Organizations involved: [a non-commercial organization heavily involved in early R&D]

Wistar Institute – R&D

Cross ref: See the hepatitis B virus vaccine entries, including two currently marketed recombinant vaccines, Engerix-B (#175) and Recombivax HB (#174) in the Recombinant DNA Products section, and a former blood-derived vaccine, Heptavax (#469). See also the entries for combination vaccines with Engerix-B as a component.

Description: Hepatitis B virus vaccines incorporate virus subunits, e.g., recombinant or human blood-derived hepatitis B virus surface (s) antigen (HBsAg), and are used for prevention of hepatitis B virus infection and for post-exposure prophylaxis (prevention of disease after exposure to the virus). Hepatitis B virus (HBV) is a double-stranded DNA virus member of the Hepadnaviridae family. The whole virus particle is essentially spherical, about 42 nm in diameter, comprising an envelope, a core, DNA, and the “Dane” particle (see Dane, D.S. et al., Lancet, 1970-I, 695, 1970). The HBV envelope contains the surface (s) antigen (HBsAg), discovered by Blumberg, et al. The core contains the immunologically distinct C antigen (HBcAg). To date, hepatitis B virus vaccines marketed in the U.S. have all been designed to induce surface antigen (HBsAg)-specific, virus-neutralizing antibodies. Studies have shown there is no difference between HBsAg antibodies induced by recombinant HBsAg vaccines, HBsAg vaccines derived from blood of infected persons (e.g., Heptavax), and natural infection by hepatitis B virus.

Hepatitis B virus vaccines are used to induce immunity against hepatitis B virus infection and disease, both for pre-exposure and post-exposure prophylaxis. As discussed in the Disease section, chronic infection develops in a small proportion of those acutely infected with HBV, with chronic infection often leading to serious liver disease, cancer, and death.

The vast majority of vaccine use is for pre-exposure prophylaxis, particularly immunization of infants and children. Universal hepatitis B vaccination is recommended by U.S. authorities, and vaccination is often legally required in many areas of the U.S., e.g., for entry into school. Vaccination is also legally required to be offered by employers to those potentially occupationally exposed to hepatitis B virus, e.g., health care professionals, police and emergency response personnel, etc. For post-exposure prevention of hepatitis B, such as after exposure to blood from a HBV-infected person, a course of vaccination may be combined with hepatitis B immune globulin (See the Hepatitis B Immune Globulin Products entry, #751).

Hepatitis B virus surface antigen (s antigen; HBsAg; formerly Australia antigen; p24) is a 226-amino acid polypeptide (protein) found in the outer envelope of the hepatitis B virus. HBsAg forms the basis for all hepatitis B virus vaccines currently available in the U.S. HBsAg, whether produced by recombinant methods or in the blood of HBV-infected persons, self-assembles into 22 nm negatively-charged spherical particles presenting immunogenic epitopes on their surface. These particles are found in the serum of persons infected with HBV, including asymp-tomatic carriers.

There are currently only two hepatitis B virus vaccines available in the U.S., and both contain recombinant HBsAg along with aluminum hydroxide adjuvant. Although it is common for those in the medical, public health and lay communities to refer to “the hepatitis B vaccine,” these are two distinct products. Current recombinant vaccines induce antibody titers that are generally higher than those induced by the inactivated, blood-derived vaccine (Heptavax-B) originally marketed in the U.S. Infection with hepatitis D virus (HDV) can occur only with concurrent hepatitis B infection, so hepatitis B vaccines also provide protection against hepatitis D.

Antibodies to HBsAg are found in the serum of persons who have been infected with hepatitis B virus, and detection of antibodies has long been used to test for hepatitis B virus infection (e.g., for blood donation screening). Numerous epidemiological studies have shown that persons who develop HBsAg antibodies following acute infection with hepatitis B virus are generally protected against the disease on re-exposure to the virus. The minimum HBsAg-specific neutralizing antibody titer considered needed to provide protection against active viral infection is 10 mIU/mL. Seroconversion, or the development of antibodies after exposure to the virus, is defined as HBsAg-specific antibody titers ≥ 1 mIU/mL. HBsAg vaccines are capable of inducing antibody titers that are orders of magnitude greater than the 10 mIU/mL minimum required for protection from disease. Antibody titers of about 2,000 mIU/mL or higher induced by these vaccines have been shown to provide long-term immunity.

