Raising awareness about hepatitis B and its vaccine

Transcript of seminar given by Dr Lara Marks to London School of Hygiene and Tropical Medicine, 24 May 2018

(This transcript has been edited for clarity and brevity. Click here for the audio version)

This project grew out of some work I did on monoclonal antibodies. During that study I got very interested in hepatitis B because a lot of the early biotechnology industry was founded on the back of diagnostics for hepatitis B. It also struck me that everyone talks about insulin as the first drug developed in biotechnology that put the industry on the map, but actually I would say hepatitis B has had far more impact in terms of both medicine and biotechnology.

Click here for a timeline of events related to hepatitis B.

The reason I'm particularly interested in the hepatitis B vaccine is because it really changed the technology for vaccine production in a dramatic way. Again, it's not a story that most people have heard of. I would argue that it has improved the safety and efficacy of vaccines. But at the same time, it's got a downside because it increased the cost of production. So it's an interesting story to tell. We also forget about the risks of those who were involved in the very early development of the vaccine for hepatitis B.

I think it's also important to give a seminar of this kind because Hepatitis B is one of those topics that raises all kinds of issues around stigma, and discrimination, which obviously, is an emotional issue. So again, I think it's very important to be doing this sort of a project.

A third of the world's population are infected by Hepatitis B at some point in their lives, and 5% of the world's population become long term carriers. Of those 3.5% are chronically infected. The reason I'm highlighting the chronically infected is because it is those who face the major risk of developing liver cancer, cirrhosis, and liver failure. And it's a major disease burden but I don't think many people are aware of this. Chronic hepatitis B is actually second only to tobacco as a human carcinogen. Yet, we don't talk about it. We talk about tobacco, and we talk about all kinds of other things, but we don't make the connection between chronic hepatitis B and cancer. That's again, why I think this is such an important story. It's an important story also, because today we talk a lot about cancer immunotherapies as the latest, newest way forward for cancer, and yet I would say one of the oldest therapies is the hepatitis B vaccine. It was the first vaccine against cancer. So that's why I feel it's an important issue to be raising.

We’re not very aware of hepatitis B in the UK. That’s because its prevalence is mostly in Africa, and in the western Pacific. This means we tend to ignore it and say it doesn't belong to us. It's not an important disease. But I will argue, actually, I think we need to be reconsidering. There's quite a few people who say we need to reconsider that image of hepatitis B. There is no doubt that yes, we have a lower rate of incidence of hepatitis B in this country, but it is a growing problem. And it's a hidden problem with some regions of the world affected more than others.

The major transmission point is through exposure to infected blood, and bodily fluids, especially semen and vaginal secretions. And again, something most people don't know is that hepatitis B is 50 to 100 times more infectious than HIV. And again, why are we not talking about this in the public sphere? It's extraordinary to me that we still are not talking about this. This is actually something that a number of historians have worked on. William Muraskin and Jenny Stanton have raised these issues before. But I think we need to be revisiting that as an issue today. because it's very important.

Most infections worldwide are due to perinatal transmissions at birth, that is between the mother and the child. And that predominantly happens in places like Asia and South Pacific. There's also a horizontal transmission between young children, particularly under the age of five. And that can happen very easily in the playground, a child gets a scratch and plays with another child, and it's very quickly transmitted at that point.

Sexual transmission is the one that most people know about, and most people associate it with. And that's why the disease has the stigma and the discrimination. Injectors of illicit drugs also tend to be associated with hepatitis B. Again, that's another reason why this disease, as you probably know, is linked with so called outsiders in society. There are also the scandals around contaminated blood for haemophiliacs infected with HIV, and also Hepatitis B, but that's already declined in recent years as a transmission point. But in fact, there is still significant contamination going on both import and well resource settings. So it's not something we can ignore, even though a lot of progress has been made.

Now, the thing also to note about this disease is it's a very high burden on infants. And again, that's something I feel that I haven't seen a lot of in the public discourse, which is that the greatest proportion of risk of hepatitis B is to those who are younger. Approximately 90% of infants at birth will progress to get chronic hepatitis B, and that is the infectious kind. That is the kind that really will lead to major problems in terms of cirrhosis and liver failure. And in terms of the under fives, 30% will become infected. And 2-5% of older children and infants who become infected, those who are older, obviously have less issues.

