When was hbv discovered

Chronic infection is responsible for most HBV-related morbidity and mortality, including chronic hepatitis, cirrhosis, liver failure, and HCC. An estimated million persons worldwide are living with HBV infection. HBV infection is an established cause of acute and chronic hepatitis and cirrhosis. The frequency of infection and patterns of transmission vary in different parts of the world.

In these high-prevalence areas, most infections are acquired at birth or during early childhood when the risk of developing chronic infections is greatest.

In these areas, because most infections are asymptomatic, very little acute disease related to HBV occurs, but rates of chronic liver disease and liver cancer among adults are very high. Infection occurs primarily during adulthood, and only 0. Diagnosis is based on clinical, laboratory, and epidemiologic findings. HBV infection cannot be differentiated based on clinical symptoms alone, and definitive diagnosis depends on the results of serologic testing.

Serologic markers of HBV infection vary depending on whether the infection is acute or chronic. The presence of HBsAg indicates that a person is infectious, regardless of whether the infection is acute or chronic. Transient HBsAg positivity can occur up to 18 days following vaccination up to 52 days among hemodialysis patients and is clinically insignificant. Anti-HBs is a protective, neutralizing antibody. The presence of anti-HBs following acute HBV infection generally indicates recovery and immunity against reinfection.

Anti-HBc generally persists for life. Persons who are HBsAg-negative and anti-HBc-positive can experience reactivation of infection during chemotherapy or immunosuppressive therapy, with reappearance of HBsAg. IgM anti-HBc appears in persons with acute disease about the time of illness onset and indicates recent infection with HBV.

IgM anti-HBc is generally detectable 4 to 6 months after onset of illness and is the best serologic marker of acute HBV infection. HBeAg is a marker that is associated with a high number of infective HBV particles in the serum and a higher risk of infectivity. Anti-HBe correlates with a reduction of replicating virus and lower infectivity, although reversion to HBeAg positivity can occur. There is no specific therapy for acute HBV infection. Treatment is supportive. These persons are at high risk for liver-related morbidity.

Maternal therapy is generally discontinued at birth to 3 months postpartum. Persons with acute or chronic HBV infections should prevent their blood and other potentially infective body fluids from contacting other persons. They should not donate blood or share toothbrushes or razors with household members. In health care settings, patients with HBV infection should be managed with standard precautions.

HBV infection occurs worldwide. The frequency of infection varies in different parts of the world but is more common in some countries in Asia, Africa, South America, and the Caribbean. HBV infection affects humans. Additionally, some primates chimpanzee, gorilla, orangutan, gibbon in Africa and Southeast Asia are infected with HBV. The highest concentrations of virus are in blood and serous fluids; lower titers are found in other fluids, such as saliva, tears, urine, and semen.

Semen is a vehicle for sexual transmission and saliva can be a vehicle of transmission through bites; other types of exposure e. HBsAg is also found in other body fluids e. However, most body fluids are not efficient vehicles of transmission unless they contain blood because they contain low quantities of infectious HBV. In the United States, the most important routes of transmission are injection-drug use, perinatal, and sexual contact with an infected person. Fecal-oral transmission does not appear to occur.

However, transmission occurs among men who have sex with men MSM , possibly via contamination from asymptomatic rectal mucosal lesions. In the s and s, outbreaks of hepatitis B occurred in long-term care facilities e.

Transmission occurs in households from persons who have immigrated from endemic areas and who have chronic HBV infection. Persons with either acute or chronic HBV infection should be considered infectious any time that HBsAg is present in the blood. When symptoms are present in persons with acute HBV infection, HBsAg can be found in blood and body fluids for 1 to 2 months before and after the onset of symptoms.

Direct, percutaneous inoculation of HBV by needles during injection-drug use is an important mode of transmission.

Breaks in the skin without overt needle puncture, such as fresh, cutaneous scratches, abrasions, burns, or other lesions, may also serve as routes for entry. Exposures such as transfusion of blood or blood products, hemodialysis, use of meters and lancets for blood glucose monitoring, insulin pens, and needle-stick or other sharps injuries sustained by health care personnel HCP have all resulted in HBV transmission.