Hepatitis B vaccines, both blood-derived and recom-binant, have a proven track record of safety from over 20 years of use, during which nearly 20 million Americans and 500 million people worldwide have been vaccinated (with these numbers probably much larger now).

History: Dr. B.S. Blumberg, Wistar Institute, and collaborators in the 1960s reported isolation of an antigen from an Australian aborigine that reacted with blood from hemophiliac, infectious hepatitis patients (see Science vol. 197, p. 17, 1977). This “Australian antigen” was later identified as hepatitis B virus surface antigen (HBsAg). Drs. Blumberg, A. Prince, and collaborators in the late 1960s established the link between Australian antigen, hepatitis B virus and chronic hepatitis B disease, and developed the first serological tests for the presence of HBsAg. Dr. D.S. Dane, Bland-Souton Institute (London, UK), reported isolation of hepatitis B virus (and Dane particles) and showed the Australian antigen to be HBsAg. A radioimmunoassay was developed for HBsAg (Ling, C. M. et al., J. Immunol. 109, 834, 1972), and HBsAg antibodies (Hol-linger, F. et al., J. Immunol. 107, 1099, 1971). More sophisticated tests are now available, including polymerase chain reaction (PCR; nucleic acid testing; NAT), and have been adapted for screening blood donations for HBV infection.

Status: The Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) both recommend universal vaccination of all infants (and vaccination of all others at risk for contracting hepatitis B virus infection). When the first hepatitis B vaccine (Heptavax-B, an inactivated subunit vaccine) was approved in 1981, the vaccine was recommended primarily for healthcare workers and various social groups (e.g., injection drug users and male homosexuals) with a high incidence of hepatitis B. Limiting use of the vaccine to these small groups was insufficient to reduce the U.S. hepatitis B epidemic at the time. With the availability of recombinant vaccines, national policy was changed in 1991 to encourage/require universal coverage, particularly vaccination of all U.S. infants/children, to provide lifetime (presumed) protection from infection, or at least into adolescence and early adulthood (when most infections are contracted).

Occupational Safety and Health Ad-ministration (OSHA), Department of Labor, regulations in the U.S. require that those occupationally at risk for exposure to blood- and biological fluid-borne pathogens be offered vaccination for hepatitis B, administered by a healthcare professional at no cost. See 29 CFR 1910.1030.

Hepatitis B virus vaccines are reimbursed by Medicare (procedure codes 90744; 90745; 90731; 90746 and 90747), using ICD-9-CM diagnosis code V05.3 and procedure code G0010 (administration fee).

Tech. transfer: See the product entries for discussion of patents and technology transfer. Patent-related royalties for recombinant hepatitis B vaccines have been reported to constitute about 13-15% of sales (with royalties not declining with increased sales). This has been estimated to be about twice the cost of labor and depreciation. Royalties and other factors have been cited as reasons keeping the price of the current recombinant vaccines relatively high and out of reach of many international vaccination programs. This is changing as patents expire, and more companies worldwide start manufacturing generic recombinant HBsAg vaccines.

Disease: Hepatitis B virus is a major cause of viral hepatitis (along with several other hepatitis viruses). The incubation period for acute infection is relatively long – six weeks to six months may elapse between exposure and the onset of symptoms. Although several drugs, e.g., lamivudine (Epivir-HBV) from GlaxoSmithKline and adefovir dipivoxil (Hepsera) from Gilead Sciences, Inc., and interferon alpha are used for treatment of chronic hepatitis B, these are only partially effective.