So we really need to be catching this at an early stage. We need to be thinking about how we can educate the public about this and why it is important to be immunising at birth. Obviously with the whole backlash against vaccines, this is a very important issue.

The key challenge with hepatitis B is essentially, it's a silent killer. For those of us who do get infected with Hepatitis B, a lot of us will just clear it from our system without even knowing we have any symptoms. Also those who are long term carriers will not also develop any symptoms. So it's a silent disease. We can live with it for years and years and years without even knowing that we have it. The majority of cases don't even know that they have it.

And again, the other problem is that there's not enough of an awareness campaign to get us out to go and get diagnosed for it. So there's a whole pool of us undiagnosed, untreated out in the population. It takes years for cirrhosis and liver cancer to manifest itself. And that is a major problem. So the fact that it takes years to manifest itself is very important. The lack of awareness is captured by the stories presented on the website of the Hepatitis B Foundation. It is particularly highlighted in the stories from Asian individuals. What they say is that they learned that their relatives have died of liver cancer, but they're never told that it's caused by Hepatitis B, so they don't make the link. And I wonder how many of us are told a relative has died of liver cancer and don't even think that it could have been Hepatitis B infection. So it's that public ignorance that needs to be challenged because it's a silent killer.

And immunisation is important because in 1982 WHO recommended universal vaccine of all newborns and adolescents. You can see why they recommend that in terms of the infant's issue. That really in order to catch people, we have to do it very young. In 2015 a study found that overall, 84% of children get the three doses in infancy, with 39% actually receiving the initial dose at birth. This shows It shows you that while progress has been made we still have a long way to solve the problem.

Now, definitely. immunisation has changed things. We know that chronic hepatitis B has reduced in children under five as a result of that universal vaccination, but in places like Africa, despite immunisation the disease is still a major problem where infections continue to be quite trenchant and are not going down (Liver Research Foundation).

So this is the challenge, that majority of cases are silent, people don't know about it. 50% of births of babies worldwide still do not get the vaccine at birth, fewer than 1% of all Hepatitis B infected pregnant women know they are infected (Curran). Now, given that it's the pregnant mother and transmission at birth, that's the major problem. And even in this country, the number of treated people is very low even though it has had a policy of selecting pregnant women to be tested, there is still an issue going on in this country.

The other problem with this disease is the stigma. The discrimination that people worry about is very real. People still worry that if they get tested, they won't be allowed to be employed, they won't get insurance. It's the same issue as I experienced with HIV. And yet, we're not talking about this, and it really is a problem.

There was a study done by the World Hepatitis Alliance where they actually did a survey of about 72 countries where respondents from only 5 countries (Taiwan, Sierra Leone, Roumania, Malawi, Gambia) reported that they didn't feel stigmatised or discriminated against. Obviously, the sample size of respondents was very small, but it shows that hepatitis B continues to be very highly stigmatised and concerns about discrimination is very high.

Treatment options are also still incredibly limited. That's again, something people don't realise. So really, immunisation is the only way forward.

The only thing that you can do is after immediate exposure, have an immunoglobulin treatment, but that has to be within 12 to 24 hours of exposure. So you've got to know you've got the exposure. So there's a real problem that if you're not getting tested you aren’t going to know you have it.

Babies who are born to pregnant women who have been diagnosed with hepatitis B, if they're given that immune globulin or HiBg they have a much better chance of not developing chronic hepatitis B. But the problem is that not all pregnant women get tested and the availability of HiBg is not accessible worldwide. So if the mother doesn't know she's got hepatitis B and lives in a deprived area the chances of getting access to it are slim. It also only gives you short term protection. Ultimately, you need the vaccine for long term protection.

So that's a variety of issues going on for treatment. We still do not have a drug yet for curing Hepatitis B. Now, a lot of work is going on with drugs. There are a number of drugs now in phase two trials, but we're a long way from getting them to market. A key problem is the lifecycle of the hepatitis B virus (Block).

Immunisation is really the only way forward at the moment. What I want to do is tell the story behind the hepatitis B vaccine. I want to go behind the scenes to look at the pioneers behind first of all those who discovered the virus, and then those who then endeavour to develop the diagnostic and develop the vaccine to bring it alive. One of the advantages that we have in telling this story is we have access to the papers belonging to some of these pioneers.