Outbreaks have been reported among patients in dialysis centers in many countries through failure to adhere to recommended infection control practices. Past outbreaks have been traced to tattoo parlors, acupuncturists, and barbers. Hepatitis B became nationally notifiable as a distinct entity during the s after serologic tests to differentiate different types of hepatitis became widely available. In , a total of 3, cases of acute hepatitis B were reported to CDC, for an overall incidence rate of 1.

After adjusting for under-ascertainment and under-reporting, an estimated 21, acute hepatitis B cases occurred in Incidence is greatest for persons age 40 through 49 years 2. Generally, the highest risk for HBV infection is associated with lifestyles, occupations, or environments in which contact with blood from infected persons is frequent.

Chronic HBV infection has been identified in 3. An estimated , to 2. Most persons in the United States with chronic HBV infection have immigrated from endemic countries in the world. Therefore, clinicians and public health workers should screen all persons born in countries with high endemicity of HBV virus.

Among children born during —, This was an increase from By age 24 months, In , HepB vaccination is the mainstay of hepatitis B prevention efforts. A comprehensive strategy to eliminate HBV transmission includes universal vaccination of infants beginning at birth, routine vaccination of previously unvaccinated children less than age 19 years, and vaccination of adults at risk for HBV infection, including those requesting protection from HBV without acknowledgement of a specific risk factor.

It also includes universal testing of pregnant women for HBsAg to identify newborns who require immunoprophylaxis for prevention of perinatal infection and to pregnant women who can benefit from antiviral therapy to reduce perinatal transmission. A second recombinant vaccine, Engerix-B, was licensed in Recombivax HB and Engerix-B are available in both pediatric and adult formulations.

A third recombinant vaccine with a novel adjuvant, Heplisav-B, was licensed in for use in adults age 18 years or older. HBV infection cannot result from use of the recombinant vaccine since no potentially infectious viral DNA or complete viral particles are produced in the recombinant system. There are two combination vaccines that contain HepB vaccine. HepA-HepB Twinrix is licensed for persons age 18 years or older. Recombinant HepB vaccine is produced by inserting a plasmid containing the gene for HBsAg into yeast Saccharomyces cerevisiae or Hansenula polymorpha ; HepB vaccines contain yeast protein.

HepB vaccines are administered by intramuscular injection. Each dose of HepB vaccine contains aluminum as an adjuvant or, for Heplisav-B, a small synthetic immunostimulatory oligodeoxynucleotide adjuvant.

HepB vaccines contain no preservative. Presentations of HepB vaccines contain latex rubber. Specific ingredients in combination vaccines containing HepB vaccine differ.

Recombivax HB and Engerix-B are available in both pediatric and adult formulations and are typically administered as a 3-dose series on a 0, 1, 6 month schedule. Although their antigen content differs, the two vaccines are interchangeable except for a 2-dose series for adolescents age 11 through 15 years, for which only Recombivax HB is approved. Heplisav-B is administered as a 2-dose series on a 0, 1 month schedule and is approved for persons age 18 years or older.

HepB vaccination is recommended for all medically stable infants weighing at least 2, grams within 24 hours of birth. Only single-component vaccine should be used for the birth dose and doses administered before age 6 weeks. The usual schedule is 0, 1 through 2, and 6 through 18 months. For infants weighing less than 2, grams, the birth dose should not be counted as part of the vaccine series because of potentially reduced immunogenicity; 3 additional doses of vaccine for a total of 4 doses should be administered beginning when the infant reaches age 1 month.

Infants whose mothers are HBsAg-positive should receive the last dose by age 6 months but not before age 24 weeks. However, after a long anergic phase, immune defense may emerge and lead to selection of escape mutants.

As soon as cellular immune responses against HBcAg appear, HBeAg has lost its immunomodulatory function and is a useless side product. HBeAg-negative variants with enhanced HBcAg expression and viral replication usually take over and partially compensate for the loss of destroyed HBV infected cells. If so, the course may be benign although expression of HBsAg may still occur Figure 6. Finally, the immune control will even suppress HBsAg to undetectable levels in many chronic carriers.

On the opposite, co-existence of cytotoxic immune responses with ongoing strong HBV DNA replication results in inflammatory disease, progressive fibrosis of the liver and potentially in hepatocellular carcinoma. In this phase of infection independent of a prior acute, occult or chronic course the variability of the HBV genome is very high and leads to many defective forms which by themselves may favor increased pathogenicity.