The prognosis following infection with hepatitis B virus is variable and dependent on at least three factors: (1) age – Infants and younger children usually experience milder initial disease than older persons; (2) dose of virus – The higher the dose, the more likely acute icteric hepatitis B will result; and (3) severity of any associated underlying liver or other disease. Underlying malignancy or pre-existing hepatic disease predisposes infected persons to increased morbidity and mortality.

Life-long persistence of viral infection (the chronic hepatitis B virus carrier state) often leads to serious disease (chronic hepatitis B). This chronic infection occurs in 5-10% of persons following acute hepatitis B infection, and occurs more frequently after initial anicteric hepatitis B than after initial icteric disease. Many persons with chronic hepatitis B infection frequently do not realize that they are infected and that their health is compromised.

Hepatitis B virus is most often transmitted by virus-contaminated blood and other biological fluids. Injection (e.g., i.v. drug users sharing needles) is the most efficient method of transmission, but the virus may also be transmitted by sexual (hetero- and homosexual) contact. Thus, hepatitis B infection shares many risk/exposure and life style-related risk factors with HIV infection. In about one-third of all cases, no specific incident or cause of infection can be identified.

The serious complications and sequelae of chronic hepatitis B virus infection include active hepatitis, massive hepatic necrosis, cirrhosis of the liver, hepatocellular carcinoma (liver cancer), and death. Chronic hepatitis B is the cause of up to 80% of hepatocellular carcinoma, which has a very high mortality rate. Many in the scientific and medical communities consider hepatitis B virus to actually be a cause of cancer (hepatocellular carcinoma), and hepatitis B vaccines as the first vaccines effective for cancer prevention.

Each year, approximately 600,000 HBV-related deaths occur worldwide (CDC and WHO, unpublished data, 2003). An estimated 93% of these deaths result from the chronic sequelae of HBV infection: cirrhosis and hepatocellular carcinoma. Approximately 21% of HBV-related deaths result from infection acquired in the perinatal period and 48% from infection acquired in early childhood (age 5 years or less).

Hepatitis B kills up to 6,000 persons in the U.S. annually, and is estimated to cost the nation about $750 million/year in medical expenses and lost productivity. Hepatitis B incidence has been on the increase with about 300,000 cases reported annually in the U.S., compared with less than 200,000 cases less than 10 years ago. The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 200-300 million chronic carriers worldwide and 1.25 million chronic carriers of hepatitis B virus in the U.S.

About one out of 20 Americans becomes infected with hepatitis B virus during their lifetime, and these chronic carriers represent the largest human reservoir of hepatitis B virus. An estimated 90% of all U.S. cases of hepatitis B infection occur in adolescents and young adults, with over half of chronically infected adolescents (and adults) not demonstrating symptoms. Most new cases occur in the same groups at high risk for HIV-infection, including male homosexuals, intravenous drug users, recipients of contaminated blood products, or from an infected mother to her newborn.

In June 2002 (MMWR, vol. 51, issue 25, June 28), the Centers for Disease Control and Prevention (CDC) published, “Achievements in Public Health: Hepatitis B Vaccination–United States, 1982-2002.” Before 1982, an estimated 200,000-300,000 persons in the U.S. were infected annually with hepatitis B, including ~20,000 children. No practical method of pre-exposure prophylaxis existed, and the only post-exposure prophylaxis available was injection with hepatitis B immune globulin. With the availability of recombinant vaccines, universal childhood vaccination, vaccination for prevention of perinatal HBV transmission, vaccination of adolescents and adults in high-risk groups, and catch-up vaccinations for susceptible children in high-risk populations were recommended in 1991. Incidence rates of acute hepatitis B subsequently subsided. During 1986-2000, the rate of acute hepatitis B among children aged 1-9 years declined >80%. During 1983-1995, the rate of hepatitis B infection in healthcare workers declined 95%, and is now lower than the rate for the general population, despite their frequent exposure. The prevalence of chronic hepatitis B infection has been reduced substantially among populations whose infection rates previously were high. For example, in 1994, the prevalence of chronic infection among Alaska Natives aged <10 years (i.e., children born after routine vaccination began) was zero, compared with 16% among those aged 11-30 years. However, despite progress in vaccinating children and adults in some occupational and racial/ethnic groups, about 1.2 million persons in the U.S. have chronic infection, and an estimated 4,000-5,000 persons die each year from related liver diseases.

