liver damage where the liver afterwards recovers. They can also be kidney damage and also things like necrotizing vasculitis. So it's not just the liver that's involved, the can be other symptoms and other diseases caused by hepatitis B infections too. The good thing is most adults at least care the infection and recover can take quite some time, several weeks until people recover but most adults more than 90% resolve the infection. The problem is that kids, specifically young children, when they get infected, they often don't resolve the infection. I think for younger children, only about 30% resolve the infection and only 5% of newborns resolve the infection. If their infection is not resolved, it can lead to chronic infection and that is highly problematic. What happens in these chronic infections is basically the viruses there, it sits in these liver cells, the DNA, basically the genome is in the nucleus, the cells can get rid of it and partially the cells die and partially the immune system goes in and of course it takes these cells. And that leads to scars, basically the scarring of the liver. That's what you typically call liver cirrhosis and if that continues, that can also lead to liver cancer. And so basically hepatitis B virus is a cancerogenic virus. And the problem is that about 15 to 40% of people with chronic hepatitis B develop liver cirrhosis and liver cancer. The chronic infection in general is often asymptomatic but this acute phase of the hepatitis can be reactivated if somebody has chronic infection and then consumes a lot of alcohol for example or consumes certain drugs. So that can be reactivated. The estimates right now are that between 250 and 300 million people worldwide live with chronic hepatitis B infections. It's estimated that about 800,000 people die every year of the consequences of these chronic infections, so mostly of liver cirrhosis and liver cancer. And approximately 1.5 million new acute infections occur every year. Just to give you some some idea about 50% of all liver cancers in Europe due to either hepatitis B infections or hepatitis C infections. So hepatitis C is another virus that can cause chronic liver infections. It's a very different virus. We'll discuss it at some point but together have B and have C are responsible for a lot of a large proportion of liver cancers. These virus infections can be found worldwide but they're most prevalent in Africa. They are 7 to 8% of the population is infected. The western Pacific region is also an area where we have a large number of the population infected especially in places like Mongolia or China but also islands, states and areas like Indonesia. And the problem is once you're chronically infected it's really hard or impossible to get rid of the virus. There's medication to treat these infections but these medications don't work perfectly and often they also have a lot of side effects and the virus can be used to target the viral polymerase and sometimes interferon therapy can also be used but again these treatments are not perfect and they can have quite severe side effects. If you're talking about hepatitis B we also have to talk about hepatitis D. Hepatitis D is an interesting virus it's part of the repulsive array and it's a satellite virus so it can't actually replicate on its own or generate infectious progeny. It actually needs hepatitis B virus to help with that and so that's why it's called a satellite virus. It only exists in core infections with hepatitis B but it can infect on its own and so its genome is circular, it's a minus and single stranded RNA genome and it only calls for basically two proteins that cover the genome and this genome covered in the proteins is then packaged in these particles that hepatitis B forms. So basically it's kind of hybrid particles where the inside the genome and the core is from hepatitis D but then the outside is made of this surface antigen from hepatitis B virus and so again you can only have this this hepatitis D virus when you have a hepatitis B infection on its own it can't infect humans. We call that a super infection in this case and this virus was discovered in 1977 and sequenced in 1986 and it turned out that there's actually eight different species of the virus that did basically do the same thing but they're genetically different. The problem and why I'm mentioning this is because if you have this super infection with hepatitis D that makes the disease much worse. First of all when you have an acute face or fresh infection it's much more likely that you have liver failure when you have a hepatitis D super infection and once you go into the chronic stage the progression is much faster. You get tyrosis faster, you get liver cancer faster and people who have these chronic infections with hepatitis B, hepatitis D, core infections typically have a 20% fatality rate so that's pretty high and there's not much one can do about it and the estimate is that about 15 to 50 million people are infected with hepatitis D and hepatitis B at the same time worldwide. Pretty bad chronic infections but the good thing is that they're very good vaccines that protect you from these infections and what is also important to mention is that immunity against hepatitis B virus also protects you from hepatitis D virus because basically the virus particle, the outside of the virus particle is the same and so if you have a neutralizing antibody that neutralizes hepatitis B it will also neutralize hepatitis D so you only need one vaccine and that basically protects you from two viruses. The development of the vaccines for hepatitis B is pretty interesting. Early on it was recognized that in serum in blood of infected people there are actually two types of particles. On the one side you have this bona fide virus particles where you have a genome, the capsid and then on the outside the hepatitis B surface antigen and then there was a second type of particle and that's basically only the hepatitis B surface antigen but there's no nucleocapsid on the inside and there's no genome on the inside and so those