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Hepatitis B Vaccines

Daniel Shouval, Hadassah University Hospital, Jerusalem, Israel

Measurement of humoral immune response to vaccination

Antibody responses after exposure to HBsAg following infection with wild type HBV or after immunization are well characterized. Anti-HBs antibodies can be either subtype specific or common to all genotypes of HBsAg, for example, against the determinant, which is a neutralizing epitope present in all HBV vaccines in use. After natural infection, Pre-S1 and pre-S2 antibodies appear first, and before anti-HBs, but also disappear rapidly15. Their detection has been inconsistent because of varying specificities and sensitivity of the experimental assays used 5, 6, 12, 15, 68, 69. Several murine monoclonal antibodies developed against HBV envelope proteins, and directed against the epitope, were shown to neutralize chimpanzee infectious doses of both ad or ay HBV subtypes. By convention, seroconversion to anti-HBs positivity is defined as detection of anti-HBs in an immunological assay at ³2.1 standard deviations from the reading of the negative control, which is usually ~1 mIU/ml (2.1-9 mIU/ml). Seroprotection against clinical disease is present when anti-HBs levels are ³10 mIU/ml. Numerous studies have shown that most children and young adults will develop hundreds to several thousand mIU/ml of anti-HBs following three doses of a conventional HBV vaccine. Vaccines who develop an anti-HBs response above 2.1 and below 10 mIU/ml after three doses, given at 0,1 and 6 months, are sometimes referred to as hyporesponders and probably are not adequately protected against challenge with HBV. Vaccines that develop an anti-HBs level between 10 and 100 mIU/ml after three doses are referred to as low responders. In the United Kingdom, seroprotection against HBV infection was recently re-defined at anti-HBs levels ³100 mIU/ml. This approach has public health implications and may require redefinition of non-responsiveness to routine immunization. Anti-HBs levels tend to fall with time, but primed immune memory will respond to challenge with wild type virus as well as to booster inoculation with HBsAg through an anamnestic anti-HBs response. Currently, there is no reason to offer booster doses of HBV vaccines to vaccines who developed anti-HBs titers >100mIU/ml following a course immunization.

Detection of antibodies to pre-S antigens remains a research tool. Several assays were evaluated to monitor anti-pre-S2 and anti-pre-S1 antibodies but none of them was considered satisfactory for clinical monitoring in humans.

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Hepatitis B Vaccines

In the late 1970s, two vaccines against HBV were developed in the United States and France, both containing purified HBsAg obtained from serum of HBsAg carriers16-18. These plasma-derived vaccines contained a suspension of HBsAg that had been subjected to a combination of aggressive biophysical and biochemical treatments, which led to partial disruption of the surface antigen. The final purified HBsAg was subjected to formaldehyde treatment and adsorbed to alum. A U.S. Product contained 22 nm HBsAg particles devoid of the pre-S proteins while a French HBV vaccine contained additional small and inconsistent amounts of pre-S2 and pre-S1 antigens in the final preparation. Later, similar vaccines were produced in Korea and China. Plasma-derived vaccines have been shown to be highly immunogenic, efficacious, and safe19-21.

Concerns as to the safety of a blood-derived product, as well as the inconsistency of a source of raw material and the availability of new recombinant DNA technology led to the development of “second-generation” recombinant vaccines produced from yeast transfected with the DNA sequence coding for the SHBs18, 21-24.Most experience available to date was gained using two recombinant vaccines, Engerix-Bâ (SmithKline Biologicals, Belgium) and RECOMBIVAX/ HB-Vax IIâ (Merck & Co., USA) 22, 23. These two vaccines contain non-glycosylated SHBs p24, which must be released from within the yeast during the manufacturing process24. All licensed HBV vaccines in conventional use contain alum (AlOH3) as an adjuvant. Although a potent B cell stimulator, alum is ineffective in inducing a Th1 response. New more potent adjuvants are under different stages of development. Such adjuvants are intended to induce a more rapid and enhanced anti-HBs response. Furthermore, Th1 inducing adjuvants may be evaluated in patients already persistently infected with HBV. Although the yeast-derived particles of different vaccine manufacturers seem to have similar physical properties, their immunogenicity differs as shown in animal potency studies25The recommended pediatric and adult dose per injection for Engerix-Bâ is double the dose for RECOMBIVAXâ HB Vax II. So far, over a billion doses of recombinant vaccines have been administered worldwide, with an excellent record of safety and immunogenicity.

Cost-benefit analyses have strongly supported the introduction of universal immunization against HBV to newborns26, 27. Indeed, over 140 countries have already introduced universal vaccination against HBV for newborns or individuals at risk. Furthermore, combination vaccines, using tetravalent diphtheria-tetanus-pertussis and hexavalent hepatitis B vaccines28, or combined A and B vaccine29, have been developed.