Hot spots of variability are the preC and core gene, the HBs antigen loop, and parts of preS. There are several mechanisms of how the preC sequence can be inactivated by a single point mutation.

Most common is the introduction of a stop codon instead of a trp codon at the end of the preC sequence, thus preventing translation of the HBeAg precursor. The replication via reverse transcription see below and the very large number of HBV genomes expressed up to 10 13 per patient day facilitate mutations of every base at least two times per day.

Since the immune selection criteria are the same in occult HBV infection, virus strains reactivated under immunodeficiency are often highly mutated, e. These highly mutated variants are usually not transmitted because viremia is in these cases much lower than in early or immune tolerant phases.

If these variants are, however, transmitted they induce either inapparent infection because of reduced fitness or very severe and even fatal hepatitis B because these variants lack the immunomodulatory potential of wild type HBV [ 47 ]. The exact topology and three-dimensional shape of the loop are unknown. One circle corresponds to one amino acid in the single letter code of the normal wildtype HBV, each square to a mutation.

The boxed-in part is named a-determinant and is believed to be immunodominant, but immune escape induced mutations occurred in the entire HBsAg loop. Yellow shaded squares cause the loss of an immunodominant HBsAg subtype determinant. This variant replicated in a patient receiving lymphoma therapy. The patient was anti-HBc and anti-HBs positive before the immunosuppressive lymphoma therapy and developed severe acute hepatitis B after end of the therapy due to immunopathogenesis against the variant which had become abundant under immunosuppression.

The serum from the acute reactivated hepatitis B phase had a high virus load, but was HBsAg negative in all assays. Blumberg [ 1 ], page — and independently Wolf Szmuness New York Blood Center [ 65 ] noted already in the s that chronic HBV infection was associated with an increased incidence of hepatocellular carcinoma HCC.

In areas with very high prevalence of chronic hepatitis B, HCC was the most frequent form of cancer. Palmer Beasley found in a large prospective study with 22, middle-aged men in Taiwan an HCC incidence of in , man-years among the HBsAg carriers but only 5 in , for HBsAg negative persons.

Similar situations are found in other regions highly endemic for HBV. HCC enhancing cofactors are co-infection with hepatitis C virus and exposure to aflatoxin.

While the immunopathogenesis of HBV is relatively well understood, the mechanisms of oncogenicity are not. Shortly thereafter the team of William Rutter identified several fragments of HBV DNA integrated at several chromosomal sites in that cell line [ 68 ].

Insertions of replication competent HBV genomes were never observed. These proteins and the HBV X protein are transcriptional transactivators that may activate deregulated cell proliferation and tumor formation [ 70 ]. The role of the X protein was not understood for a long time, because it was not essential for HBV replication in permanent cell cultures. As shown by Ulrike Protzer Munich and Massimo Levrero Rome and their coworkers, it is however an essential transcription activator for expression of the HBV proteins in differentiated hepatocytes [ 71 ].

Besides these directly oncogenic products, insertion of HBV DNA promoters and enhancers may activate cellular oncogenes like myc see below or disrupt negative regulators of proliferation. In some cases fusion proteins of cellular growth factors and HBV proteins were even observed [ 72 ]. However, there is no typical insertion site or conserved altered cellular factor in human HCC. In fact, integration seems to be a normal event during chronic HBV-infection and leads to clonal growth of seemingly normal hepatocytes, a small proportion of which may finally turn to frank malignancy [ 73 ].

According to clinico-epidemiological studies the main driving force for development of HCC seems to be continuous HBV replication, particularly in HBeAg negative patients. Successful antiviral therapy can stop chronic hepatitis B and the progression of liver cirrhosis but a slightly elevated risk of HCC remains.

Consequently, Jesse Summers proposed the definition of a new virus species and a new virus family named hepadnaviridae according to the organ tropism hepa for liver and the nature of the nucleic acid. Both animals have proven very useful in the study of hepadnaviruses. HCC was also known to occur in Peking ducks in China. Chinese researchers found virus-like particles in duck sera and sent serum samples to Blumberg ref.

DHBV was also hepatotropic, caused very high viremia without obvious disease, overproduced the viral surface protein and had a similar morphology and genomic organization [ 78 ].