are basically virus-like particles. They look like a virus but they're not infectious, they have no genome and these two particles have a different density and what that means is that you can separate them for example by centrifugation and so in 1971 Morris Hilleman was trying to do exactly that so Morris Hilleman was a historic vaccine developer developer in my opinion the most important vaccine developer ever and so he thought okay if there's a density difference and he was working at Merck at this point in time he thought if there's a density difference then these particles can be separated and if you would just have a preparation of the particles without the genome just the surface of the virus that could be used as vaccine and so he basically developed a process that was based on serum from infected individuals so they would take platinations from infected individuals and then they would process that and they would purify out these empty particles and then basically dissolve them with a chaotic reagent in this case as in curia was used this was super purified this was treated this for formaldehyde to kind of basically kill any infectious particle that would be in there and then when you remove the chaotic reagent this surface antigens kind of reformed this particles the basically self-assembly self-assemble again into these particles and that was basically the vaccine and this vaccine was improved in 1981 and actually worked pretty well but then it turned out there's an easier way to make such a vaccine based on these empty particles in fact if you take the gene for the surface antichin and you put that in
into a second-remise the cerevisiae, so into bakeacias. And you force the bakeacias to make that protein, this particles also form, and you can purify them from the bakeacias. Now, the advantage here is that, of course, there's no infectious particles involved because it's a recombinant protein that is made. So it's super safe. And then, of course, if you force the bakeacias to make that protein in large quantities, you get a lot of vaccine, and it's super easy to purify this, and to basically manufacture large amounts of vaccine. And so this vaccine was in license in 1986, and it replaced the earlier version, which was based on these serum particles, purified serum particles. And that's basically the vaccine that we're still using nowadays. The base immunization is three doses, typically. Sometimes boosted doses are given. And it works pretty well. There's also a next-generation version of that vaccine that only has to be given twice, and we'll get a faster immune response. That was then licensed in 2017 by the FDA, and in 2020 by the email in the European Union. So there's pretty good vaccines out there that can be used to prevent hepatitis B infections. I mentioned earlier that a lot of infections happen during birth. When chronic infected mother gives birth, then the virus can spread to the baby. And I also mentioned earlier that incubation time is very long, right? 30 days often longer. And it turned out that if baby is born to a hepatitis B infected mom, and you vaccinate that baby very, very quickly, typically within 24 hours, better within 12 hours, then you can actually prevent the infection. And so that's really recommended globally for newborns that they receive this first dose of hepatitis B vaccine, very quickly after birth. And this makes a lot of sense in countries where you have high rates of hepatitis B in countries where it's harder to test if the mothers are infected or not. And so this is a good recommendation this should actually be done. In a lot of European countries, the vaccine is recommended for babies, but often is given later on a few weeks after they were born. The reason for that is that healthcare is pretty good in many European countries. The screening is pretty tight, and so it's very unlikely that you miss moms that are chronically infected. And so the risk that the baby would get hepatitis at birth is pretty low. Of course, if they detected the mother is infected, then the baby is getting the vaccine dose right away. So in countries in Europe, the recommendation often is that yes, the baby should get vaccinated, but it's not necessarily, it's not necessary to do that right after birth. The US, I think since 1991, followed the recommendation that all babies should be vaccinated right after birth. We say hepatitis B vaccine. And recently this recommendation was changed and that led to a lot of discussion and a lot of controversy. So some people might know this, but there's a committee that develops vaccine recommendations for the CDC. And this committee was exchanged very recently with the Trump administration taking over and that committee then changed the recommendation. And now it's not a universal recommendation in the US anymore to vaccinate babies at birth with hepatitis B vaccine. Now it's basically a decision that should be made by the parents together with their physician. And again, this change has led to a lot of discussion because it is felt that it's much safer to vaccinate no matter what, because actually maybe if the screening is not as good or if the parents decide it's not good idea to vaccinate the baby, then there's a higher risk for the babies to acquire the infection at birth. And if that happens for babies, there's a very high chance that the infection becomes chronic over time. So again, an interesting discussion, pretty heated discussion that happened recently. So to summarize this, hepatitis B is an old human virus that in the acute phase can be pretty nasty, but not necessarily highly problematic. The problem is really the chronic infections that lead to liver damage, liver cirrhosis and liver cancer. And the other problem here is that there's limited treatment options and it's really hard to get rid of the virus, basically. On the other side, we have very good vaccines that protect from infection and should be used. As always, if you have comments, questions, suggestions, please write an email to
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