In 1992, the World Health Organization (WHO), United Nations (UN), set a goal for all countries to integrate hepatitis B vaccination into their universal childhood vaccination programs by 1997. In 2001, the most recent year for which complete data are available, 126 (66%) of 191 WHO member countries had universal infant or childhood hepatitis B vaccination programs, with an estimated 32% of children aged less than 1 year vaccinated fully with the 3-dose hepatitis B vaccination series. As of May 2003, a total of 151 (79%) of 192 WHO member countries had adopted universal childhood hepatitis B vaccination policies, including six with policies for vaccinating adolescents. Of the 137 countries that have adopted universal childhood hepatitis B vaccination and for which data are available, 76 (55%) have a policy for administering the first dose of vaccine soon after birth. Goals for global hepatitis B vaccination are for the vaccine to be introduced in all countries by 2007, and for coverage with the 3-dose hepatitis B vaccination series to reach 90% by 2010.

As of 2006, 81 (42%) of 193 WHO member states indicated that a HepB vaccine birth dose was included in theier national infant immunization schedule. Of the 87 countries where chronic HBV infection prevalence has been high historically (>8%), 38 (44%) reported including a HepB vaccine birth dose in their immunization schedule. Of the 135.0 million infants born worldwide in 2006, 62.7 million infants were born in countries where chronic HBV infection prevalence has been high historically. Birth dose coverage worldwide was 27% and varied widely by region, from 3% to 71%. Birth dose coverage for countries with >8% chronic HBV infection prevalence was 36% (range by region: 1%-92%), and for countries with <8% prevalence was 20%.

Medical: In recent years, consensus has developed within the health care policy and public health communities (e.g., CDC and WHO) that hepatitis B vaccination should be universal, and that vaccination should be performed in infancy, starting very soon after birth. Certain groups that are known to be at a significantly higher risk for hepatitis B infection and should definitely be vaccinated, e.g., health care workers and pregnant women (because of the high risk of transmission to the fetus). Homosexual men are a high-risk group for hepatitis B, and vaccination has been recommended for them since 1982.

The need for universal pediatric vaccination is controversial. For example, many parents proclaim/believe their children do not need the vaccine because they have negligible exposure to the virus during childhood (generally true), and that their children would not engage in high risk behavior as teenagers or young adults (a common fallacy). While neonates, infants, and children are targeted for immunization, infection most often occurs during the teen years and early adulthood, while the disease itself occurs much more frequently later in life, almost exclusively, in adults. This has lead some critics to argue that universal vaccination of infants is wrong or not needed, while others argue that infant vaccination provides protection during childhood, and that universal vaccination would never be attained unless it was performed on infants (along with other pediatric vaccinations).

Higher dosages of vaccine are often required in some classes of patients, e.g., dialysis and immune compromised patients. Immunogenicity of hepatitis B vaccines is somewhat reduced in persons over 40.

Hepatitis B virus vaccines are considered highly effective. For example, pediatric vaccination coverage is now 93% among native Americans in Alaska, and there are now essentially no cases of infant transmission of hepatitis B in this population, while the carrier rate in this population prior to immunization campaigns was 16%. Taiwan began a pediatric vaccination campaign in 1984, and since 1994 the incidence of infections and hepato-carcinoma in children has declined to near zero from a prior rate of ~10%.

As reported in the New England Journal of Medicine (June 26, 1997), prophylactic hepatitis B vaccines, in addition to lowering the incidence of chronic hepatitis B infection, significantly lower the rates of hepatocarcinoma (liver cancer) in populations where universal vaccination has been implemented. Hepatitis B virus vaccines are, thus, often cited claimed to be the first prophylactic cancer vaccines.