Despite the extraordinary efficacy of “second-generation” HBV vaccines, immunization failure may occur and can sometimes be explained by variables such as improper storage or administration, advanced age, obesity, renal failure, chronic liver disease and especially, immunosuppression. Another important factor that may affect non-responsiveness to SHBs immunization seems to be genetically determined resistance30, 31. The ability to produce antibodies in response to immunization with HBsAg is controlled by autosomal dominantly expressed HLA Class II molecules30-33. Hohler and co-workers have reported enhanced expression of DRB 1*3, DRB 1*7 and DRB 1*14 in non-responders to an HBV vaccine33. In contrast, response to vaccination is related to DRB 1*13, which seems to have a promoting effect on anti-HBs seroconversion. It was suggested that the differential association of DRB 1*13 and DRB 1*14 might allow identification of non-responsiveness to immunization with HBsAg. Milich and others have shown that non-responsiveness to SHBs immunization in mice can be circumvented through immunization with pre-S proteins32. Furthermore, immunization with synthetic MHBs (pre-S2 or pre-S2/S) peptides, as well as with yeast and mammalian CHO cell derived pre-S2/S vaccines, may induce neutralizing antibodies and protect chimpanzees against HBV challenge10

Yeast (and plasma) derived HBV vaccines are highly efficacious in preventing HBV and in reducing the incidence of persistent infection as well as of hepatocellular carcinoma. In a recent report, a total of 181 clinical studies were reviewed in which 24,277 individuals were immunized with Engerix BR and 8627 with Recombivax/HB-Vax IIR.34 The recommended pediatric dose per injection was 10 and 5 microgram for both vaccines and the adult dose was 20 and 10 microgram respectively. Seroprotection (>10 mIU/ml) was achieved in 95.8% and 94.3% respectively using the licensed 3 dose schedule at 0, 1 and 6 months. Children and adolescents (1-19y) achieved the highest seroprotection rates, namely 98.6% and 98.8% respectively. Thus degree of non-response in children and young adults is low. Accelerated immunization schedules using two to four doses are effective although titer of anti-HBs antibodies is lower when interval between injections is reduced.

In summary, serum-derived and recombinant HBV vaccines have gained worldwide acceptance based on demonstration of efficacy, safety and cost effectiveness.

Do we need more immunogenic hepatitis B vaccines?

Currently available vaccines are immunogenic, efficacious and safe. Yet there is justification for producing more immunogenic vaccines that could eventually be more efficacious in defined groups such as non-responders to yeast derived vaccines or travelers and healthcare workers who need rapid protection even after priming dose of a vaccine. The main target groups for such a vaccine should consist of genetically, overweight and age associated non-responders to conventional immunization, immunosuppressed and dialysis patients, as well as patients with chronic liver disease. A more immunogenic vaccine may also enable a reduction in the number of injections required for long-term protection against HBV, which could be administered alone or in combination with an HAV or other childhood vaccines, thus reducing the cumulative load of alum used as adjuvant in vaccines.

There is also the issue of vaccine-induced mutants. HBV-envelope variants (“escape mutants”) have been described in Italy, Singapore, Gambia and the USA, in recipients of serum derived, as well as recombinant, HBV vaccines3, 35-37. Similar mutants have also been described in liver transplant patients receiving polyclonal or monoclonal HBIG for protection against reinfection with HBV35, 38. The common reason for generation of such mutants is a single point mutation in one of the amino acids coding for a determinant of the viral surface protein (often at aa 145). It is likely that inclusion of pre-S2 and pre-S1 epitopes in future HBV vaccines may eliminate or reduce the generation of vaccine- associated escape mutants.

Several new experimental designs for novel HBV vaccines were reported in the last decade including:

Yeast derived Pre-S/S vaccines

Mammalian-cell derived pre-S/S vaccines

DNA vaccines

Polypeptide micelle vaccine derived from HBsAg

Expression of immunogenic HBV peptides in vaccinia virus

Synthetic polypeptides containing immunogenic surface or core epitopes

Anti-idiotype vaccines

Oral immunization with a recombinant salmonella gene product containing HBcASg epitopes

The following discussion will concentrate on Pre S/S HBV vaccines with a focus on mammalian cell derived vaccines. Mammalian-cell derived vaccines expressing pre-S/S antigens have undergone clinical trials and three of them are already licensed in a number of countries39-67. These vaccines were developed following the pioneering studies of Neurath, Milich, Gerlich and Tiollais on the role of the pre-S antigens in neutralization and prevention of HBV 8, 9, 14, 32.

Pre-S/S hepatitis B vaccines

Yeast-Derived pre-S2/S HBV Vaccines

Vaccines containing pre-S2/S particles expressed in yeast have been developed in Japan, the US and Belgium42-44. A preliminary study with one experimental pre-S2/S vaccine developed in the US, suggested a somewhat higher immunogenicity and good tolerability for the pre-S2/S vaccine as compared to the S vaccine, in male volunteers. A larger scale comparative trial did not confirm the preliminary observation. More encouraging results were reported from Japan, where a yeast-derived pre-S2/S recombinant vaccine was reported to produce a faster seroconversion rate, in non-responders to conventional vaccination and in overweight Sumo wrestlers42-45. However, efforts to produce a yeast derived pre-S/S vaccine have not resulted in a licensed product in the Western Hemisphere.

