#9 – Hepatitis B: Prevention, Vaccines And Ongoing Challenges

00:00:05: And so basically hepatitis B virus is a cancerogenic virus.

00:00:10: The problem is that about fifteen to forty percent of people with chronic hepatitis b develop liver cirrhosis and liver cancer.

00:00:46: Hello, welcome to Virological!

00:00:49: This episode was recorded on January thirty first of twenty-twenty six in New York City.

00:00:57: Today we are going to talk about hepatitis B and Hepatitis B virus.

00:01:02: This virus is part of the Hepatinaviridae, it has four serotypes in a number of different genotypes.

00:01:10: The disease severity and complications and treatment success is somewhat influenced by the genotype.

00:01:16: so there differences between the different circulating viruses.

00:01:22: In terms of molecular biology ,the virus is pretty interesting.

00:01:26: It has a double-stranded DNA genome, the circular.

00:01:31: In a way it's only partially double stranded but I guess its little bit too much to go into details there.

00:01:38: Basically the DNA or the genome would be called Covalently Closed Circular DNA or CCCDNA.

00:01:47: The virus particle itself is pretty small.

00:01:49: Its only forty two nanometers in diameter.

00:01:52: The structure of the virion includes the genome on inside.

00:01:57: Then we have a nucleocapsid structure which looks like small sphere and that's regular shaped.

00:02:06: And then we have lipid envelope, this lipid envelopes the surface antigen or HBSHE so hepatitis B-surface antigen.

00:02:16: The genome of the virus is actually pretty interesting.

00:02:19: while it isn't a retrovirus.

00:02:21: It can switch between RNA and DNA So basically from DNA to RNA and then back to DNA, the virus polymerase has reverse transcriptase activity.

00:02:36: Again it's not a retrovirus like HIV but you can do the same thing.

00:02:42: The other important thing about hepatitis B viruses is that they can persist in cells of the nucleus as a mini chromosome And that allows it to cause chronic infections and thats highly problematic as we will see.

00:02:59: Hepatitis B virus is a human virus but there's lot of related viruses around, closely-related viruses circulate in apes and primates But theres also similar viruses in birds for example.

00:03:12: The idea is that these mammalian bird viruses split about three hundred million years ago So thats quite long time ago.

00:03:21: This virus, or the human version of this virus has co-evolved with humans and also evolved in different human populations.

00:03:31: We can detect that it's been found in relatively old samples.

00:03:37: It is now possible to take bones for example from people who died during a stone age And then sequence their genome from those bones which are pretty cool.

00:03:47: And if you do that, of course sequence DNA.

00:03:50: If these people had infections with hepatitis B virus the DNA is there too and so from this sequencing data sets that exist in old bones and partially also frozen bodies... ...from stone age, bronze age or middle ages.

00:04:08: we can reconstruct a genome of Hepatitis B Virus which caused infection back then.

00:04:14: That's pretty interesting.

00:04:17: basically also shows us that there were some genotypes of hepatitis B virus, that we're circulating back then and they are not around anymore.

00:04:26: They seem to be extinct!

00:04:28: And then there's other genotypes which are very similar or identical to what is circulating in humans right now.

00:04:34: The disease itself, Hepatitis Which is basically liver inflammation, liver infection.

00:04:40: I have been recognized early on.

00:04:41: It was described by the Babylonians for example by Hippocrates, then there's more recent historic descriptions.

00:04:49: By Lurman for example.

00:04:50: in eighteen eighty-five There was an outbreak in Bremen and Germany.

00:04:56: It seems that a small box vaccination campaign typically the smallbox vaccine was produced on cows but it seemed to be human material of the Xenia virus which is used as a vaccine for smallpox was used And this seem to have been contaminated with Hepatitis B virus.

00:05:14: And so when the vaccinated people didn't have an outbreak in this, vaccinated people with hepatitis and that's well described.

00:05:22: There is also a historic description from nineteen oh nine where hepatitis outbreak was associated with needles used for syphilis treatment.

00:05:31: again back then the needles were reused probably not sterilized between different patients can explain how Hepatitis B virus was spread between these.

00:05:43: There was also a pretty big outbreak during World War II in US soldiers and that was traced back to contaminated yellow fever vaccine.

00:05:52: That involved about three hundred thirty thousand soldiers, so it's really very big outbreak.

00:05:58: In the nineteen fifties people started to differentiate between different types of hepatitis.