In the March 1, 2005 issue of Annals of Internal Medicine, results from a study were reported finding that the duration of protection from HBsAg vaccination extends to 15 years. Formerly, it was presumed to extend to 10 years. Investigators reviewed data on 1,578 Alaska Natives vaccinated at 6 months of age and older who between 1981 and 1982 received three doses of hepatitis B vaccine. In all age groups, hepatitis B vaccination “strongly protected against infection for at least 15 years.” If confirmed to extend beyond 15 years, booster vaccination of adolescents or adults may not been needed (although, this presumes that adults will not engage in risky behaviors).

There have been reports in recent years that hepatitis B vaccination is or is not associated with an increased risk for developing multiple sclerosis. It is not known whether vaccination may subtly cause MS or hasten its development in those already prone to the disease, or whether the life styles of those adults receiving the vaccine (where not admininstered universally, e.g., to intravenous drug users, individuals with multiple sexual partners frequently, health care workers, prisoners and prison staff, and others at high risk) contribute to what some report as increased risk. In the Feb. 2001 issue of the New England Journal of Medicine, the results of a long-term Harvard School of Public Health study of hepatitis B vaccine and MS in nurses did not show a significant increase in MS. But other epidemiological studies have found a link. Even if vaccination increased risk for MS, for many the small risk of MS is stil far outweighed by the protection against chronic hepatitis B and potentially fatal liver disease.

In June 2005, the Advisory Committee for Immu-nization Practices (ACIP), Centers for Disease Con-trol and Prevention (CDC) strengthened childhood immunization recommendations for hepatitis B (and chickenpox). Following-on the 1991 recommendations for universal vaccination for all infants receive three doses before they are 18 months of age, ACIP recommended that all newborn babies receive their first dose before leaving the hospital, with physicians requested to explain any exceptions in patient medical records.

Market: Worldwide, the market for hepatitis B vaccines has been reported to total $1.4 billion (including blood-derived and recombinant vaccines). The current U.S. manufacturers, both large pharmaceutical companies, have not disclosed sales in recent years. SciGen, manufacturer of Sci-B-Vac, a recombinant hepatitis B vaccine marketed internationally, reports, “Worldwide sales of hepatitis B vaccines are estimated to be US $1.2 billion.” Biogen (holder of key HBsAg patents) has reported that total worldwide 1995 sales of licensed recombinant HBsAg vaccines (primarily GSK’s Engerix-B and Merck’s Recombivax HB vaccines) totaled over $1 billion. Sales of hepatitis B vaccines have increased since then. Europe and the Asia Pacific region currently represent 40% of the world market, but is expected to increase due to rising awareness of hepatitis B, increased public health expenditures and growing middle class populations.

In Nov. 2004, the Centers for Disease Control and Prevention (CDC) reported that hepatitis B vaccine coverage (percentage of those vaccinated) among U.S. children entering school (kindergarten) in 2003-2004 was 95.7%. On July 30, 2004 (MMWR, 53(29);658-661), CDC reported an ~92.4% (±0.6) of U.S. children aged 19-35 had received three or more injections of hepatitis B vaccine, with the annual cohort of infants about 4 million/year. The CDC reported in 2002 (20th anniversary of availability of hepatitis B vaccines) that since 1982, 40 million U.S. infants and 20 million adults have received hepatitis B vaccine.

The current U.S. market for hepatitis B virus vaccines may be approaching $1 billion. Sales have increased in recent years in the U.S. and other developed countries where mandated universal pediatric vaccination and increased infant and school age vaccination programs have been directed towards widespread, if not universal, vaccination of infants, children, and adolescents for hepatitis B..