The story of hepatitis goes back a long way. There are clay tablets that mention the disease from the Bablylonian times. And in fact, Hippocrates writes about a kind of jaundice or hepatitis sort of disease. So we've had awareness of this disease for a very long time. And in the 17th and 19th centuries, there were a number of outbreaks of jaundice in the military and civilian populations during the wars. By 1939, we had the first suggestion that hepatitis is transmitted by an infective agent or virus in the blood. And that partly came out of the yellow fever vaccine studies that caused a problem because the troops were getting jaundice and other problems that brought the issue out into the open. It was at that point, they began to think ‘hang on what's going on here, could blood be causing this jaundice?’ But nobody really knew what it was.

Then in 1947, a British doctor worked out that there were two different kinds of hepatitis - hepatitis A and B. Later on, we realised there's another one hepatitis C. Hepatitis A is spread by faecal contamination, whereas hepatitis B is from blood. So different types of hepatitis began to be distinguished in 1947.

But it was Baruch Blumberg’s chance finding that set us on the way to taking a different direction with hepatitis B. His papers are archived in Philadelphia at the American Philosophical Society. So we can go back and look at his papers to see how he went on this journey. What is important to note about Blumberg was he was a geneticist and he didn't deliberately go out to find hepatitis. Instead he was looking for clues as to why individuals vary in disease susceptibility. This led him to start collecting blood samples from different populations around the world.

By collecting blood samples from all over the world Blumberg aimed to start doing some tests on them to see if he could find any protein variations which he believed might provide a clue about the genetic variations in disease. At that time he did not have access to DNA sequencing, so his only way of doing this was through antibody testing, looking at the clumping of cells that happen when antibodies bind to antigens in blood samples. This was done using blood from haemophiliacs. Blumberg chose this source because haemophiliacs they develop antibodies to the foreign blood as result of transfusions. By using blood from haemophiliacs Blumberg hoped he would be able to study the genetic variations.

In 1964, Blumberg detected an unusual protein antigen, or cell marker in serum taken from a New York haemophiliac patient, when he mixed it with blood he'd taken from a visiting Korean physician and then an Aborigine. At that point, he wondered 'what's triggering this reaction? What is common between the person over in Australia and a person in New York? What's the commonality here? What's going on?'. Blumberg called the new marker the ‘Australia antigen’.

Blumberg then tested other blood samples and found that in fact the antigen was also common in leukaemia patients. Being a geneticist, Blumberg wondered if it's a genetic marker for leukaemia. In hunting to understand the phenomenon Blumberg began looking at Down Syndrome patients, who were known to suffer disproportionately from leukaemia. One of the Down Syndrome patients investigated was a twelve year old boy. Initially the boy showed no signs of having the virus, but when tested several months later (20 July 1966) his liver tests showed he had chronic hepatitis. Soon after this Barbara G Werner, one of Blumberg’s technician, who was working on the isolation of the Australia antigen- tested her own serum after not feeling well - found it was positive for the antigen and had hepatitis. She made full recovery (Blumberg).

Blumberg also started talking to other people about his results. One of them was Alfred Prince. Now, he's a virologist so he approaches the problem from a very different angle. Prince questioned whether it is a genetic marker for susceptibility to leukaemia because Blumberg also found the antigen to be common in blood of people from tropical regions of Africa, Asia and Asia but less common in African Americans. Based on this Prince hypothesised that the antigen or protein might be part of the hepatitis B virus. But he doesn't quite know how it's part of the virus.

It was only in 1970, that David Dane, who's a British pathologist, showed the antigen was actually a surface particle of the hepatitis B virus. And it's at that point, it changes from being known as the Australian antigen, to being known as the hepatitis B surface antigen, or HbsAg for short. David discovered it under the microscope in some blood from patients testing positive for the antigen that Blumberg had already found.

Meanwhile, we have another episode in the story which is important. Many of you might have heard of the Willowbrook experiments which Henry Beecher first wrote about. That was an episode that took place between 1955 and 1977 and is important in terms of developing ethical guidelines for research in vulnerable subjects (Anon).

The research at Willowbrook State School was conducted by Saul Krugman who was aware of Blumberg’s research. He was also aware of Alfred Prince's research. He was called in to help Willowbrook because they noticed that a lot of the children with mental and learning difficulties were suffering from hepatitis. The school was a very crowded, poverty stricken institution, so an obvious place where Hepatitis B can spread. Krugman was called in to try and control the disease and also to work out what the natural history is of this disease. Because at this point, nobody knows. At this point, we don't even know about the hepatitis B antigen or anything like that.