00:06:05: We know now that there's several different hepatitis viruses, viruses can cause hepatitis.

00:06:11: Hepatitis A virus, hepatitis B virus, hepatitis C virus and then hepatitis E virus.

00:06:19: Hepaditis D virus is something interesting we'll talk about later but so there are several types right?

00:06:26: And in the nineteen fifties it was already determined at least two.

00:06:30: There was a type A Basically, people figured out that hepatitis was transmitted through the oral thickly route.

00:06:40: So basically it's through feces or contaminated water and food.

00:06:45: And then they had determined other types of infection.

00:06:49: were serum related so basically transmitted to human material.

00:06:56: That is called Serum Hepatitis.

00:06:58: In the nineteen sixties Baruch Bloomberg then discovered basically the virus.

00:07:05: He discovered an antigen that he called Australia Antigen and it was this surface antigen of the Hepatitis B Virus, And It Was Called Australian Antigen Because He Founded In Blood Of Aboriginal People From Australia .He Also Got The Nobel Prize in nineteen seventy six for That Discovery ,And In The Seventies David Dain could visualize the virus using electron microscopy and using specimens from human serum.

00:07:38: And, uh...the particles were then also called Dane Particles!

00:07:43: In already in nineteen seventy one 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.

00:07:57: So little bit about disease.

00:08:00: How can you get infected with this virus?

00:08:03: Basically through blood, blood products needles and here intravenous drug use is an issue.

00:08:11: Sexual contacts end also during birth so it can be transmitted from infected moms to their babies And that's a big issue.

00:08:22: Historically In the nineteen eighties, for example there were also infections through that tooth.

00:08:28: So when you get a tattoo and use a needle to kind of pierce this skin can basically lead to hepatitis B infection if the needles are not cleaned.

00:08:40: Acupuncture was another way to get infected but the hygiene has changed quite a bit.

00:08:47: people are now well aware that this equipment has to be sterilized and so, it's not very common anymore.

00:08:55: The virus is a very long incubation time between thirty-and hundred eighty days And once symptoms start typically starts with body aches mild fever nausea vomiting fatigue abdominal pain And then because the liver is infected, you get often jaundice.

00:09:20: Basically you see yellow skin or develop your yellow skin.

00:09:25: The eyes can become yellow.

00:09:27: Also there's a symptom that urine can become pretty dark That it's because bilirubin secreted through urine Because the liver cant metabolize anymore.

00:09:40: After these initial symptoms People often develop jaundice.

00:09:45: Symptoms for that are yellowing of the skin, often yellow eyes.

00:09:49: so basically the liver is damaged.

00:09:51: Often people also have relatively dark urine because bilirubin which is usually metabolized by the liver it's now secreted through the kidneys because deliver doesn't work properly anymore and then also a relatively pale or almost whitish stools.

00:10:11: In the small fraction of individuals, this can also lead to liver failure which is a little bit more dangerous than just liver damage where the liver afterwards recovers.

00:10:23: There could be kidney damage and things like necrotizing vasculitis.

00:10:29: so it's not just the liver that involves other symptoms or diseases caused by hepatitis B infections too.

00:10:37: The good thing Most adults at least clear the infection and recover.

00:10:44: It can take quite some time, several weeks until people recover but most adults more than ninety percent resolve the infection.

00:10:53: The problem is that kids specifically young children when they get infected They often don't resolve the infections And I think for younger children only about thirty percent resolved the infection and only five percent of newborns resolve the infection.

00:11:12: And if their infection is not resolved, it can lead to chronic infection... ...and that's highly problematic!

00:11:20: What happens in these chronic infections?

00:11:22: Basically the virus sits there in this liver cells.

00:11:26: The DNA basically the genome is in the nucleus, the cells get rid off and partially the cells die, and partially immune system goes in.

00:11:37: And of course it attacks these cells.

00:11:39: that leads to scars basically to scarring off the liver.

00:11:44: That's what you typically call liver cirrhosis.

00:11:48: If they continue this can also lead to liver cancer.

00:11:52: Basically hepatitis B virus is a cancerogenic virus And the problem is that about fifteen to forty percent of people with chronic hepatitis B develop liver cirrhosis and liver cancer.

00:12:08: The chronic infection in general, it's often asymptomatic but this acute phase up after hepatitis can be reactivated.

00:12:17: if somebody has chronic infection then consumes a lot alcohol for example or consume certain drugs so that can be re-activated.