Internationally, despite very discounted prices on vaccines used in international public health programs, a major barrier to the introduction of hepatitis B vaccination has been the relative high cost of vaccines. Although the price of monovalent hepatitis B vaccine for developing countries has been reported to have decreased from approximately $3.00 per dose in 1990 to $0.30 per dose in 2001, the cost remains higher than that of other older vaccines (e.g., DTP, oral polio, and measles), which cost $0.06-$0.10 per dose. Since 1999, support from the Global Alliance for Vaccines and Immunization (GAVI) and the Vaccine Fund (VF) has accelerated introduction of hepatitis B vaccination in the world’s poorest countries. As of May 2003, of 75 countries eligible for GAVI/VF support, 48 (64%) had received funding for hepatitis B vaccination introduction. However, increasing vaccination is difficult, e.g., 50% of infants in developing countries are born at home and do not have immediate access to health care.

Competition: Various recombinant hepatitis B vaccines, including generic (biogeneric, biosimilar, biocomparable, follow-on etc.) recombinant hepatitis B surface antigen (HBsAg) vaccines, are manufactured and marketed in markets other than the U.S., where patents on recombinant HBsAg held by Biogen have kept vaccines containing this component off the market and/or where pharmaceutical patents are not allowed or enforced. U.S. approval and launch of some of these involving recombinant HBsAg will likely not occur until key U.S. patents, particularly those assigned to Biogen, expire (see the entries for the recombinant vaccines for further information).

Heptavax-Gene is marketed in various countries where lack of patents held by Biogen Idec or their enforcement allow. In June 2008, Crucell reported over 90 million doses had been sold in over 90 countries since its launch in 2006. The vaccine uses recombinant hepatitis B virus surface antigen (HBsAg) expressed by Hansenula polymorpha (a yeast). Heptavax-Gene was developed, manufactured and marketed Rhein Biotech, which merged into Berna Biotech, which was acquired by Crucell N.V., which divested Rhein Biotech to Dynavax in March 2006 and renamed the company Dynavax Dusseldorf. The vaccine is manufactured in South Korea. Heptavax-Gene had been Rhein’s and Berna Biotech’s top selling product. Hepavax-Gene was launched in 1996 and was licensed (granted prequalification status) by the World Health Organization (WHO) in 1997. The vaccine cannot be sold in Europe or U.S. for patent reasons. In Dec. 2006, Crucell N.V. received contracts totaling over $230 million from undisclosed “ supranational organizations “ for supply of its Quinvaxem combination vaccine and Hepavax-Gene. In Dec. 2006, Crucell reported that Heptavax-Gene is “one of today’s major hepatitis B vaccines supplied to more than 90 countries.” In Dec. 2008, Hepatavax-Gene received approval in China (PRC)

Dynavax is also developing Heplisav, a recombinant HBsAg vaccine formlated with an immunostimulatory sequence (ISS) adjuvant that specifically targets Toll-Like Receptor 9 (TLR9) to stimulate an innate immune response. Trials to date have shown 100% seroprotection after two doses in subjects 18-39 years of age, and after three doses in difficult-to-immunize subjects 40-70 years of age. The vaccine is currently in a pivotal Phase III trial in Canada and Germany and another in the U.S. Lot-to-lot consistency trials started in the second half of 2007, comparing three consecutive lots of Heplisav manufactured at Dynavax Europe. A clinical hold on the two U.S. INDs for Heplisav has been in effect since March 2008 following FDA's request for a complete review of safety data, including all available information about a single case of Wegener's granulomatosis reported in a Phase III clinical trial. In Oct. 2008, FDA requested additional information prior to considering further development of Heplisav in end-stage renal disease (ESRD) patients, and advised Dynavax that the balance of risk versus potential benefit no longer favored continued clinical evaluation of Heplisav in healthy adults and children. Merck & Co., Inc. had been collaborating in development of Heplisav, but in Dec. 2008, Dynavax terminated the development agreement, retaining full rights for itself. In a completed Phase III trial, 95% of subjects receiving 2 doses of Heplisav were seroprotected compared to 81% of subjects receiving 3 doses of Engerix-B. In 9 clinical trials conducted over a period of nearly 10 years, a total of approximately 2,500 individuals have been vaccinated with more than 5,000 doses of Heplisav. Heplasav is not on clinical hold in any market outside of the U.S. In Feb. 2009, FDA requested additional datak, not only in ESRD patients but also in healthy adults.