The advantage of the duck virus was that it could be propagated in embryonated eggs and in readily available primary duck hepatocyte cultures. There were, however, also distinct differences to the mammalian hepadnaviruses. The surface and core proteins had a different structure, there was seemingly no HBx protein and the overall sequence homology was low. The phylogenetic relationships suggested that the genera orthohepadnavirus of mammalians and avihepadnavirus of birds could be distinguished.

The group of Hans Will Hamburg, Germany identified further avian hepadnaviruses in various species of water fowl such as herons, cranes and storks. Studies of these viruses confirmed the usually narrow host range of hepadnaviruses and the conservation of the seemingly non-essential HBV proteins HBx and HBeAg [ 79 ]. In contrast to orthohepadnaviruses, the avihepadnaviruses do not cause HCC but they may cause hepatitis when infecting adult birds.

The duck HCC in China is caused by chemical carcinogens. Neither ortho- nor avi-hepadnaviruses have economic importance as animal pathogens. The animal viruses were, however essential for the progress in our understanding of HBV infection. DHBV was crucial for the elucidation of the hepadnaviral replication cycle and the WHV-infected woodchuck has become an important animal model for pathogenicity and therapy of human HBV infections.

In contrast to polyoma- or papillomaviruses the circular DNA was not covalently closed but had a nick in one strand and a variable gap in the other [ 19 ]. All hepadnavirus species have this genome structure Figure 3. The mechanism by which these structures were generated appeared enigmatic. With this discovery, it became evident that the replication of the hepadnaviridae was in some steps similar to that of the retroviridae.

After specific attachment to differentiated hepatocytes and endocytosis see below , the viral envelope is removed, the core particle is actively transported to the nuclear pore and within the nuclear pore the viral DNA is released to the nucleoplasm [ 83 ]. There it is converted to covalently closed circular ccc DNA by cellular repair factors and remains an episomal minichromosome.

The core protein subunits assemble spontaneously to immature core particles which with the help of cellular chaperones encapsidate their own mRNA and the viral DNA polymerase. Hepadnaviruses use a hydroxyl group of a tyrosine residue in their DNA polymerase for priming of their first minus DNA strand.

As shown by Volker Bruss, only mature core particles which contain a complete DNA minus strand and a partial plus strand interact with the preS domain of the membrane associated viral surface proteins and acquire the viral envelope [ 84 ]. Interestingly, the preS domain is initially in the cytosol, but later about half of these preS domains are translocated to the virus surface where they can function as attachment site [ 85 ].

Complete HBV was recently shown by Reinhild Prange to be exported via multivesicular bodies like many other enveloped viruses [ 86 ]. The very interesting details of this entire process shall not be presented here and are still under investigation in many laboratories. Life cycle of HBV. These are transported to the nucleus and arrested at the nuclear pore complex where the HBV genome is released to the nucleus. In interaction with transcription factors not shown , the ccc DNA is transcribed to the pregenomic and subgenomic mRNAs.

The mRNAs are transported, mainly without splicing, to the cytoplasm. The two subgenomic mRNAs for the three HBs proteins are translated at the endoplasmic reticulum, assemble to subviral HBsAg particles and are secreted via the Golgi apparatus. In parallel, the pregenomic mRNA is translated in the cytosol to the HBV core protein and the viral polymerase, whereby the three components assemble to the immature core particle.

The mature core particles can migrate again to the nuclear pore complex or are enveloped by the surface proteins and secreted via the multivesicular bodies MVB. This replication cycle is very different from that of the retroviridae. Retrovirus particles contain their genome as two copies of RNA and start reverse transcription only after entry into the target cell. The completed double stranded DNA is linear and needs to be integrated into the host genome before synthesis of the pregenomic RNA.

The progeny virus is assembled and released at the plasma membrane as immature particles which require cleavage of the viral gag proteins by the viral protease to become infectious. But this and similar cell lines did not facilitate the search for the factors mediating efficient attachment and entry of HBV.

Many publications claimed to have detected functional receptors for HBV, but the search for them remained unsuccessful for decades. Only recently, Camille Sureau Tours, France could prove by a meticulous mutational analysis that the previously by J.