Rationale for Developing Mammalian-Cell Derived HBV Vaccines

Choosing a host cell for expression of a recombinant vaccine depends upon the safety, efficacy, potential for scaling-up production and cost effectiveness. Early expression systems used initially for production of recombinant HBsAg, included E. coli, yeast (S. cerevisiea or H. polymorpha), insect-derived Baculovirus, and vaccinia virus. The yeast has been developed to an excellent expression system for SHBsAg. It is cost-effective, easy to scale up, and its HBsAg product was shown to be well tolerated safe and immunogenic. Nevertheless, it has a number of disadvantages, including the fact that the antigen is internal and the yeast must be broken to release the recombinant product. Furthermore, the yeast is unable to provide the same post translational modifications, protein folding, macromolecular assembly, and glycosylation, as observed in infected human hepatocytes, properties which are important for inducing enhanced immunogenicity, and which are present in mammalian cells. Indeed, studies in mice and in humans suggest an immunogenic advantage of mammalian-cell derived envelope particles (pre-S2/S or pre-S1/pre-S2/S), as compared to yeast-derived non-glycosylated small surface antigen25, 40, 46-47. Available information suggests that Chinese hamster ovary cell line (CHO) and mouse-cell line derived pre-S/S hepatitis B vaccines seem to be more immunogenic on the T cell level (even with the use of alum as an adjuvant). Such vaccines were shown to generate T cell help leading to higher seroconversion rates and anti-HBs titers at lower immunogenic doses, as compared to yeast-derived SHBsAg containing products46-54. Concern has been raised as to the safety of mammalian-cell line proto-oncogenes, which theoretically may be able to induce neoplastic transformation in the vaccinee. Temin has already stated that the risk must be very low55. Current CHO derived HBV vaccines have a residual DNA content estimated at <10 pg/dose, which is 1/10 of the WHO recommended limit and one billions of the dose shown to induce tumors in mice56. The current safety record of mammalian-cell derived biological products, and especially CHO-derived antigens, is excellent, and a number of such products are already licensed. Specifically, significant adverse effects were not reported in four clinical trials, in which 920 newborns and adults received the pre-S2/S CHO-derived vaccine57 and in a number of clinical trials using either CHO or mouse derived mammalian cell Pre-S1/Pre-S2/S vaccines46, 49, 50-51, 53-54, 61-66.

Mammalian-cell derived Pre-S2/S HBV vaccines

Early observations using serum-derived vaccines which contained low levels of pre-S2 antigen suggested an enhanced immunogenicity as compared to recombinant vaccines58. A” third-generation” mammalian-cell derived vaccine was first developed at the Pasteur Institute in transfected CHO cells, expressing S and pre-S2 antigens39. A large-scale clinical trial with the CHO-derived vaccine was conducted in French Polynesia starting in 198857. Newborns received 3 or 4 doses of 20 mg Gen Hevac B, given at different time intervals. The vaccine was well tolerated without significant adverse events. Moreover, seroconversion rates were 88-98% after the first and second dose, respectively, implying an extraordinary immunogenicity. Out of 582 vaccinated children, four children became HBsAg carriers (most probably as a result of intrauterine infection), as compared with the theoretically expected 38 HBsAg carriers in non-vaccinated individuals. Sixteen percent of vaccinees seroconverted to anti-HBc despite vaccination, but did not develop clinical disease or persistent viral infection. This result was obtained without the coverage of hepatitis B immune globulin, and presumably these anti-HBc+ children were born to HBV infected or recovered mothers, since some of them lost anti-HBc over time. The high immunogenicity of this new vaccine was also demonstrated in a study where 120 chronic uremic pre-dialysis patients received 4 doses of either 20 mg/dose of the pre-S2/S Gen Hevac Bâ vaccine or 5 mg/dose of the Pasteur plasma-derived vaccine59. The new recombinant vaccine elicited higher seroconversion rates (94%), as compared to the plasma-derived vaccine (76%) in this population of vaccine-resistant patients.

Mammalian-cell derived pre-S1/pre-S2/S HBV vaccines

Two such vaccines, Bio-Hep BR/Sci B VacTM 42, 48 ,50, 53, 54, 56, 57, 62-69 and HepacareR 43, 49, 51, 52, 55 were developed in CHO cells and in a mouse cell line respectively, both expressing pre-S1/pre-S2/S epitopes. Both vaccines were shown to induce a rapid and augmented anti-HBs response with seroconversion appearing earlier as compared to yeast derived vaccines66. Furthermore, non-response to conventional SHBs containing vaccines was by passed as shown in a limited number of clinical trials. The role of such vaccines in protecting defined risk groups against HBV infection is under discussion. Available evidence already suggests that the high seroconversion rates observed after the priming dose with a pre-S1/pre-S2/S vaccine may enable reduction in the number of recommended doses from three to two (with a one-five month interval between injections).

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Summary

Yeast derived hepatitis B vaccines, containing the small HBV envelope protein SHBAg are immunogenic, safe and cost effective in prevention of hepatitis B virus infection in neonates, children and adults. Newly developed pre-S/S hepatitis B vaccines may play a role in inducing fast and augmented seroconversion rates in special risk groups.

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