Since 1997, Shantha Bio-technics Pvt. Ltd. (Hyderabad, India) has manufactured and marketed Shanvac-B, a recombinant HBsAg vaccine expressed in Pichia pastoris (yeast) in India where it holds process patents. A recombinant Hansenula polymorpha (yeast)-expressed hepatitis B surface antigen vaccine (Supervax) from Berna Biotech/Crucell, formulated with RC-529 (monophosphoryl lipid A; MPL) adjuvant from Corixa Corp. received its first approval, in Argentina, in Oct. 2003.

The Cuban Biotechnology Centre (CIGB) is developing an intranasal recombinant vaccine, Herberbiovac, with acemannan (from Aloe vera) as adjuvant, licensed in Cuba since 1990 and also in some other countries. In June 2006, CIGB received Cuban approval for recombinant hepatitis B virus monoclonal antibody produced in transgenic tobacco plants for the purification of recombinant HBsAg.

Other hepatitis B vaccines marketed inter-nationally include: recombinant HBsAg vaccine (Gen Hevac B) from Aventis Pasteur S.A./Sanofi Aventis S.A.; plasma derived vaccine from Cheil Je-dang Ichon II Plant; a recombinant HBsAg vaccine (Hep-a-vax-Gene) from Rhein Biotech N.V., now Dynavax Dusseldorf); a recombinant HBsAg vaccine (Sci-B-Vac) from SciGen (China) marketed in Asian markets including Australia, New Zealand, and India; Euvax-B, a recombinant HBsAg vaccine from Lucky Gold-star Chemical Ltd. (LG Life Science; S. Korea); Biovac B from Wockhardt Ltd (India) marketed in India and other countries; and Bio-Hep B from BioTechnology General, later Savient Corp, now Ferring AB. In Jan. 2004, LG Life Science received contract(s) to provide Euvax-B to UNICEF/United Nations (UN) and the Pan American Health Organization (PAHO); and LG now provides about one-half of hepatitis B vaccine used by the UN. Sinovac Biotech Ltd. manufactures and markets a recombinant hepatitis B vaccine, Healive, in China (PRC); and reported $2.7 million in sales in 2005, up 18% from 2004. Sinovac also markets Euvax-B from LG in China.

SciGen (Singapore) is actively expanding the market for its recombinant vaccine, Sci-B-Vac, which contains recombinant Chinese hamster ovary (CHO) cell-expressed hepatitis B virus pre-S1and pre-S2 antigens, besides CHO-expressed rHBsAg. The company opened a manufacturing facility in Rehovot, Israel, in early 2007 with three million doses/year capacicity, adding a third manufacturing facility. Most vaccine, currently ~15 million doses/year, is manufactured by a contractor in India. Another plant is in Hefei, Anhui Province, China (PRC). Sci-Gen expects to “capture 2 per cent of the world market in the first year going to 5 per cent in the second year and 15 per cent in the third.” The vaccine received approval in India in Nov. 2006, with marketing by Shreya Life Sciences.

Many of these vaccines could be considered biogenic, biosimilar, biocomparable, follow-on biologic or protein, or other forms of generic biopharmaceuticals, with these being manufactured and marketed in countries where lack of patent coverage (e.g., by Biogen Idec’s recombinant HBsAg patents) or lack of patent enforcement allows.

Bharat Biotech International Ltd. launched Revac-B, a recombinant HBsAg vaccine in India in Oct. 1998 using its HIMAX technology allowing manufacture without ultracentrifugation and the use of toxic metals, including cesium chloride for density gradient separation, while increasing the recovery of antigenic protein to levels highest in the world. Revac-B became the world’s first recombinant Hepatitis-B vaccine to be manufactured without the use of cesium chloride. In India , Latin America and Africa , Revac-B has a market share of 50% or more. The vaccine has WHO GMP Certification. In Nov. 2008, Bharat reported having manufactured 150 million doses to date. A thimerosal (mercury)-free formulation was introduced in Oct. 2007.