So Krugman is called in to work at Willowbrook where he conducts a series of experiments. One involves feeding the virus in milkshakes to these children. It's a live virus. Today the experiment is seen as awful but the rationale that Krugman gave for doing it was that most of the children will get hepatitis B anyway, even if you don't feed it to them. For him it was what needed to be done to work out what the natural course of this disease was. Today we would say the experiment was 100% unethical. In fact, Maurice Hilleman, who I will come back to, said it was the most medically unethical experiment you can have. From our perspective, it was 100% unethical. If you look at the Nuremberg laws, it's also unethical.

But Krugman’s experiment was actually approved at the time by the state, the University, and the Federal Review Board. So he was working within the ethical parameters of what was expected at that time. So to blame him him totally is to ignore historical period he was actually working in. The problem is his experiment prompted an outcry and set a precedent that henceforth no more experiments could be carried out on children with learning difficulties, mentally disabled kids.

But the Willowbrook story means that the history of hepatitis B has a troubling episode. What we forget in the story is that the episode actually demonstrated the existence of two types of hepatitis - A and B - for the first time. It had been suggested in 1947, but we have no definitive proof until Willowbrook.

Klugman was also looking not just at the natural history of the disease, but also for treatments. He started by trying to work out if antibodies from sufferers with hepatitis B could be used as a treatment. He did this by giving the children immunoglobulin as a treatment.. And he proved that actually the children could be treated with immunoglobulin, it does seem to help. He also tested out on the children Blumberg's theory that the hepatitis B surface antigen could provide a vaccine. So while the experiments at Willowbrook is a very troubling episode, it actually provided the next step for developing hepatitis B vaccine.

We cannot hide the history of what happened at Willowbrook, but it is important to say that some good came out of it. Also it is important to emphasise that Krugman was only operating within the context of what he knew. In fact, the senator who severely criticised him in 1971 later said in 1974 that he had been wrong to criticise him because he did follow the guidelines of the day. So it's an interesting historical note (Saxon).

By 1968 a diagnostic test had been developed for hepatitis B. It emerged on the back of Blumberg’s search to establish if the antibody against the Australian antigen was protective against hepatitis B. This involved Blumberg distributing reagents for the antigen to laboratories around the world, including to blood banks. One of those sent the reagent was Philadelphia General Hospital who noted that when a donor’s sample tested positive it could be used to forestall use of that blood. Another was Albert Prince at New York Blood Center who in 1968 persuaded his director to start screening all of the bank’s blood for the antigen.

By 1971, New York State passed legislation that now all donors had to be tested for hepatitis B and it did take long before it was developed commercially by Abbott. Considering the antigen was first found in 1968, that was quite a quick leap to commercialise research originally found at the bench.

It took a lot longer though to get a vaccine. Merck was the first company that manufactured the first vaccine, which was put on the market in 1982. It was the result of the work of Mauriuce Hilleman. Hilleman was known for being quite an aggressive fellow within Merck, but he got things done. At the same time, he hid his light under a bushel and didn't make a big thing of what he'd actually achieved (Offit). The very fact that he developed 9 out of the 14 childhood vaccines most people in this room would never have heard of him on is quite something. But because he was in industry, he tends to be shy and hidden away, he's never been given a Nobel Prize. Whereas Baruch Blumberg got given the Prize in 1976.

Anyway, Hilleman started getting interested in hepatitis B back in 1957, when he was at the Walter Reed Institute. The same year he joined Merck and at that point, he launched a project to look into Hepatitis B, but he really struggled at that point to grow the virus in live cells. In fact, you can't grow the virus in the laboratory at all. It's very, very difficult. But when Hilleman heard the news from Alfred Prince, in 1968, he began in earnest to go for a vaccine for Hepatitis B.

Merck actually has a very interesting history in terms of ethical practice. As early as World War Two, it found out that Japan had a major problem with a supply of antibiotics and actually gave equipment to Japan's industry to set up its streptomycin production. So it has a long history of giving developing countries the technology, and Hilleman was at the forefront of a lot of this stuff. I'll come back to that later.