Allain identified heparansulfate proteoglycan binding capacity of the small HBsAg protein [ 88 ] is essential but not sufficient for infectivity and that the binding sites coincide with neutralizing epitopes of HBsAg [ 89 ]. However, this receptor cannot explain the peculiar species specificity of HBV because it is present in livers of all mammalians. The species-specificity of attachment to an uptake mediating receptor rests in the amino terminal preS1 domain of the large viral surface protein.

It remained unrecognized for many years but was finally identified by the author together with Klaus Heermann in [ 90 ]. Soon after in , Alfred Neurath New York characterized the preS1 domain as potential attachment site of HBV to hepatic cells [ 91 ] but it took another 26 years to identify a functional cellular receptor for this attachment site.

Don Ganem San Francisco showed in that the species-specificity of HBV-like viruses in birds was mediated by the preS domains of their large surface proteins [ 92 ] and identified later an avian receptor for this attachment protein [ 93 ].

The studies from Dieter Glebe on the preS1-dependent infection of Tupaia hepatocytes [ 94 ] inspired Li Wenhui and colleagues Beijing, China to start a genome-wide search for liver-specific surface molecules common to humans and Tupaias. Very recently, they identified the liver-specific sodium-dependent taurocholate cotransporting polypeptide NTCP as an essential receptor for the preS1 attachment site of HBV and could prove its specificity by the fact that this receptor from Tupaias and man a susceptible primate species but not from non-susceptible primates mediates HBV infectivity [ 95 ].

The receptor is only expressed in the intact liver, disappears within a few days in primary hepatocyte cultures and is absent in undifferentiated hepatoma cell cultures. In the 20th century, therapy of viral infections lagged far behind the impressive antibiotic therapies against pathogenic bacteria.

The in vitro cultivation of viruses was and is much more difficult than cultivation of most bacteria. An alternative approach was the adoption of natural antiviral defense factors for therapy. In Isaacs and Lindenmann reported that the presence of inactivated influenza virus in an infected cell induced production of a secreted cellular factor, called interferon, which protected neighboring cells against infection not only by influenza virus but many other viruses as well.

The early hopes to use interferon as a universal drug against all or at least many viruses did not materialize in clinical practice. But in , William Robinson and Thomas Merigan Stanford, California reported that interferon alpha at that time produced in human leukocyte cultures and very expensive suppressed HBV replication and cured some patients suffering from chronic hepatitis B [ 96 ].

Further clinical studies showed that only a minority of the patients could be cured by this therapy while the majority showed a relapse after the end of therapy or even viral breakthrough under therapy. After 36 years of experience, interferon alpha meanwhile recombinant and in polyethylene glycol-conjugated form still has its place in HBV therapy, but the patients need to be carefully selected, because interferon has many severe side effects and contra-indications, and only a minority will show a sustained response.

Interferon suppresses HBV replication but the exact mechanism is not known and today more dependable chemical antivirals with less side effects are available. Thus, patients with active inflammation, i. The cccDNA form of the HBV genome is probably as stable as the host chromosome and can currently not be attacked by any available drug. However, interferon may induce innate defense mechanisms e. Long-term follow-up has confirmed that patients with a sustained viral response regain a normal life expectancy [ 97 ].

Since best results are obtained with 48 weeks of interferon therapy, it is necessary to recognize as early as possible those patients who will not develop a sustained response. The decrease of the HBV DNA level in plasma is a necessary condition but not suitable as predictor for long-term success.

The usefulness of monitoring the HBsAg concentration for the early prognosis of acute hepatitis B was reported by the author already in the s [ 98 ], but these findings were ignored until recently. In the last years many clinical studies showed that the decrease of the HBsAg level indicates in most cases indirectly the decreasing amount of intrahepatic cccDNA due to immune elimination of infected cells.

If the interferon therapy leads to sustained response, a significant decrease of HBsAg is detectable within 12 weeks. An important point to consider is that not all HBV genotypes are equally susceptible to this therapy: genotype A and B are more responsive than C or D [ 97 ].

Although viruses become parts of their host cell during their life cycle, basic research on their replication mechanisms identified various virus-specific biochemical pathways that could be targets of pharmaceutical intervention. The nucleoside analogue acyclovir against herpes simplex and varicella zoster virus was the first example of a successful nontoxic antiviral drug taylored to the biochemistry of its viral target.

Merigan and Robinson turned in the late s to then available inhibitors of DNA polymerases when they realised that interferon alone would not help the majority of patients.