LG Life Sciences Ltd. (S. Korea) manufactures a recombinant hepatitis B vaccine. Panacea Biotec (India) received approval in India for its recombinant hepatitis B vaccine in summer 2006, and in Aug. 2006 received pre-qualification accreditation from the World Health Organization (WHO) for the supply of recombinant hepatitis B vaccine to UN agencies. Chongqing Brewery Co., Ltd. (Sichuan, China) is developing a hepatitis B vaccine.

Various novel hepatitis B vaccines are in development. A recombinant multi-antigen (HBV pre-S1 and pre-S2 epitopes plus HBsAg) vaccine has been in development by Evans Vaccines Ltd., later PowderJect Ltd., now Chiron Corp. (which merged into Novartis AG in spring 2006).

A prophylactic recombinant HBsAg vaccine, Heplisav, with an immunostimulatory DNA sequence (ISS) that targets Toll-like receptor 9 (TLR9) as adjuvant from Coley Pharmaceutical Group, to be marketed by Dynavax Technologies Corp., entered Phase III trials in June 2005, with a second Phase III trial starting in 3rd quarter 2006. In Nov. 2006, results from a Phase III study in 400 subjects aged 40 to 70 years in Singapore, Korea and the Philippines showed that after three doses Heplisav provided seroprotection to 100% of subjects, compared to 73.1% given GlaxoSmithKline’s Engerix-B. The greatest difference in seroprotection after three doses was seen in subjects 56 to 70 years of age, where Heplisav provided 100% protection versus 56.1% with Engerix-B. After just two doses, Heplisav provided 98.5% seroprotection against Engerix-B’s 25%. Dynavax has decided to seek approval of a two-dose regimen administered at zero and one month, and has initiated international Phase III trials in Europe, Canada and the U.S. to assess the two-dose regimen against Engerix-B in patients from 11 to 55 years of age. The pivotal multicenter Phase III trial, PHAST (Phase 3 HeplisAv Short-regimen Trial), is comparing a two-dose regimen of HEPLISAV administered at 0- and 1-month to the conventional three-dose regimen of Engerix-B in 1,740 subjects, ages 11 to 55 years. Trials are expected to be completed in 2008. A two-dose regimen would make the vaccine very attractive and, potentially, cheaper to purchase and use than current three-dose vaccines.

In Dec. 2004, Intercell AG (Vienna, Austria) and SciGen Ltd. (Singapore) formed a collaboration for development of a therapeutic hepatitis B vaccine. This will combine SciGen’s already licensed preS1-, preS2- Hepatitis B virus antigen (Sci-B-Vac) with Intercell’s novel synthetic Immunizer IC31 adjuvant. In March 2005, SciGen Ltd. and OctoPlus N.V. (The Netherlands) joined to develop a Sci-B-Vac formulation using OctoPlus’ unique administration technology. Dynavax Technologies Corp. (Berkeley, CA) is collaborating developing a recombinant hepatitis B virus surface antigen (HBsAg) vaccine incorporating an immunostimulatory DNA sequence (ISS) adjuvant. Positive Phase II trial results were reported in fall 2004. In March 2005, Lorantis (Cambridge, U.K.) and Corixa Corp. (Seattle, WA) formed a collaboration to continue development of a immunotherapeutic hepatitis B vaccine containing Corixa’s RC-529 adjuvant and Lorantis’ CV-1831, a hepatitis B core antigen acquired from Apovia, Inc. In Oct. 2005, RxKinetix Inc. formed a collaboration with Indian Immunologicals Ltd. to develop thermostable Hepatitis B vaccines with improved stability at non-refrigerated temperatures using RxKinetix’s ProJuvant vaccine delivery system. Virexx Medical is develop HepaVaxx B Vaccine, and began Phase I trials in summer 2006. The vaccine involves a recombinant chimeric molecule containing hepatitis B virus antigen and a portion of a murine hepatitis B virus monoclonal antibody, and is designed to induce both cellular and humoral immune responses