Hilleman launched the hepatitis B vaccine project [in 1968] on the back of some microlitres of fluid that Alfred Prince supplied him. Prince had shown, through his [blood bank] test, that a tiny, tiny sample of antigen could give protection against Hepatitis B. When he learnt this Hilleman thought ‘Hang on a minute, if you can do it with such a tiny sample of this antigen, then we can actually develop a vaccine that's economically feasible’ because he's interested in the economics of doing this obviously.

Meanwhile, in 1968 Blumberg also took out a patent with Fox Chase Centre, where he was based, to make a vaccine using the hepatitis B surface antigen. In part the patent reflected the pressure that academics were now under from the Federal government to show applications from basic research. The application was submitted in October 1969 and granted in 1972 (Blumberg).

In fact a number of different people were thinking along the same lines, including Prince and Hillman. What is interesting about the FCC patent is that they offered it to Merck, but according to Hilleman it had a major problem. First of all the patent proposed to grow the virus in monkey kidney cells, but the virus will not grow in any live cells. So there were all kinds of problems with that patent.

Merck offered to licence the Blumberg patent in 1971, with $5 million upfront payment and a team of 10 people. But the problem was that the FCC was not willing to give exclusive rights to it. From Merck's point of view, that was a real issue because they were taking on a big gamble. A lot of vaccine companies had gone out of business at this point, because in the 1960s, there was a contamination problem with vaccines and a lot of companies withdrew from the market because of fears of litigation. So for Merck to develop the hepatitis B vaccine was quite a big gamble. In the end Merck decided to go it alone because it couldn’t get exclusive rights to the FCC patent.

So Hilleman carried on and he managed to purify his own surface antigen in 1971 to start working on the vaccine. And eventually in 1975, Merck finally licenced the patent despite the limitations. According to Hilleman this was because he was concerned that the Blumberg patent would stand in the way of Merk’s vaccine. At that point they only gained rights to it within the domestic market, not foreign rights.

Even when they licenced it in 1975, there was a problem with the FCC administrators in that they tried to get Merck to agree that Blumberg would be the director of the programme. And according to Offit’s book about Hilleman say he thought the idea was crazy Offit. Eventually, the centre actually relented and abandoned their idea of having Blumberg direct the programme. What I find fascinating is the disjunction between academia and industry in this case where the translation between the two worlds doesn't kind of come together. And it's very early days of biotechnology.

Anyway, by 1971 Hilleman had started to work on the vaccine in earnest with the sample from Prince and he purified the antigen.To do this he faced a number of technical obstacles. The key one was where to get blood that contained the antigen. Where are you going to find that antigen in the best place? He realised one good source might be drug addicts and male homosexuals, that sort of person. To obtain it he went to the stairwells, doorways and fire escapes in the Bowery neighbourhood of New York to persuade the people living there to give him their blood source to source the antigen. Again, this story is not well known. We assume it was easy, but it was not.

Then Hilleman also faces the danger of the infectious nature of the hepatitis B virus. Now remember, hepatitis B is more infectious than HIV. He is taking an enormous risk personally, because it is highly infectious. It is so infectious in fact that one of Blumberg laboratory technicians working with the antigen, herself got Hepatitis B when working with it. So it's not an unknown risk. He knows it's a risk.

So Hilleman was collecting all this blood and didn't know that HIV was also emerging. Now he has to find a way of making this pure and 'deadlier than dead' as he puts it. Initially he tried to do this by heating the antigen. That's actually what Krugman had tried to do in his experiments at Willowbrook, but it doesn't really get rid of the virus. Eventually, Hilleman settled on a chemical process using pepsin, urea, and formaldehyde. What is interesting is that Hilleman at this stage doesn't know about HIV, but he does know about prion disease which is just beginning to rear its head. So he wants to make sure that whatever he produces hasn't got any vulnerability to prion disease. That's why he goes the extra step to get to that safety level and why he eventually developed the three step chemical process Offit.

Now, who at this point is going to take a drug that's been made out of blood sample from illicit drug users and gay homosexuals? Who's going to take it at that point? Virtually nobody. Hilleman really struggles to get the FDA permission to test the product, for obvious reasons. He struggles in the company to get anyone to say 'Yes, I'll take it as the first guinea pig'.