With the advent of HIV in the developed countries, research on antiviral therapy got a strong boost leading to the first drug azidothymidine in which inhibited more specifically the reverse transcriptase of HIV, but it was unfortunately inactive against HBV.

After licensing lamivudine for therapy of HIV it was noted by Yves Benhamou and colleagues that patients who were co-infected with HBV lost transiently their HB viremia and showed clinical improvement of hepatitis [ ]. The first successful short term clinical trial with lamivudine in HBV monoinfected patients was published in by Jules Dienstag [ ]. Although it appears logical, it is not self-evident that RT inhibitors lead to rapid improvement of HBV associated inflammatory liver disease because they do not inhibit HBV antigen expression.

As pointed out above, the current view of HBV induced immune pathogenesis would suggest that the RT inhibitors act slowly by preventing infection of new cells while the still ongoing antigen expression of viral antigen in the infected cells would lead to their immune recognition and elimination. For unknown reasons, the suppressed DNA replication leads directly to a decrease of cell damage with enhanced survival of the already infected cells.

Lamivudine was quite effective and well tolerated, but did not turn out to be the solution to the problem. Unfortunately, resistance soon developed in cases with high replication. Due to the overlapping polymerase and HBsAg reading frame some of the resistance mutations also led to a mutated HBsAg sequence with reduced binding to diagnostic or protective anti-HBs antibodies [ ]. With HIV, the resistance problem was rapidly countered by introduction of a triple combination therapy, but for HBV this concept was not immediately feasible.

Newer drugs had to be developed. Today, lamivudine is no longer justified as a first line drug against HBV due to the resistance problem and this has to be considered when planning HIV therapy in HBV-coinfected patients. An additional problem is that lamivudine resistant strains are able to acquire resistance to the very efficient drug entecavir which is not prone to resistance if used as first drug.

For short term treatment, e. The acyclic nucleotide analog adefovir was described as early as by DeClercq as an inhibitor of various retroviruses in vitro, but it took until to receive approval for the therapy of lamivudine resistant HBV infections. Unfortunately, its activity on HBV was relatively low and completely absent in about one quarter of the patients. In the meantime Adefovir should be completely replaced by newer drugs such as tenofovir.

This structurally very similar drug was approved in as HIV drug and was soon shown to be superior to adefovir for HBV as well [ ], but it was only approved for HBV in Today it is the drug of choice for chronic hepatitis B, because it is well tolerated and resistance has never been observed [ 97 ]. However, both adefovir and tenofovir have nephrotoxicity as side effect. The guanosine analog entecavir was originally developed against herpes simplex virus but was not adequately effective. In , a first proof of principle short term study showed its efficacy in patients with lamivudine resistant chronic hepatitis B.

Official approval followed in after large clinical studies proved the superiority of entecavir over lamivudine. In rare cases of suboptimal tenofovir efficacy a combination with entecavir may be useful [ 97 ]. Several other RT inhibitors have been licensed but they have not reached widespread application. Telbivudin has a significant resistance problem, but it has been successfully used to suppress high viremia in HBV infected pregnant women before delivery, thus protecting the newborn from an excessive viral load [ ].

Together with tenofovir it is the only NIH class B drug for treatment during pregnancy. In contrast to HIV, combination therapies, e. The competitive attachment inhibitor myrcludex [ ], a preS1-lipopeptide developed by Stephan Urban Heidelberg is undergoing clinical trials and may be particularly useful against hepatitis delta virus which has adopted the HBV envelope.

Therapeutic vaccination with HBsAg in combination with RT inhibitors or immunostimulatory substances has not been successful in clinical studies. Immunotherapy with various HBV-derived antigens or HBV antigen-expressing DNA in combination with antiviral therapy has been undertaken in various experimental systems, e.

Targeted destruction or silencing of the hepadnaviral cccDNA would be the ultimate therapy, but is still science fiction. In view of the still unsatisfactory therapy of HBV infections prevention has highest priority. Besides obeying strict hygiene with all invasive procedures and a considerate life style, vaccination is the most important way to prevent hepatitis B diseases.