00:12:27: The estimates right now are that between two hundred fifty and three hundred million people worldwide live with chronic hepatitis B infections.

00:12:36: It's estimated at about eight-hundred thousand people die every year after consequences of these chronic infections, so mostly of liver cirrhosis in liver cancer And approximately one point five million new acute infections occur.

00:12:52: Just to give you some idea, about fifty percent of all liver cancers in Europe are due either hepatitis B infections or hepatitis C infections.

00:13:02: Hepatitis C is another virus that can cause chronic liver infections.

00:13:07: It's a very different virus.

00:13:09: we'll discuss it at some point but together.

00:13:11: hep-B and hep-C are responsible for large proportion of liver cancer.

00:13:18: These virus infections can be found worldwide, but they're most prevalent in Africa.

00:13:25: There are seven to eight percent of the population is infected.

00:13:29: The western Pacific region also an area where you have a large number of the populations infected especially places like Mongolia or China But also island states and areas like Indonesia And once your chronically infected it's really hard or impossible to get rid of the virus, there's medication to treat these infections but this medications don't work perfectly and often they also have a lot side effects.

00:14:02: And the vials can be used that target the viral polymerase and sometimes interferon therapy.

00:14:08: it can also be used.

00:14:09: ,but again these treatments are not perfect.

00:14:15: If you're talking about hepatitis B, we also have to talk about hepatitis D. Hepatitis T is an interesting virus.

00:14:22: it's part of the repulsive urea and its a satellite virus so can't actually replicate on its own or generate infectious progeny.

00:14:33: It actually needs hepatitis b virus To help with that.

00:14:38: And so thats why called as Satellite Virus The only exists in co-infections with hepatitis in fact on its own.

00:14:47: And so, it's genome is circular and a minus sense single-stranded RNA genome... ...and only codes for basically two proteins that cover the genome.. ..and this genome covered by the protein is then packaged into these particles that hepatitis B forms.

00:15:08: So basically they are kind of hybrid particles where inside the genome and core is from hepatitis D, but then the outside is made of this surface antigen from Hepatitis B virus.

00:15:22: And so again you can only have these hepatitis d-virus when you have a hepatitis b infection.

00:15:29: on its own.

00:15:30: it cant infect humans.

00:15:32: we call that as super infection in this case and this virus was discovered in nineteen seventy seven and sequenced in nineteen eighty six and it turned out that there's actually eight different species of dead virus.

00:15:44: They basically do the same thing, but they're genetically different.

00:15:50: The problem while mentioning this is because if you have this super infection with hepatitis D That makes the disease much worse.

00:15:58: First off all when you have an acute phase or a fresh infection It's more likely to have liver failure When you have a Hepatitis D superinfection And once you go into the chronic stage, the progression is much faster.

00:16:13: You get cirrhosis faster... ...you get liver cancer faster and people who have these chronic infections with hepatitis B, hepatitis D co-infections typically have a twenty percent fatality rate.

00:16:25: so that's pretty high in there.

00:16:27: not much one can do about it.

00:16:32: Estimates that about fifteen to fifty million people are infected with hepatitis D and hepatitis B at the same time worldwide.

00:16:42: Pretty bad chronic infections, but a good thing is they're very good vaccines that protect you from these infections.

00:16:51: And what's also important to mention is immunity against Hepatitis B virus also protects your from Hepatiditis D virus because basically the virus particle, outside of that is the same.

00:17:04: And so if you have a neutralizing antibody that neutralizes hepatitis B it will also neutralize hepatitis D. So we only need one vaccine and that basically protects us from two viruses.

00:17:16: The development of vaccines for hepatitis b... ...is pretty interesting.

00:17:22: Early on it was recognized in serum in blood infected people.

00:17:28: there are actually two types of particles.

00:17:31: On the one side you have this bona fide virus particle where we have a genome, the capsid and then on the outside hepatitis B surface antigen And that's basically only the Hepatitis B Surface Antigen but there is no nuclear capsid in it inside basically virus-like particles, they look like a virus but are not infectious.

00:17:59: They have no genome and these two particles have different density.

00:18:05: what that means is you can separate them for example by centrifugation in one of the most important vaccine developers ever.

00:18:25: And so he thought, okay if there is a density difference and he was working at Merckett this point in time.

00:18:32: He thought that if there's a density different then these particles can be separated.

00:18:38: If you would just have the preparation of their particles without genome or surface of virus it could use as vaccine.

00:18:49: So basically developed process based on serum from infected individuals.