Eventually, being the kind of character that he is, he arranges a meeting with all the middle level executives at Merck and says, 'Look, you're in, I'm not going to take no for an answer. I want you to sign this informed consent, and you're going to have it and I'll be the first one to take it.' And he takes a photograph of him taking it. But he insists that laboratory technicians shouldn't take it, the reason being because of the infectiousness of the whole thing. The risk was they could then contaminate the whole of the company. What is interesting is that Hilleman himself is willing to take it at this point. He gets the injection done and coerces all the other executives to test the vaccine (Offit).

Then what happens is Hilleman gets in touch with Wolf Szmuness, a Polish born epidemiologist working at the New York Blood Centre. He'd spent 10 years in a labour camp in Siberia before he came to New York. Hilleman came to know about Szmuness because he was also working with Prince. Szmuness had become familiar with the epidemiology of hepatitis B after his wife contracted the disease. He had worked out that the homosexual community were the most likely to have hepatitis B using the diagnostic that Prince had developed. And as a result of that Hilleman suggests and that they launch clinical trials for the vaccine with the gay community. These were conducted between 1978 and 1980. This established that the men injected with the vaccine were 75% less likely to get hepatitis B than those who didn’t get it.

Eventually the vaccine was approved in 1981. It was the second hepatitis B vaccine on the market. The first (Hevac B) was developed by a research group at the Pasteur Institute with Merieux. Because both of the vaccines are plasma based there is very low uptake because by now AIDS is beginning to hit the headlines. Even healthcare workers who are the targeted groups for the vaccine, including nurses, refused to take it.

So at this point it looks like Merck is actually going to make a real loss on the vaccine, and consider ditching the whole project. At that point, Hellman's on the verge of retirement. But then a new person, Roy Vagelos, comes in and decides that the way forward is to re-engineer the vaccine. The aim is to switch from using antigens isolated from plasma to antigens made with the help of genetic engineering. And this is what rescues the project.

In 1986 the first genetically engineered hepatitis B vaccine was approved. And this marks a new era, because essentially, what's happened is you've gone from vaccines being made in the past with the live virus and attenuated virus to now being made with a sub particle of a virus. So it's a very different kind of vaccine. But the biggest step I think, is with the plasma vaccine, because it was a short hop from that to the genetically engineered vaccine.

I just want to sum up at this point where we've got to. Essentially when the hepatitis B diagnostic was developed for the first time it provided a means for testing for asymptomatic carriers. That provided an insight that actually a lot of the population was carrying this virus, which we didn't even know about. So the diagnostic was very important for establishing hepatitis B to be an issue, and something to be concerned with. It also provided an important platform for the early biotechnology companies who built their business on the back of providing such tests.

The hepatitis B vaccine were also obviously key breakthroughs because it was the first time a subunit of the virus was being used for immunisation instead of the whole virus. In addition it's the first genetically engineered vaccine, and it's the first vaccine for cancer. But the vaccine is very costly. So while it raised the safety and efficacy of vaccines, it raised the cost of vaccines which caused a lot of outrage as well at the time.

One person who addressed the issue of cost was Alfred Prince. Concerned that the one produced by Merck and elsewhere was going to be far too costly, he found a way of developing the plasma vaccine using a less expensive purification step. This enabled him to develop a vaccine that's a 10th of the dose required by the vaccine. He licenced that to a South Korean company and to institutes in China and Burma. Prince called the vaccine 'the poor man's vaccine'. That enabled 75 million doses of the vaccine to go around in Asia, which is a region where hepatitis B is a major problem.

A lot of people at the time were aghast at the price that Merck wanted to charge for its hepatitis B vaccine. But the cost of the vaccine went down radically after that. In part this reflected the competition that emerged after Merck’s first got its vaccine approved. By 1992 Merck had also helped build a manufacturing site for making the recombinant Hepatitis B vaccine which was its way of helping to get the vaccine to a country where the disease was especially acute.


My work on hepatitis B was greatly helped by the support of Paul Offit at the Children's Hospital in Philadelphia (CHOP), and Donald Mitchell, who's a documentary filmmaker. Both of them have worked on the life story of Maurice Hilleman, who developed nine out of the 14 childhood vaccines that are routinely used today. Offit also generously supported my undertaking a research trip to Philadelphia to examine the papers of Baruch Blumberg that are housed at the American Philosophical Society's archives. I am also grateful to Charlotte Moser at CHOP and Chari Cohen at the Hepatitis B Foundation for the additional support and materials they provided for the project.


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