In the early s, R. However, the passively administered anti-HBs fades with a half-life of 22 days and is, if given alone, only an interim solution. Saul Krugman was the first to report on a so-called vaccination against hepatitis B in He diluted Australia antigen positive serum from his previous human experiments , boiled it briefly to kill the virus and injected this material to mentally handicapped children as a kind of vaccine. After two injections, he injected infectious HBV containing serum as challenge to the children and found incomplete, but statistically significant protection [ ].

Philippe Maupas and Alain Goudeau went one step further and used purified formalin-treated purified HBsAg as vaccine later produced by Institute Pasteur, Paris for staff and patients of hemodialysis wards who at that time had a very high risk of HBV infection. In they reported good protection rates particularly in the staff [ ] but they had only a historical control group and, thus, not all observers acknowledged these findings as convincing.

A state of the art field study was published by Wolf Szmuness in using the plasma-derived vaccine produced at MSD. Szmuness had recognized that male homosexuals in New York had an extremely high incidence of HBV infections and performed a large placebo-controlled study with truly voluntary participants [ ].

After this study, the recommendation to vaccinate all kinds of high risk groups, including medical staff, was adopted in many countries.

However, the newly developed vaccine was not well accepted. At that time the agent of AIDS was not yet identified and it could not be guaranteed that this unknown agent would be inactivated by the treatments sufficient for HBV infectivity.

Furthermore many unspecific fears existed about oncogenicity or autoimmunity caused by the vaccine. The main disadvantage was, however, that with increasing acceptance and success, this type of vaccine would have dried out its own resource, i. With the cloning of the HBV genome and the identification of the HBs gene in a new era of vaccine production was opened, although the beginning was not straightforward.

HBsAg could not be expressed in E. The open reading frame for HBsAg was identified with the aid of the partial amino acid sequence of the major protein of the plasma-derived HBsAg which had been determined in by Darrell Petersen and Girish Vyas San Francisco. They found that the major HBsAg protein existed in an unglycosylated and a single N-glycosylated form with ca.

The larger proteins found in purified HBsAg see Figure 2 could be removed by treatment with proteases seemingly without loss of HBs antigenicity. The vaccine from MSD was in fact treated with pepsin and did not contain these larger proteins. Expression of glycosylated and secreted HBsAg particles in mammalian host cells was possible but the yield was relatively low and mammalian cell culture is relatively expensive.

Rapid immunization schemes for urgent cases e. With the advent of an inexpensive, but highly protective and well tolerated hepatitis B vaccine, WHO recommended in to implement universal childhood vaccination worldwide and meanwhile ca.

Taiwan was the first country to begin with universal childhood vaccination in At that time, the rate of perinatal transmission was extremely high leading to a nation-wide HBsAg carrier rate of ca. Twenty years later only 1. Although HCC is mainly a disease of advancing years, the impact of the vaccination quickly became apparent in children and adolescents because its incidence dropped significantly from 0.

Thus, the hepatitis B vaccine was the first successful vaccine against a specific form of cancer [ ]. Similar observations were reported from other parts in the world. In low prevalence countries like Italy the vaccination has probably contributed among other factors to a very strong decrease of hepatitis B incidence.

Observations in Taiwan [ ] and Thailand [ ] or in high risk groups of other countries suggest that the protection becomes weaker within 20 years but the immune memory is good enough to mitigate the infection in the ca.

Those with no or with low anti-HBs are still protected against HBV disease but they get a clinically silent infection with transient HBs antigenemia, or anti-HBc seroconversion or increase of the anti-HBs titer. The necessity or timing of later booster injections is a matter of debate.

Risk factors for non-response are numerous: male gender, old age, obesity, smoking and various situations in which the immune system is impaired, e. Most important is the failure of protection against perinatal transmission in ca. In ca. Fortunately, they no longer appear to be on the increase and have not yet?

The clinically silent virus breakthroughs in vaccinated persons may be considered insignificant but these infections may create a problem for the HBV safety of blood [ ] or organ donations. Furthermore, it appears that these silent infections may persist in occult form in the liver and may reactivate with serious consequences if the person becomes immunodeficient [ ].

The occult or reactivated HBV strains in most cases contain several HBsAg escape mutants against which the vaccine-induced immune response may not protect as shown in Figure 8. The important benefit of the vaccination is that these heterologous infections remain clinically silent and do not result in frank chronicity [ ].