00:18:57: So they would take blood donations, from infected individual and then they will process that and purify out these empty particles And basically dissolve them with a kaotropic reagent.

00:19:12: In this case as in curia was used This is super-purified, treated for maldehyde to kind of kill any infectious particle.

00:19:23: And then when you remove the chaotropic reagent, these surface antigens kind of reformed this particles.

00:19:32: They basically self-assembled again into these particles and that was basically a vaccine.

00:19:40: This vaccine was improved in one hundred years ago and actually worked pretty well but it turned out there's an easier way to make such a vaccine based on these empty particles.

00:19:53: In fact, if you take the gene for this surface antigen and put that into saccharomyces cerevisiae so in to baker's yeast.

00:20:04: And you force the bakers yeast make their protein these particles also form.

00:20:10: You can purify them from the baker's yeast.

00:20:13: Now advantage here is of course there are no infectious particles involved because it's a recombinant protein made So its super safe.

00:20:22: And then of course, if you force the bakeries to make that protein in large quantities.

00:20:28: You get a lot of vaccine and it's super easy... ...to purify this and basically manufacture large amounts of vaccines.

00:20:39: This vaccine was then licensed in nineteen eighty-sixth.

00:20:43: It replaced earlier version which is based on these serum particles, purified serum particles And that's basically the vaccine we're still using nowadays.

00:20:57: The base immunization is three doses typically, sometimes booster doses are given and it works pretty well.

00:21:06: There also a next generation version of that vaccine That only has to be given twice when you get faster immune response.

00:21:14: It was then licensed in two thousand seventeen by FDA and in twenty-twenty by the email at the European Union.

00:21:23: So there's pretty good vaccines out that can be used to prevent hepatitis B infections I mentioned earlier, a lot of infections happen during birth when chronically infected mother gives birth then the virus can spread through baby.

00:21:40: And i also mentioned early that incubation time is very long right?

00:21:45: Thirty days often longer.

00:21:47: And it turned out that if baby is born to a hepatitis B infected mom and you vaccinate the baby very, very quickly.

00:21:57: Typically within twenty-four hours better than in twelve hours then actually prevent infection.

00:22:06: So thats really recommended globally.

00:22:09: for newborns they receive this first dose of Hepatitis B vaccine after birth And this makes a lot of sense in countries where you have high rates of hepatitis B. In countries, it's harder to test if the mothers are infected or not and so... This is good recommendation that should actually be done!

00:22:37: often is given later on a few weeks after they were born.

00:22:41: The reason for that, health care in many European countries is pretty good and the screening is really tight.

00:22:49: so it's very unlikely you miss moms who are chronically infected.

00:22:54: So the risk of babies getting hepatitis at birth is low.

00:22:59: Of course if they detect that their mother is infected then baby is getting the vaccine right away.

00:23:07: In countries in Europe, the recommendation often is that yes.

00:23:11: The babies should get vaccinated but it's not necessary to do that right after birth.

00:23:18: The US I think since nineteen ninety one followed a recommendation that all babies should be vaccinated Right After Birth with Hepatitis B vaccine and recently this recommendation was changed And That led To A Lot Of Discussion & A Lot of Controversy.

00:23:37: Some people might know this, but there's a committee that develops vaccine recommendations for the CDC.

00:23:46: And this committee was exchanged very recently with Trump administration taking over and the committee then changed their recommendation.

00:23:57: now it is not universal recommendation in 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.

00:24:12: And again this change has led to a lot of discussion because It is felt like its much safer to vaccinate no matter what.

00:24:22: Because actually maybe if the screening isn't as good or If the parent decided not have an idea how they can vaccinate there's a higher risk for the babies to acquire the infection at birth.

00:24:36: and if that happens, for babies.

00:24:38: There is very high chance of the infection becoming chronic over time.

00:24:43: so again an interesting discussion pretty heated discussions happened recently.

00:24:48: So to summarize this hepatitis B is old human virus.

00:24:53: in acute phase can be pretty nasty but not necessarily highly problematic.

00:25:00: The problem is really the chronic infections that lead to liver damage, liver cirrhosis and liver cancer And another problem.

00:25:10: here there are limited treatment options.

00:25:12: It's hard to get rid of the virus.

00:25:14: basically On other side we have very good vaccines which protect from infection.

00:25:21: As always, if you have comments questions suggestions please write an email to virological at podcastwerkstatt.com and thanks for listening in until next week!

00:26:10: Bye.