Overall the current vaccine is an enormous success, however, with a few obvious improvements nonresponse, viral breakthroughs and occult infections could be minimized. Furthermore, a highly potent vaccine could possibly be the basis for an immune therapy of chronic hepatitis B and high chronic viremia. While a complete elimination of the virus from the organism is probably impossible, a successful therapy would lead to a significant decrease of infectivity in the HBV carriers.

Together with a high rate of immune persons, this will finally allow for eradication of HBV from the population as suggested e. Decades of experience suggest that the protection induced by the vaccine depends mainly on a sufficient level of neutralizing antibodies and a long-lasting B cell memory.

The preS1 domain of the large HBs protein is the most important attachment factor and the most effective target of neutralizing antibodies [ ]. In contrast to the HBs antigen loop, it is highly conserved in the various HBV genotypes and escape mutants are virtually unknown.

The designers of the recombinant vaccines [ , ] knew in that there was a preS sequence upstream of the HBs gene but since the protease treated HBsAg seemed to have full antigenicity and immunogenicity, they neglected it.

Once the preS domain was discovered to be a real viral component and its functions for HBV were understood, several entrepreneurs have developed and tried to introduce preS-containing vaccines [ , ], but they are rarely used in spite of superior results in field trials particularly in non-responders to the yeast-derived vaccine [ ].

HBsAg with or without preS1 expressed in mammalian cell culture would be an additional improvement because it contains only the relevant conformational HBs epitopes and no misfolded antigen [ ]. The approach of DNA vaccination was in fashion for a while but it turned out to be more suitable for mice than for men. All kinds of viral vectors were considered as potential carriers for the HBs and preS gene, e. Semliki forest virus with promising preliminary results [ ], but none of these have ever entered human trials.

After almost 30 years of recombinant hepatitis B vaccines some of their deficits are now quite apparent, but the only recognizable progress in practice is the introduction of stronger adjuvants for certain groups of weak responders. This course is a double edged sword because improved immunogenicity may be paid for with more side effects.

Looking back on the 50 years since the discovery of Australia antigen the development in viral hepatitis is an exemplary reflection of the progress in medicine as a whole through biomedical science.

The level that has been reached is formidable, and the scientific possibilities are almost too great to imagine. There is still much to do, especially in medical practice. Specificity and sensitivity of anti-HBc assays is still unsatisfactory. The significance of occult HBV infections and the danger of reactivation are too often unknown or neglected. The dimensions of HBV variability and pathogenicity have still to be explored. Indication and monitoring of therapy including well-founded stopping rules should be further optimized.

Medications leading to sustained cure should be sought for. Vaccination coverage should be constantly increased, particularly in those populations in which it is most necessary.

Current hepatitis B vaccines are quite good compared to other anti-viral vaccines but this does not mean that improvement is unnecessary. An effective immune therapy for HBV would be highly desirable and a great stimulus for research on infections against which not even preventive vaccines are available, e. With sufficient efforts in diagnosis, prevention and therapy, HBV could be eradicated. The author was a consultant to Abbott Laboratories and Novartis Diagnostics and Vaccines before retirement.

National Center for Biotechnology Information , U. Journal List Virol J v. Virol J. Published online Jul Wolfram H Gerlich 1. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Wolfram H Gerlich: ed. Received Jul 8; Accepted Jul This article has been cited by other articles in PMC.

Introductory remark The history of modern research on viral hepatitis began in the year , when Nobel Prize winner Baruch S. Early methods of virology Virus detection In the s, virology was still a young science, primarily dedicated to basic research. Detection of antiviral antibodies As an alternative approach, detection of antibodies which the patients had produced against the antigens of the disease-causing agents was adopted as a diagnostic method.

A century earlier, Virchow provided an authoritative explanation of "catarrhal jaundice," which did not consider an infectious etiology, but the transmission of jaundice by human serum was clearly identified in two outbreaks in , and the distinction between "infectious" and "serum" hepatitis was recognized by the early s.

The inability to culture a virus or reproduce either syndrome in laboratory animals led to numerous studies in human volunteers; by the end of World War II, it was known that the diseases were caused by different filterable agents, and the terms "hepatitis A" and "B" were introduced in though some long-incubation cases then designated B must in retrospect have been hepatitis C.

The development of a number of liver function tests during the s led to the recognition of anicteric infections and the existence of chronic carriers, but little more could be done until an infectious agent had been identified.